InterTADs: integration of multi-omics data on topologically associated domains, application to chronic lymphocytic leukemia

ABSTRACT The integration of multi-omics data can greatly facilitate the advancement of research in Life Sciences by highlighting new interactions. However, there is currently no widespread procedure for meaningful multi-omics data integration. Here, we present a robust framework, called InterTADs, for integrating multi-omics data derived from the same sample, and considering the chromatin configuration of the genome, i.e. the topologically associating domains (TADs). Following the integration process, statistical analysis highlights the differences between the groups of interest (normal versus cancer cells) relating to (i) independent and (ii) integrated events through TADs. Finally, enrichment analysis using KEGG database, Gene Ontology and transcription factor binding sites and visualization approaches are available. We applied InterTADs to multi-omics datasets from 135 patients with chronic lymphocytic leukemia (CLL) and found that the integration through TADs resulted in a dramatic reduction of heterogeneity compared to individual events. Significant differences for individual events and on TADs level were identified between patients differing in the somatic hypermutation status of the clonotypic immunoglobulin genes, the core biological stratifier in CLL, attesting to the biomedical relevance of InterTADs. In conclusion, our approach suggests a new perspective towards analyzing multi-omics data, by offering reasonable execution time, biological benchmarking and potentially contributing to pattern discovery through TADs.

Structural and functional characterizations of altered infectivity and immune evasion of SARS-CoV-2 Omicron variant

The SARS-CoV-2 Omicron with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the Spike (S) from Omicron reveals amino acid substitutions forging new interactions that stably maintain an active conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of viral fusion step. Alterations in local conformation, charge and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Apart from already existing mutations, we have identified three new immune escape sites: 1) Q493R, 2) G446S and 3) S371L/S373P/S375F that confers greater resistance to five of the six classes of RBD-antibodies. Structure of the Omicron S bound with human ACE2, together with analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.

Venetian Lagoon Mussel Farming Between Tradition and Innovation An Example of Changes in Perception and Multispecies Relations

In Venetian lagoon, mussels as a food, together with technical innovations and new knowledge for their exploitation, are a recent discovery. In the past, the lagoon’s fishers considered them inedible. The first mussel farming was launched in 1939 and mussels began a new process of rehabilitation. It is the beginning of a new relationship. Mussels turn themselves into delicate animals that need care and fishers develop new interactions with the other non-human components of the environment. A mutual relationship (or inter-agentivity) is created between mussel farmers and mussels, and it brings undeniable advantages to both species.

Matching N3LO QCD calculations to parton showers

The search for new interactions and particles in high-energy collider physics relies on precise background predictions. This has led to many advances in combining precise fixed-order cross-section calculations with detailed event generator simulations. In recent years, fixed-order qcd calculations of inclusive cross sections at n3lo precision have emerged, followed by an impressive progress at producing differential results. Once differential results become publicly available, it would be prudent to embed these into event generators to allow the community to leverage these advances. This note offers some concrete thoughts on me+ps matching at third order in qcd. As a method for testing these thoughts, a toy calculation of e+e− → u$$ \overline{u} $$ u ¯ at $$ \mathcal{O} $$ O ($$ {\alpha}_s^3 $$ α s 3 ) is constructed, and combined with an event generator through unitary matching. The toy implementation may serve also as blueprint for high-precision qcd predictions at future lepton colliders. As a byproduct of the n3lo matching formula, a new nnlo+ps formula for processes with “additional” jets is obtained.

Enhancement of Activity and Thermostability of Keratinase From Pseudomonas aeruginosa CCTCC AB2013184 by Directed Evolution With Noncanonical Amino Acids

A keratinase from Pseudomonas aeruginosa (KerPA), which belongs to the M4 family of metallopeptidases, was characterised in this study. This enzyme was engineered with non-canonical amino acids (ncAAs) using genetic code expansion. Several variants with enhanced activity and thermostability were identified and the most prominent, Y21pBpF/Y70pBpF/Y114pBpF, showed an increase in enzyme activity and half-life of approximately 1.3-fold and 8.2-fold, respectively. Considering that keratinases usually require reducing agents to efficiently degrade keratin, the Y21pBpF/Y70pBpF/Y114pBpF variant with enhanced activity and stability under reducing conditions may have great significance for practical applications. Molecular Dynamics (MD) was performed to identify the potential mechanisms underlying these improvements. The results showed that mutation with pBpF at specific sites of the enzyme could fill voids, form new interactions, and reshape the local structure of the active site of the enzyme.

Smart Charging Needs, Wants and Demands, Charging Experiences and Opinions of EV Drivers

To reduce emissions of harmful substances (such as CO2, NOx and particulate matter) from transportation a fuel transition is essential. Electric transport is one of the most promising options for achieving this. In order to make this new electric transport market function efficiently, new interactions between new and existing parties are required. The growth of electric transport increases the peak demand for electricity. This creates a greater mismatch between moments of supply and moments of demand. In other words, EV drivers want to have their car charged before departure, and grid operators need to allocate resources to meet this demand. Flexibility from both players is required. Charging must be further optimised (become “smarter”) to facilitate this flexibility. Smart charging means: controlling and optimising the time and speed of charging. For example, when there is a large supply of solar and wind energy, there is little other demand for electricity and the price for electricity is low. With the contribution of many organisations, the Vereniging Elektrische Rijders (VER) and ElaadNL have jointly investigated the experiences and opinions of electric drivers about the smart charging of electric cars with a broad survey called the “National Charging Research”. In total, more than 1800 Dutch electric drivers took part in this study. Among other things, the research paid attention to the way in which EV drivers charge their electric cars, which bottlenecks they experience (at home and away) and what the experience is with smart charging. The main finding was that many EV drivers are familiar with smart charging. They are willing to apply smart charging, but they want to be in control of their sessions. To give them that control, both insight and transparency are essential. To meet the needs and wants of both EV drivers and grid operators, alignment with the momentum of European legislation is required to avoid a mismatch of energy between moments of supply and demand.

Constant-roll inflation in the generalized SU(2) Proca theory

The generalized SU(2) Proca theory (GSU2P for short) is a variant of the well known generalized Proca theory (GP for short) where the vector field belongs to the Lie algebra of the SU(2) group of global transformations under which the action is made invariant. New interesting possibilities arise in this framework because of the existence of new interactions of purely non-Abelian character and new configurations of the vector field that result in spatial spherical symmetry and the cosmological dynamics being driven by the propagating degrees of freedom. We study the two-dimensional phase space of the system that results when the cosmic triad configuration is employed in the Friedmann-Lemaitre-Robertson-Walker background and find an attractor curve whose attraction basin covers almost all the allowed region. Such an attractor curve corresponds to a primordial inflationary solution that has the following characteristic properties: 1.) it is a de Sitter solution whose Hubble parameter is regulated by a generalized version of the SU(2) group coupling constant, 2.) it is constant-roll including, as opposite limiting cases, the slow-roll and ultra slow-roll varieties, 3.) a number of e-folds $N > 60$ is easily reached, 4.) it has a graceful exit into a radiation dominated period powered by the canonical kinetic term of the vector field and the Einstein-Hilbert term. The free parameters of the action are chosen such that the tensor sector of the theory is the same as that of general relativity at least up to second-order perturbations, thereby avoiding the presence of ghost and Laplacian instabilities in the tensor sector as well as making the gravity waves propagate at light speed. This is a proof of concept of the interesting properties we could find in this scenario when the coupling constants be replaced by general coupling functions.

Emerging of new bioartificial corticospinal motor synergies using a robotic additional thumb

It is likely that when using an artificially augmented hand with six fingers, the natural five plus a robotic one, corticospinal motor synergies controlling grasping actions might be different. However, no direct neurophysiological evidence for this reasonable assumption is available yet. We used transcranial magnetic stimulation of the primary motor cortex to directly address this issue during motor imagery of objects’ grasping actions performed with or without the Soft Sixth Finger (SSF). The SSF is a wearable robotic additional thumb patented for helping patients with hand paresis and inherent loss of thumb opposition abilities. To this aim, we capitalized from the solid notion that neural circuits and mechanisms underlying motor imagery overlap those of physiological voluntary actions. After a few minutes of training, healthy humans wearing the SSF rapidly reshaped the pattern of corticospinal outputs towards forearm and hand muscles governing imagined grasping actions of different objects, suggesting the possibility that the extra finger might rapidly be encoded into the user’s body schema, which is integral part of the frontal-parietal grasping network. Such neural signatures might explain how the motor system of human beings is open to very quickly welcoming emerging augmentative bioartificial corticospinal grasping strategies. Such an ability might represent the functional substrate of a final common pathway the brain might count on towards new interactions with the surrounding objects within the peripersonal space. Findings provide a neurophysiological framework for implementing augmentative robotic tools in humans and for the exploitation of the SSF in conceptually new rehabilitation settings.

A pedagogical view about the design of isoxazolyl-penicillins of the ampc betalactamase receptor 1fcm using the docking molecular technique

The present work mainly exposes the result of the search for molecules, derived from the structural changes of the drug Cloxacillin in its phenyl radical, which is chlorinated, likewise, the selection of the pharmacophore group is evidenced, which allowed to specify the aforementioned objective. Secondly, the selected target was beta-lactamase, with 1FCM nomenclature, registered in the database, Protein Data Bank, in the same way, the amino acids involved in non-covalent interactions are found, in this order of ideas, they were raised, 22 molecules that presented an affinity energy lower than -8.0 Kcal/mol, this data stated above, will become the reference value, to postulate 6 molecules that have registered a lower affinity, generated by the Autodock Vina software. To conclude, the structural optimization of the leading drug is given as a result, together with its new interactions in the amino acids LYS64, ASN149, THR313 and SER61.

The Digital Story as a Reading Response to the Literary Text Revisiting Camus’ The Outsider in the French Foreign Language Classroom

This contribution discusses the potentialities of the Digital Story as a complement to literary analysis in the French foreign language (L2) classroom. The case study examines the Digital Story as an instructional tool in the reading of Camus’ seminal text, The Outsider, reflecting on the role it may play in addressing learning challenges in the L2 classroom and in moving beyond traditional reading postures and approaches. The Digital Story is shown to cultivate a scholarship of engagement and collaborative action in the teaching of literature. Furthermore, as a multimodal, multigenre form, it fosters potential for mapping out new interactions between reader, text and technology in the context of emerging literacies.