The RNA-binding landscape of HAX1 protein indicates its involvement in ribosome biogenesis and translation.

HAX1 is a human protein with no known homologues or structural domains, mutations in which cause severe congenital neutropenia through mechanisms that are poorly understood. Previous studies reported RNA-binding capacity of HAX1, but the role of this binding in physiology and pathology remains unexplained. Here we report transcriptome-wide characterization of HAX1 RNA targets using RIP-seq and CRAC, indicating that HAX1 binds transcripts involved in ribosome biogenesis and rRNA processing. Using CRISPR knockouts we find that RNA targets of HAX1 partially overlap with transcripts downregulated in HAX1 KO, implying a role in mRNA stabilization. Gene ontology analysis demonstrated that genes differentially expressed in HAX1 KO (including genes involved in ribosome biogenesis and translation) are also enriched in a subset of genes whose expression correlates with HAX1 expression in four analyzed neoplasms. Functional connection to ribosome biogenesis was also demonstrated by gradient sedimentation ribosome profiles, which revealed differences in the small subunit:monosome ratio in HAX1 WT/KO. We speculate that changes in HAX1 expression may be important for the etiology of HAX1-linked diseases through dysregulation of translation.

A cluster-based multiparametric similarity test for the compartmentalization of crystalline rocks into structural domains

Usually, fracture sampling studies comprise the collection of several fracture samples, which involve many fracture clusters. Grouping fracture samples into structural domains is generally useful for geologists, hydrogeologists, and geomechanicians as a region of fractured rocks is subdivided into sub-regions with similar behavior in terms of their hydromechanical properties. One of the common methods used for grouping fracture samples into structural domains considers the fracture orientation of clusters and ignores several fracture parameters, such as fracture spacing, aperture, and persistence, which are important for fluid circulation in the rock mass.In this study, we proposed a new cluster-based similarity method that considered the orientation of clusters as well as clusters’ aperture, persistence, and fracture spacing. Field investigations were conducted in the Grenville geological province of the Canadian Shield in the Lanaudière region, Quebec, Canada, where fractures were sampled from 30 outcrops and four boreholes. The proposed method is more suitable than other methods, and has applications in hydrogeology, rock mechanics, and especially in studies of fluid circulation in the rock mass. In addition, a method for the compartmentalization of a given study area into structural domains by means of Voronoi diagrams was also proposed.

Protein Receptors Evolved from Homologous Cohesion Modules That Self-Associated and Are Encoded by Interactive Networked Genes

Previously, it was proposed that protein receptors evolved from self-binding peptides that were encoded by self-interacting gene segments (inverted repeats) widely dispersed in the genome. In addition, self-association of the peptides was thought to be mediated by regions of amino acid sequence similarity. To extend these ideas, special features of receptors have been explored, such as their degree of homology to other proteins, and the arrangement of their genes for clues about their evolutionary origins and dynamics in the genome. As predicted, BLASTP searches for homologous proteins detected a greater number of unique hits for queries with receptor sequences than for sequences of randomly-selected, non-receptor proteins. This suggested that the building blocks (cohesion modules) for receptors were duplicated, dispersed, and maintained in the genome, due to structure/function relationships discussed here. Furthermore, the genes coding for a representative panel of receptors participated in a larger number of gene–gene interactions than for randomly-selected genes. This could conceivably reflect a greater evolutionary conservation of the receptor genes, with their more extensive integration into networks along with inherent properties of the genes themselves. In support of the latter possibility, some receptor genes were located in active areas of adaptive gene relocation/amalgamation to form functional blocks of related genes. It is suggested that adaptive relocation might allow for their joint regulation by common promoters and enhancers, and affect local chromatin structural domains to facilitate or repress gene expression. Speculation is included about the nature of the coordinated communication between receptors and the genes that encode them.

Structural transformation and dynamical heterogeneity in Germania melt under compression: molecular dynamic simulation

The structural transformation and dynamical heterogeneity in Germania (GeO2) are investigated via molecular dynamics (MD) simulation. The MD model with 5499 atoms was constructed under pressure up to 150 GPa and at a temperature of 3500 K. The structural transformation mechanism has been studied by observing domain structures and boundary oxygen atoms. The simulation result reveals that GeO2 consists of separate domains and boundaries in its melt structure. Under compression, the structure of GeO2 changes gradually and represents many types of structures. The melt structure exhibits many structural domains Dx, and polymorphism appears at pressures of 12 and 20 GPa. The change of tetrahedral structure to octahedral structure in germanium coordination occurred in parallel with the process of merging and splitting of domain structure. Moreover, the existence of high- and low-density phases in GeO2 melt is indicated. The high-density phase is D6 domain and boundary oxygen while the low-density phase is D4 and D5 domain. The compression mechanism in GeO2 melt mainly is a reduction of average Voronoi volume of oxygen and Voronoi volume of D6, boundary atoms oxygen. Furthermore, we find the dynamical heterogeneity at ambient pressure. The separate “fast” regions and “slow” regions in GeO2 are detected via link-cluster function.

RYR1-related myopathies: Expanding the spectrum of morphological presentation

Mutations in the RYR1 gene are the most common cause of nondystrophic congenital myopathies. Mutations in RYR1 were initially identified in individuals susceptible to malignant hyperthermia, a pharmacogenetic disorder triggered by volatile anesthetics and succinylcholine. Shortly after, mutations in RYR1 were identified in patients with central core disease, which is the most frequent congenital myopathy, and in other muscle disorders, collectively referred to as RYR1-related myopathies. RYR1 mutations are also responsible of some acute pathological conditions triggered by heat- and exercise-induced stress, named exertional heat stroke and exertional-induced rhabdomyolysis, which, similarly to malignant hyperthermia, occur in otherwise healthy individuals with normal skeletal muscle functions. Hundreds of causative mutations linked to RYR1-related diseases have been identified. These mutations are clustered in three regions that are referred to as the N-terminal, central, and C-terminal hot spots. Recent developments in cryo-EM techniques have provided high-resolution reconstructions of the channel, allowing a much better definition of the structural domains within the large N-terminal cytoplasmic region and in the C-terminal domain containing six transmembrane helices and the pore region of the channel. RYR1 mutations may either activate or inhibit channel function or, in some cases, can reduce the expression levels of RYR1 protein. However, similar clinical phenotypes can result from mutations with opposing effects on RYR1 function, or little or no correlation can be found between the observed clinical phenotype and localization of mutations in the structural domains of the RYR1 channel, even though recent studies indicate that clinically severe cases are mostly recessive or due to mutations located in the bridging solenoid. Recent results on the identification of RYR1 mutations in patients with myopathies will be presented.

Dutch preposition stranding and ellipsis: ‘Merchant’s Wrinkle’ ironed out

This paper provides an explanation for the unexpected ban on preposition stranding by wh-R-pronouns under sluicing in Dutch. After showing that previous prosodic and syntactic explanations are untenable, we propose that the observed ban is a by-product of an EPP condition that applies in the PP domain in Dutch. Our analysis revolves around the idea that ellipsis bleeds EPP-driven movement, an idea that already has empirical support from independent patterns of ellipsis found in English and in other structural domains in Dutch. Our claim is that: (1) R-pronominalization involves a pronominal argument of P moving to the periphery of its extended PP domain (PlaceP) in order to satisfy a PP-internal EPP condition, (2) this EPP-driven movement is bled under sluicing, and (3) because SpecPlaceP is the ‘escape hatch’ through which R-pronouns must move in order to exit the PP domain to form preposition stranding configurations, bleeding the EPP-driven movement of R-pronouns to SpecPlaceP therefore precludes R-pronouns from undergoing the wh-movement required to form a sluicing configuration.

SINEUPs: a novel toolbox for RNA therapeutics

RNA molecules have emerged as a new class of promising therapeutics to expand the range of druggable targets in the genome. In addition to ‘canonical’ protein-coding mRNAs, the emerging richness of sense and antisense long non-coding RNAs (lncRNAs) provides a new reservoir of molecular tools for RNA-based drugs. LncRNAs are composed of modular structural domains with specific activities involving the recruitment of protein cofactors or directly interacting with nucleic acids. A single therapeutic RNA transcript can then be assembled combining domains with defined secondary structures and functions, and antisense sequences specific for the RNA/DNA target of interest. As the first representative molecules of this new pharmacology, we have identified SINEUPs, a new functional class of natural antisense lncRNAs that increase the translation of partially overlapping mRNAs. Their activity is based on the combination of two domains: an embedded mouse inverted SINEB2 element that enhances mRNA translation (effector domain) and an overlapping antisense region that provides specificity for the target sense transcript (binding domain). By genetic engineering, synthetic SINEUPs can potentially target any mRNA of interest increasing translation and therefore the endogenous level of the encoded protein. In this review, we describe the state-of-the-art knowledge of SINEUPs and discuss recent publications showing their potential application in diseases where a physiological increase of endogenous protein expression can be therapeutic.

Structural Modelling and in-silico characterization of a Novel Thermophilic β-amylase from Clostridium thermosulfuregenes

β-amylase is a hydrolytic enzyme that is involved in breaking down starch and producing energy. Since the discovery of β-amylase, it has been applied in various applications especially in the food industry. In this study, a novel β-amylase from Clostridium thermosuluregen, a thermophilic anaerobic bacterium that ferments its extracellular emulsion to ethanol at 62 ℃ was modelled and studied using bioinformatics tools and compared with B. cereus β-amylases that functions at mesophilic conditions. The results showed that the overall structural conformations, secondary structures, and important residues involved in active and binding sites were identified in both proteins. The results revealed that the modelled β-amylase of C. thermosulfuregen is very similar with respect to the global conformation, location of active and binding sites. Both proteins showed identical structural domains with the thermophilic variant possessing a high percentage of hydrophobic amino acid residues, polar amino acid residues, and differences in secondary composition such as loops and beta sheets as the potential evolutionary thermal adaptations that make it stable enzyme that functions up to 70 ℃. The results suggest that the thermal stability are not dependent on one single unique mechanism and may use one or a combination of the mechanisms to sustain its structural conformation at a higher operating temperature. Overall, considering the common properties of this modelled protein with the β-amylase of B. cereus, it can be assumed that if the β-amylase of C. thermosulfuregen were expressed in-vitro, it would produce a stable protein that possesses the hydrolysis function for C. thermosulfuregen to break down the starch and sugar formation.

Rheological inheritance controls the formation of segmented rifted margins in cratonic lithosphere

Observations from rifted margins reveal that significant structural and crustal variability develops through the process of continental extension and breakup. While a clear link exists between distinct margin structural domains and specific phases of rifting, the origin of strong segmentation along the length of margins remains relatively ambiguous and may reflect multiple competing factors. Given that rifting frequently initiates on heterogenous basements with a complex tectonic history, the role of structural inheritance and shear zone reactivation is frequently examined. However, the link between large-scale variations in lithospheric structure and rheology and 3-D rifted margin geometries remains relatively unconstrained. Here, we use 3-D thermo-mechanical simulations of continental rifting, constrained by observations from the Labrador Sea, to unravel the effects of inherited variable lithospheric properties on margin segmentation. The modelling results demonstrate that variations in the initial crustal and lithospheric thickness, composition, and rheology produce sharp gradients in rifted margin width, the timing of breakup and its magmatic budget, leading to strong margin segmentation.