Non-canonical Configurations Research Articles

Unveiling metabolo-genomic insights of potent antitumoral and antibiotic activity in Streptomyces sp. VB1 from Valparaíso Bay.

Streptomyces sp. VB1, an actinomycete isolated from marine sediments in Valparaíso Bay, Chile, synthesizes antimicrobial and antiproliferative compounds. This study presents comprehensive metabolomics and comparative genomics analyses of strain VB1. LC-HRMS dereplication and Molecular Networking analysis of crude extracts identified antibiotics such as globomycin and daunorubicin, along with known and potentially novel members of the arylomycin family. These compounds exhibit activity against a range of clinically relevant bacterial and cancer cell lines. Phylogenomic analysis underscores the uniqueness of strain VB1, suggesting it represents a novel taxon. Such uniqueness is further supported by its Biosynthetic Novelty Index (BiNI) and BiG-SCAPE analysis of Gene Cluster Families (GCFs). Notably, two Biosynthetic Gene Clusters (BGCs) were found to be unique to VB1 compared to closely related strains: BGC #15, which encodes potentially novel anthracycline compounds with cancer cell growth inhibition properties, and BGC #28, which features a non-canonical configuration combining arylomycin, globomycin, and siamycin BGCs. This supercluster, the first described to consist of more than two adjacent and functional BGCs, co-produces at least three antimicrobial compounds from different antibiotic families. These findings highlight Streptomyces sp. VB1's potential for discovering new bioactive molecules, positioning it as a promising candidate for further research.

Stability of the CAG Tract in the ATXN2 Gene Depends on the Localization of CAA Interruptions.

It is known that the presence of CAA codons in the CAG tract affects the nature and time of disease onset caused by the expansion of trinucleotide repeats. The mechanisms leading to the occurrence of these diseases should be sought not only at the level of the physiological role of the ATXN2 protein, but also at the DNA level. These mechanisms are associated with non-canonical configurations (hairpins) that can form in the CAG tract. The tendency of hairpins to slide along the corresponding threads is usually considered important to explain the expansion of the CAG tract. At the same time, hairpins occur in areas of open states. Previous studies on the role of CAA interruptions have suggested that, under certain conditions, they can stabilize the dynamics of the hairpin, preventing the expansion of the CAG tract. We calculated the probability of additional open state zones occurrence in the CAG tract using an angular mathematical model of DNA. The calculations made it possible to establish that CAA interruptions affect the stability of the CAG tract, and this influence, depending on the localization of the interruption, can both increase and decrease the stability of the CAG tract.

Abnormal open states patterns in the ATXN2 DNA sequence depends on the CAG repeats length

Hereditary ataxias are one of the «anticipation diseases» types. Spinocerebral ataxia type 2 occurs when the number of CAG repeats in the coding region of the ATXN2 gene exceeds 34 or more. In healthy people, the CAG repeat region in the ATXN2 gene usually consists of 22–23 CAG trinucleotides. Mutations that increase the length of CAG repeats can cause severe neurodegenerative and neuromuscular disorders known as trinucleotide repeat expansion diseases. The mechanisms causing such diseases are associated with non-canonical configurations that can be formed in the CAG repeat region during replication, transcription or repair. This makes it relevant to study the zones of open states that arise in the region of CAG repeats under torque. The purpose of this work is to study, using mathematical modeling, zones of open states in the region of CAG repeats of the ATXN2 gene, caused by torque. It has been established that the torque effect on the 1st exon of the ATXN2 gene, in addition to the formation of open states in the promoter region, can lead to the formation of additional various sizes open states zones in the CAG repeats region. Moreover, the frequency of additional large zones genesis increases with increasing number of CAG repeats. The inverse of this frequency correlates with the dependence of the disease onset average age on the CAG repeats length. The obtained results will allow us to get closer to understanding the genetic mechanisms that cause trinucleotide repeat diseases.

Translating Noncanonical Ancillary Qur’anic Oppositions Into English: An Etiotypological Analysis

Translating the sacred in a so-called divine language has been shown to be so difficult and challenging a task for translators of the Bible or the Qur’an. The human reproduction of the divine product(ion) has biblically and qur’anically been found to raise (in)soluble challenges and (in)surmountable hurdles in bicultural and cross-cultural communication and transfer in translation. One great challenge or big obstacle thereof is the (un)transferability of noncanonical ancillary oppositions from SL (QA) to TL (E) which is sought to be explored and investigated by the current study from a linguistic-translational perspective. Based on corpus data across several languages, noncanonical ancillary opposition has been shown to co-occur in preponderant syntactic frames loaned from fellow categories, such as coordination, subordination, transition, and so forth, to perform cross-categorial discourse functions in canonical, semicanonical, and noncanonical configurations, and to entertain a propensity and penchant for special multi-principled and rule-governed sequences based on morphology, gender, agency, and so on. The specific objectives of this study are to compare and contrast SL and TL frequent frameworks and ordering sequences in the process and product of translation. It was found that a number of these frames and functions have gone untended and unrendered by the two Qur’an translators under scrutiny due to their incognizance of colligational forms and discursive functions as translation units of functional sentence perspective contributing to the semantic ends of intraversially sentential structures. It was also revealed that SL paradigmatic lexical choices were too semantically distinct and complex to lexicalize into TL.

Structural vulnerability in EPCR suggests functional modulation

The endothelial protein C receptor (EPCR) is a fundamental component of the vascular system in mammals due to its contribution in maintaining blood in a non-prothrombotic state, which is crucial for overall life development. It accomplishes this by enhancing the conversion of protein C (PC) into the anticoagulant activated protein C (APC), with this property being dependent on a known EPCR conformation that enables direct interaction with PC/APC. In this study, we report a previously unidentified conformation of EPCR whereby Tyr154, critical for PC/APC binding, shows a striking non-canonical configuration. This unconventional form is incompatible with PC/APC binding, and reveals, for the first time, a region of structural vulnerability and potential modulation in EPCR. The identification of this malleability enhances our understanding of this receptor, prompting inquiries into the interplay between its plasticity and function, as well as its significance within the broader framework of EPCR's biology, which extends to immune conditions.

Cooperative lipolytic control of neuronal triacylglycerol by spastic paraplegia-associated enzyme DDHD2 and ATGL

Intracellular lipolysis—the enzymatic breakdown of lipid droplet-associated triacylglycerol (TAG)—depends on the cooperative action of several hydrolytic enzymes and regulatory proteins, together designated as lipolysome. Adipose triglyceride lipase (ATGL) acts as a major cellular TAG hydrolase and core effector of the lipolysome in many peripheral tissues. Neurons initiate lipolysis independently of ATGL via DDHD domain-containing 2 (DDHD2), a multifunctional lipid hydrolase whose dysfunction causes neuronal TAG deposition and hereditary spastic paraplegia. Whether and how DDHD2 cooperates with other lipolytic enzymes is currently unknown. In this study, we further investigated the enzymatic properties and functions of DDHD2 in neuroblastoma cells and primary neurons. We found that DDHD2 hydrolyzes multiple acylglycerols in vitro and substantially contributes to neutral lipid hydrolase activities of neuroblastoma cells and brain tissue. Substrate promiscuity of DDHD2 allowed its engagement at different steps of the lipolytic cascade: In neuroblastoma cells, DDHD2 functioned exclusively downstream of ATGL in the hydrolysis of sn-1,3-diacylglycerol (DAG) isomers but was dispensable for TAG hydrolysis and lipid droplet homeostasis. In primary cortical neurons, DDHD2 exhibited lipolytic control over both, DAG and TAG, and complemented ATGL-dependent TAG hydrolysis. We conclude that neuronal cells use noncanonical configurations of the lipolysome and engage DDHD2 as dual TAG/DAG hydrolase in cooperation with ATGL.

EEG decoding of finger numeral configurations with machine learning

In this study, we used multivariate decoding methods to study processing differences between canonical (montring and count) and noncanonical finger numeral configurations (FNCs). While previous research investigated these processing differences using behavioral and event-related potentials (ERP) methods, conventional univariate ERP analyses focus on specific time intervals and electrode sites and fail to capture broader scalp distribution and EEG frequency patterns. To address this issue a supervised learning classifier—support vector machines (SVM)—was used to decode ERP scalp distributions and alpha-band power for montring, counting, and noncanonical FNCs (for integers 1 to 4). The SVM was used to test whether the numerical information presented in FNCs can be decoded from the EEG data. Differences in the magnitude and timing of accuracy rates were used to compare the three types of FNCs. Overall, the algorithm was able to predict numerical information presented in FNCs beyond the random chance level accuracy, with higher rates for ERP scalp distributions than alpha-power. Montring had lower peak accuracy compared to counting and noncanonical configurations, likely due to automaticity in processing montring configurations leading to less distinct scalp distributions for the four numerical magnitudes (1 to 4). Paralleling the response time data, the peak decoding accuracy time for montring was earlier for montring (472 ms), compared to counting (577 ms) and noncanonical FNCs (604 ms). The results provide support for montring configurations being processed automatically, somewhat similar to number symbols, and provide additional insights for processing differences across different forms of FNCs. This study also highlights the strengths of decoding methods in EEG/ERP research on numerical cognition.

Canonical representations of fingers and dots trigger an automatic activation of number semantics: an EEG study on 10-year-old children

Over the course of development, children must learn to map a non-symbolic representation of magnitude to a more precise symbolic system. There is solid evidence that finger and dot representations can facilitate or even predict the acquisition of this mapping skill. While several behavioral studies demonstrated that canonical representations of fingers and dots automatically activate number semantics, no study so far has investigated their cerebral basis. To examine these questions, 10-year-old children were presented a behavioral naming task and a Fast Periodic Visual Stimulation EEG paradigm. In the behavioral task, children had to name as fast and as accurately as possible the numbers of dots and fingers presented in canonical and non-canonical configurations. In the EEG experiment, one category of stimuli (e.g., canonical representation of fingers or dots) was periodically inserted (1/5) in streams of another category (e.g., non-canonical representation of fingers or dots) presented at a fast rate (4 Hz). Results demonstrated an automatic access to number semantics and bilateral categorical responses at 4 Hz/5 for canonical representations of fingers and dots. Some differences between finger and dot configuration's processing were nevertheless observed and are discussed in light of an effortful-automatic continuum hypothesis.

Processing of numerical representation of fingers depends on their location in space.

Fingers can express quantities and thus contribute to the acquisition and manipulation of numbers as well as the development of arithmetical skills. As embodied entities, the processing of finger numerical configurations should, therefore, be facilitated when they match shared cultural representations and are presented close to the body. To investigate these issues, the present study investigated whether canonical finger configurations are processed faster than noncanonical configurations or spatially matched dot configurations, taking into accounttheir location in the peripersonal or the extrapersonal space. Analysis of verbal responses to the enumeration of small and large numerosities showed that participants (N = 30) processed small numerosities faster than large ones and dots faster than finger configurations despite visuo-spatial matching. Canonical configurations were also processed faster than noncanonical configurations but for finger numerical stimuli only. Furthermore, the difference in response time between dots and fingers processing was greater when the stimuli were located in the peripersonal space than in the extrapersonal space. As a whole, the data suggest that, due to their motor nature, finger numerical configurations are not processed as simple visual stimuli but in relation to corporal and cultural counting habits, in agreement with the embodied framework of numerical cognition.

Mutations in penicillin-binding protein 2 from cephalosporin-resistant Neisseria gonorrhoeae hinder ceftriaxone acylation by restricting protein dynamics

The global incidence of the sexually transmitted disease gonorrhea is expected to rise due to the spread of Neisseria gonorrhoeae strains with decreased susceptibility to extended-spectrum cephalosporins (ESCs). ESC resistance is conferred by mosaic variants of penicillin-binding protein 2 (PBP2) that have diminished capacity to form acylated adducts with cephalosporins. To elucidate the molecular mechanisms of ESC resistance, we conducted a biochemical and high-resolution structural analysis of PBP2 variants derived from the decreased-susceptibility N. gonorrhoeae strain 35/02 and ESC-resistant strain H041. Our data reveal that mutations both lower affinity of PBP2 for ceftriaxone and restrict conformational changes that normally accompany acylation. Specifically, we observe that a G545S substitution hinders rotation of the β3 strand necessary to form the oxyanion hole for acylation and also traps ceftriaxone in a noncanonical configuration. In addition, F504L and N512Y substitutions appear to prevent bending of the β3-β4 loop that is required to contact the R1 group of ceftriaxone in the active site. Other mutations also appear to act by reducing flexibility in the protein. Overall, our findings reveal that restriction of protein dynamics in PBP2 underpins the ESC resistance of N. gonorrhoeae.

Structural Basis of Response Regulator Function.

Response regulators function as the output components of two-component systems, which couple the sensing of environmental stimuli to adaptive responses. Response regulators typically contain conserved receiver (REC) domains that function as phosphorylation-regulated switches to control the activities of effector domains that elicit output responses. This modular design is extremely versatile, enabling different regulatory strategies tuned to the needs of individual signaling systems. This review summarizes structural features that underlie response regulator function. An abundance of atomic resolution structures and complementary biochemical data have defined the mechanisms for response regulator enzymatic activities, revealed trends in regulatory strategies utilized by response regulators of different subfamilies, and provided insights into interactions of response regulators with their cognate histidine kinases. Among the hundreds of thousands of response regulators identified, variations abound. This article provides a framework for understanding structural features that enable function of canonical response regulators and a basis for distinguishing noncanonical configurations.

Concentration-dependent and configuration-dependent interactions of monovalent ions with an RNA tetraloop.

Monovalent salt solutions have strongly coupled interactions with biopolymers, from large polyelectrolytes to small RNA oligomers. High salt concentrations have been known to induce transitions in the structure of RNA, producing non-canonical configurations and even driving RNA to precipitate out of solution. Using all-atom molecular dynamics simulations, we model a monovalent salt species (KCL) at high concentrations (0.1-3m) and calculate the equilibrium distributions of water and ions around a small tetraloop-forming RNA oligomer in a variety of structural arrangements: folded A-RNA (canonical) and Z-RNA (non-canonical) tetraloops and unfolded configurations. From these data, we calculate the ion preferential binding coefficients and Donnan coefficients for the RNA oligomer as a function of concentration and structure. We find that cation accumulation is highest around non-canonical Z-RNA configurations at concentrations below 0.5m, while unfolded configurations accumulate the most co-ions in all concentrations. By contrast, canonical A-RNA structures consistently show the lowest accumulations for all ion species. Water distributions vary markedly with RNA configuration but show little dependency on KCL concentration. Based on Donnan coefficient calculations, the net charge of the solution at the surface of the RNA decreases linearly as a function of salt concentration and becomes net-neutral near 2.5-3m KCL for folded configurations, while unfolded configurations still show a positive solution charge. Our findings show that all-atom molecular dynamics can describe the equilibrium distributions of monovalent salt in the presence of small RNA oligomers at KCL concentrations where ion correlation effects become important. Furthermore, these results provide valuable insights into the distributions of water and ions near the RNA oligomer surface as a function of structural configuration.

Suspension-Driven gravity surges on horizontal surfaces: Effect of the initial shape

We present results from highly resolved direct numerical simulations of canonical (axisymmetric and planar) and non-canonical (rectangular) configurations of horizontal suspension-driven gravity surges. We show that the dynamics along the initial minor and major axis of a rectangular release are roughly similar to that of a planar and axisymmetric current, respectively. However, contrary to expectation, we observe under certain conditions the final extent of the deposit from finite releases to surpass that from an equivalent planar current. This is attributed to a converging flow of the particle-laden mixture toward the initial minor axis, a behaviour that was previously reported for scalar-driven currents on uniform slopes [31]. This flow is observed to be correlated with the travelling of a perturbation wave generated at the extremity of the longest side that reaches the front of the shortest side in a finite time. A semi-empirical explicit expression (based on established relations for planar and axisymmetric currents) is proposed to predict the extent of the deposit in the entire x-y plane. Finally, we observe that for the same initial volume of a suspension-driven gravity surge, a release of larger initial horizontal aspect-ratio is able to retain particles in suspension for longer periods of time.

Structural and functional basis for p38-MK2-activated Rsk signaling in toll-like receptor-stimulated dendritic cells.

Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration. Until recently, Rsk activation was thought to be exclusively initiated by Erk1/2, but in dendritic cells (DC) Rsk is also activated by p38 mitogen-activated protein (MAP) kinase via its downstream substrates, MK2/3. How and why this noncanonical configuration of the MAP kinase pathway is adopted by these key immune cells are not known. We demonstrate that the Erk1/2-activated C-terminal kinase domain of Rsk is dispensable for p38-MK2/3 activation and show that compared with fibroblasts, a greater fraction of p38 and MK2/3 is located in the cytosol of DC prior to stimulation, suggesting a partial explanation for the operation of the noncanonical pathway of Rsk activation in these cells. p38/MK2/3-activated Rsk phosphorylated downstream targets and is physiologically important because in plasmacytoid DC (pDC) stimulated with Toll-like receptor 7 (TLR7) agonists, Erk1/2 activation is very weak relative to p38. As a result, Rsk activation is entirely p38 dependent. We show that this unusual configuration of MAP kinase signaling contributes substantially to production of type I interferons, a hallmark of pDC activation.

Contrast Source Extended Born Inversion in Noncanonical Scenarios Via FEM Modeling

The contrast source extended Born formulation of the electromagnetic scattering is based on a simple rewriting of standard source type integral equations and allows enhancing the reliability of the inverse problem's solution, especially when losses are present in the scenario. The method has been developed in the framework of integral equations, so that its application has been so far limited to canonical scenarios, where the Green's function is available. To overcome this drawback, in this work we consider a generalization of the contrast source extended Born scheme based on a finite element formalism, which opens the way to a much more flexible algorithm, capable of handling noncanonical configurations. Additionally, we also propose a new hybrid strategy that simultaneously exploits both the well-known contrast source formulation and the contrast source extended Born one and it is capable to achieve improved imaging performance with respect to both of them. Numerical examples are reported to illustrate the performance of the proposed inversion methods

Place and summation coding for canonical and non-canonical finger numeral representations

Fingers can be used to express numerical magnitudes, and cultural habits about the fixed order in which fingers are raised determine which configurations become canonical and which non-canonical. Although both types of configuration carry magnitude information, it has been shown that the canonical ones are recognized faster and directly linked to number semantics. Here we tested whether this difference is a consequence of differences in the qualitative way of processing the two types of configurations. When participants named Arabic digits (Experiment 1) or verbal numerals (Experiment 2) primed by canonical and non-canonical finger configurations, qualitatively different priming patterns were observed for the two types of configurations. Canonical configurations activated a place coding representation, with priming spreading to close smaller and larger magnitudes as a function of the prime–target distance. Conversely, non-canonical configurations activated a summation coding representation priming smaller and equal magnitudes independently of the prime–target distance, and larger targets depending on this distance.

Absence of Low-Level Visual Difference Between Canonical and Noncanonical Finger-Numeral Configurations

Canonical finger numeral configurations are named faster than less familiar finger configurations and activate a semantic place-coding representation as symbolic stimuli. However, this does not exclude categorically the possibility that mere visuo-perceptual differences between canonical and noncanonical finger configurations may induce differences in processing speed. This study capitalizes on the fact that, in typical visual-detection tasks, participants focus on low-level visuo-perceptual features to detect a target among distractors sharing the same high-level semantic features, producing the so-called pop-out effect. Participants had to decide whether a canonical finger configuration was present among a set of distractors expressing the same numerosity in a noncanonical way. The results showed that the time needed to detect the presence of the target grew linearly with the number of distractors. This indicates that the canonical target enjoyed no perceptual saliency among the noncanonical configurations (i.e., no pop-out effect) excluding visuo-perceptual differences as the source of the better identification of and semantic access of canonical configurations.

A new, efficient stellar evolution code for calculating complete evolutionary tracks

We present a new stellar evolution code and a set of results, demonstrating its capability at calculating full evolutionary tracks for a wide range of masses and metallicities. The code is fast and efficient, and is capable of following through all evolutionary phases, without interruption or human intervention. It is meant to be used also in the context of modelling the evolution of dense stellar systems, for performing live calculations for both normal star models and merger products. The code is based on a fully implicit, adaptive-grid numerical scheme that solves simultaneously for structure, mesh and chemical composition. Full details are given for the treatment of convection, equation of state, opacity, nuclear reactions and mass loss. Results of evolutionary calculations are shown for a solar model that matches the characteristics of the present sun to an accuracy of better than 1 per cent; a 1 M⊙ model for a wide range of metallicities; a series of models of stellar Populations I and II, for the mass range 0.25 to 64 M⊙, followed from pre-main-sequence to a cool white dwarf or core collapse. An initial–final mass relationship is derived and compared with previous studies. Finally, we briefly address the evolution of non-canonical configurations, merger products of low-mass main-sequence parents.

Pseudocleft Connectedness: Implications for the LF Interface Level

Pseudoclefts constitute a difficult challenge for linguistic theory, displaying effects of core syntactic conditions in a noncanonical configuration that cannot be normalized with standard syntactic operations. We argue that these “connectedness” effects follow from the nature of pseudoclefts as equatives. This treatment yields an integrated account of the syntactic and semanticopragmatic properties of the construction, but leads to the conclusion that certain syntactic constraints apply to a level of representation more abstract than LF under most current conceptions. This representation is built up in the process of discourse interpretation and may constitute the interface with the conceptual-intentional system of mind.

Pulsed beam diffraction by a perfectly conducting wedge: local scattering models

Develops local scattering models for a collimated wavepacket (pulsed beam, PB) impinging on a perfectly conducting wedge. They are derived from an exact solution that has been derived previously. Unlike the exact solution, the local solutions have explicit space-time forms which parameterize the problem in terms of tractable phenomena that may be extended to noncanonical configurations. This is done in the second half of the paper wherein the local models are extended to accommodate astigmatic wavepackets for which there is no exact solution. The local models developed have the format of the geometrical theory diffraction and of the uniform theory of diffraction (UTD), extended to accommodate PB fields: they are governed by transient diffraction functions (time-domain counterparts of the UTD diffraction coefficient) but also include structure functions that describe the space-time distribution of the scattered wavepacket. They explain, uniformly, the physics of the scattering phenomena as a function of the PB parameters: direction, distance from the edge, spatial collimation, and pulse length.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>