Functional Duality Research Articles

Atomic‐Precision Manipulation of Defects in RuO2 Nanocrystals via Electron‐Beam

AbstractManufacturing nanocrystals with desired structures is the basis for realizing designed properties in their applications. As an important top‐down fabrication technique, although electron beam (e‐beam) has been well used for atomic etching on one hand, it is still challenging to precisely repair the undesired crystal defects on the other. Herein, utilizing the e‐beam probe in a spherical aberration‐corrected scanning transmission electron microscope, the possibility of e‐beam in the atomic‐level‐controllable construction/repair of crystalline defects in ruthenium oxide (RuO2) nanocrystals is systematically explored. It is found that the functional duality of beam effects can be well controlled, with the domination of either constructing or repairing defects in atomic scale, by tuning e‐beam parameters. With the aid of real‐time observation of the atom‐by‐atom repairing process via in situ scanning transmission electron microscopy and density functional theory calculations, the e‐beam‐assisted repairing mechanism is revealed. This work is anticipated to provide insights into controllable top‐down manufacturing nanomaterials at the sub‐nanoscale by e‐beam.

The Unique Morphofunctional Structure of the Reptilian Heart

The paper analyzes the evolution of the thermoenergetic statuses of vertebrates and the associated evolutionary development of their heart. The analysis shows that in most modern lepidosaurs and turtles, the heart is not completely, conditionally five-chambered: it has two atria and one ventricle, in which two incomplete septas divide it into three functional chambers. In some of them, these two septas were modified in evolution so that they turned into one with vertical and horizontal elements, as a result of which the heart became functionally four-chambered, with improved separation of arterial and venous blood flows. Crocodiles have a fully morphologically four-chambered heart. But the hearts of all reptiles, both recent and extinct, perform two opposite functions in parallel – the separation of arterial and venous blood flows and at the same time their regulated mixing. To do this, there are special morphological and physiological mechanisms in their hearts. Such a strange functional duality in the work of the reptilian heart aims to regulate the metabolism level by controlling the amount of carbon dioxide entering the blood flow: increasing the amount of CO2 in the blood flow reduces the metabolic rate, reducing its amount increase metabolism. Mixed blood in reptiles’ blood flow is not an immature, primitive state, but a physiological necessity. Moreover, this method of regulating of metabolic rate is most adequate to the initial, ancestral thermoenergetic state in reptiles, because basal terrestrial tetrapods and most ancient reptiles were meso- and even tachymetabolic, i.e. almost or completely warm-blooded, endothermic animals. It was just these endothermic animals that needed such type of metabolism regulation. As a result, all recent reptiles have a complex morphophysiological organization of the heart, which was functionally more suitable for their almost warm-blooded ancestors. Recent reptiles use part of their ancestral properties as an adaptation to new environmental conditions, new environmental requirements, and their new morphophysiological state. This unique organization of the heart is characteristic of all modern and extinct reptiles, and, importantly, it is characteristic exclusively for reptiles due to their original endothermic state.

Dissecting the immune response of CD4+ Tcells in Alzheimer's disease.

The formation of amyloid-β (Aβ) plaques is a neuropathological hallmark of Alzheimer's disease (AD), however, these pathological aggregates can also be found in the brains of cognitively unimpaired elderly population. In that context, individual variations in the Aβ-specific immune response could be key factors that determine the level of Aβ-induced neuroinflammation and thus the propensity to develop AD. CD4+ Tcells are the cornerstone of the immune response that coordinate the effector functions of both adaptive and innate immunity. However, despite intensive research efforts, the precise role of these cells during AD pathogenesis is still not fully elucidated. Both pathogenic and beneficial effects have been observed in various animal models of AD, as well as in humans with AD. Although this functional duality of CD4+ Tcells in AD can be simply attributed to the vast phenotype heterogeneity of this cell lineage, disease stage-specific effect have also been proposed. Therefore, in this review, we summarized the current understanding of the role of CD4+ Tcells in the pathophysiology of AD, from the aspect of their antigen specificity, activation, and phenotype characteristics. Such knowledge is of practical importance as it paves the way for immunomodulation as a therapeutic option for AD treatment, given that currently available therapies have not yielded satisfactory results.

The fork protection complex promotes parental histone recycling and epigenetic memory

The inheritance of parental histones across the replication fork is thought to mediate epigenetic memory. Here, we reveal that fission yeast Mrc1 (CLASPIN in humans) binds H3-H4 tetramers and operates as a central coordinator of symmetric parental histone inheritance. Mrc1 mutants in a key connector domain disrupted segregation of parental histones to the lagging strand comparable to Mcm2 histone-binding mutants. Both mutants showed clonal and asymmetric loss of H3K9me-mediated gene silencing. AlphaFold predicted co-chaperoning of H3-H4 tetramers by Mrc1 and Mcm2, with the Mrc1 connector domain bridging histone and Mcm2 binding. Biochemical and functional analysis validated this model and revealed a duality in Mrc1 function: disabling histone binding in the connector domain disrupted lagging-strand recycling while another histone-binding mutation impaired leading strand recycling. We propose that Mrc1 toggles histones between the lagging and leading strand recycling pathways, in part by intra-replisome co-chaperoning, to ensure epigenetic transmission to both daughter cells.

Long-lived central memory γδ T cells confer protection against murine cytomegalovirus reinfection.

The involvement of γδ TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. γδ T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of αβ T cell deficient mice in order to analyze the memory potential of γδ T cells. As for CMV-specific αβ T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ γδ TEM that principally localized in infected organ vasculature. Typifying T cell memory, γδ T cell expansion in organs and blood was higher after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection was prevented when masking γδ T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR δ chain repertoire composed of a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, long-term-primed γδ TCM cells, but not γδ TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. This better survival potential of TCM cells was confirmed by a detailed scRNASeq analysis of the two γδ T cell memory subsets which also revealed their similarity to classically adaptive αβ CD8 T cells. Overall, our study uncovered memory properties of long-lived TCM γδ T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches.

The autophagy protein RUBCNL/PACER represses RIPK1 kinase-dependent apoptosis and necroptosis

ABSTRACT Mesenchymal stem cells (MSCs) are used in cell therapy; nonetheless, their application is limited by their poor survival after transplantation in a proinflammatory microenvironment. Macroautophagy/autophagy activation in MSCs constitutes a stress adaptation pathway, promoting cellular homeostasis. Our proteomics data indicate that RUBCNL/PACER (RUN and cysteine rich domain containing beclin 1 interacting protein like), a positive regulator of autophagy, is also involved in cell death. Hence, we screened MSC survival upon various cell death stimuli under loss or gain of function of RUBCNL. MSCs were protected from TNF (tumor necrosis factor)-induced regulated cell death when RUBCNL was expressed. TNF promotes inflammation by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We determine that MSCs succumb to RIPK1 kinase-dependent apoptosis upon TNF sensing and necroptosis when caspases are inactivated. We show that RUBCNL is a negative regulator of both RIPK1-dependent apoptosis and necroptosis. Furthermore, RUBCNL mutants that lose the ability to regulate autophagy, retain their function in negatively regulating cell death. We also found that RUBCNL forms a complex with RIPK1, which disassembles in response to TNF. In line with this finding, RUBCNL expression limits assembly of RIPK1-TNFRSF1A/TNFR1 complex I, suggesting that complex formation between RUBCNL and RIPK1 represses TNF signaling. These results provide new insights into the crosstalk between the RIPK1-mediated cell death and autophagy machineries and suggest that RUBCNL, due to its functional duality in autophagy and apoptosis/necroptosis, could be targeted to improve the therapeutic efficacy of MSCs. Abbreviations: BAF: bafilomycin A1; CASP3: caspase 3; Caspases: cysteine-aspartic proteases; cCASP3: cleaved CASP3; CQ: chloroquine; CHX: cycloheximide; cPARP: cleaved poly (ADP-ribose) polymerase; DEPs: differential expressed proteins; ETO: etoposide; MEF: mouse embryonic fibroblast; MLKL: mixed lineage kinase domain-like; MSC: mesenchymal stem cell; MTORC1: mechanistic target of rapamycin kinase complex 1; Nec1s: necrostatin 1s; NFKB/NF-kB: nuclear factor of kappa light polypeptide gene enhancer in B cells; PLA: proximity ligation assay; RCD: regulated cell death; RIPK1: receptor (TNFRSF)-interacting serine-threonine kinase 1; RIPK3: receptor-interacting serine-threonine kinase 3; RUBCNL/PACER: RUN and cysteine rich domain containing beclin 1 interacting protein like; siCtrl: small interfering RNA nonsense; siRNA: small interfering RNA; TdT: terminal deoxynucleotidyl transferase; Tm: tunicamycin; TNF: tumor necrosis factor; TNFRSF1A/TNFR1: tumor necrosis factor receptor superfamily, member 1a

Decoding the functionality of plant transcription factors.

Transcription factors (TFs) intricately govern cellular processes and responses to external stimuli by modulating gene expression. TFs help plants to balance the trade-off between stress tolerance and growth, thus ensuring their long-term survival in challenging environments. Understanding the factors and mechanisms that define the functionality of plant TFs is of paramount importance for unravelling the intricate regulatory networks governing development, growth, and responses to environmental stimuli in plants. This review provides a comprehensive understanding of these factors and mechanisms defining the activity of TFs. Understanding the dynamic nature of TFs has practical implications for modern molecular breeding programmes, as it provides insights into how to manipulate gene expression to optimize desired traits in crops. Moreover, recent studies also report the functional duality of TFs, highlighting their ability to switch between activation and repression modes; this represents an important mechanism for attuning gene expression. Here we discuss what the possible reasons for the dual nature of TFs are and how this duality instructs the cell fate decision during development, and fine-tunes stress responses in plants, enabling them to adapt to various environmental challenges.

Text on Book Cover: Blurb as a Genre

This article examines the annotation to book editions as a genre of publishing discourse. The aim is to provide an overview of the existing linguistic understanding of the genre’s characteristics, its functional-pragmatic communicative specificity, as well as the features related to the linguistic and cultural traditions of book publishing. The material consists of scientific articles and monographs in Russian and English published from the early 2000s to the present, selected based on keywords. The first review of the degree of research and current directions in the study of the declared genre revealed a problem of an unsettled terminological designation of this genre both in domestic and foreign practice. An approach to differentiating existing terms is proposed and justified. The functions of texts in the genre of publishing annotation are summarized and systematized, with the functional duality of informing and persuasive impact proposed as the foundation. A small number of comparative and diachronic studies were identified, the results of which would be useful for justifying the ongoing transformation process within the studied genre, according to some linguists. The conclusion is drawn that the annotation to book editions is shifting from being a reference apparatus to the realm of marketing communication, advertising, and book promotion.

한국어 '보다' 구문과 중국어 '看' 구문의 대조 연구 - 양태의 중의성을 중심으로 -

The purpose of this study is to compare the syntactic characteristics and examine the modal meanings of ‘boda' and ‘kan', which denote visual perceptual acts, in Korean and Chinese. The lexical meanings of ‘boda' and ‘kan' acquire their modal meanings through a process of semantic abstraction. Both ‘boda' and ‘kan' can convey the speaker's objective attitude towards a proposition and also express the occurrence of an event, thus exhibiting a dual modality function. They can be interpreted as either epistemic modals or event modals. This duality of modality function in ‘boda' and ‘kan' presents different syntactic characteristics, which are interpreted in terms of the structure of modality realization.

Discovery and optimization of thieno[3,2-d]pyrimidine derivatives as highly selective inhibitors of cyclin-dependent kinase 7

Targeting cyclin-dependent kinase 7 (CDK7) has emerged as a highly sought-after therapeutic strategy in oncology due to its duality of function in regulating biological processes, including cell cycle progression and transcriptional control. Herein, we describe the design, optimization and characterization of a series of thieno[3,2-d]pyrimidine derivatives as potent CDK7 inhibitors. The involvement of thiophene as core structure plays critical role in leading to the remarkable selectivity and incorporation of a fluorine atom into the piperidine ring enhances metabolic stability. Structure-activity relationship (SAR) study generated compound 36 as lead compound with potent inhibitory activity against CDK7 and good kinome selectivity in vitro. Compound 36 demonstrated strong efficacy against a triple negative breast cancer (TNBC) cell line-derived xenograft (CDX) mouse model upon oral administration at 5 mg/kg once daily. Therefore, it exhibits immense potential as a lead candidate for further exploration in the development of cancer therapy.

Functional Roles of DYRK2 as a Tumor Regulator.

The dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) regulates the induction of apoptosis and DNA repair, metastasis inhibition, cell cycle G1/S transition, protein scaffold stability for E3 ligase complexes, and embryogenesis. Owing to these functions, DYRK2 is thought to regulate tumorigenesis, and its function in cancer has been investigated. Notably, DYRK2 has been reported to function as a tumor suppressor; however, it has also been reported to act as an oncogene in some cancers. This discrepancy makes it difficult to elucidate the conserved functions of DYRK2 in cancer. Here, we reviewed the functions of DYRK2 in various cancers. Patient tissue samples were evaluated for each cancer type. Although some studies have used cell lines and/or xenografts to elucidate the mechanism of DYRK2 function, these studies are not sufficient to understand the role of DYRK2 in cancers. In particular, studies using genetically modified mice would help us to understand the reported functional duality of DYRK2 in cancer.

The Relish/miR-275/Dredd mediated negative feedback loop is crucial to restoring immune homeostasis of Drosophila Imd pathway

The NF-κB/Relish, as a core transcription factor of Drosophila immune deficiency (Imd) pathway, activates the transcriptions of antimicrobial peptides (AMPs) to combat gram-negative bacterial infections, but its role in regulating miRNA expression during immune response has less been reported. We here describe a negative feedback loop of Imd signaling mediated by Relish/miR-275/Dredd that controls Drosophila immune homeostasis after Escherichia coli (E. coli) infection. Our results demonstrate that Relish may directly activate the transcription of miR-275 via binding to its promoter in vitro and vivo, particularly miR-275 further inhibits the expression of Dredd through binding to its 3′UTR to negatively control Drosophila Imd immune response. Remarkably, the ectopic expression of miR-275 significantly reduces Drosophila lifespan. More importantly, our work uncovers a new mechanism by which Relish can flexibly switch its role to maintain Drosophila immune response and homeostasis during infection. Collectively, our study not only reveals the functional duality of Relish in regulating immune response of Drosophila Imd pathway, but also provides a new insight into the maintenance of animal innate immune homeostasis.

Context-dependent function of the transcriptional regulator Rap1 in gene silencing and activation in Saccharomyces cerevisiae

In Saccharomyces cerevisiae, heterochromatin is formed through interactions between site-specific DNA-binding factors, including the transcriptional activator Repressor Activator Protein (Rap1), and Sir proteins. Despite an understanding of the establishment and maintenance of Sir-silenced chromatin, the mechanism of gene silencing by Sir proteins has remained a mystery. Utilizing high-resolution chromatin immunoprecipitation, we found that Rap1, the native activator of the bidirectional HMLα promoter, bound its recognition sequence in silenced chromatin, and its binding was enhanced by the presence of Sir proteins. In contrast to prior results, various components of transcription machinery were not able to access HMLα in the silenced state. These findings disproved the long-standing model of indiscriminate steric occlusion by Sir proteins and led to investigation of the role of the transcriptional activator Rap1 in Sir-silenced chromatin. Using a highly sensitive assay that monitors loss-of-silencing events, we identified a role for promoter-bound Rap1 in the maintenance of silent chromatin through interactions with the Sir complex. We also found that promoter-bound Rap1 activated HMLα when in an expressed state, and aided in the transition from transcription initiation to elongation. Highlighting the importance of epigenetic context in transcription factor function, these results point toward a model in which the duality of Rap1 function was mediated by local chromatin environment rather than binding-site availability.

On the exponential growth rates of lattice animals and interfaces

AbstractWe introduce a formula for translating any upper bound on the percolation threshold of a lattice$G$into a lower bound on the exponential growth rate of lattice animals$a(G)$and vice versa. We exploit this in both directions. We obtain the rigorous lower bound${\dot{p}_c}({\mathbb{Z}}^3)\gt 0.2522$for 3-dimensional site percolation. We also improve on the best known asymptotic bounds on$a({\mathbb{Z}}^d)$as$d\to \infty$. Our formula remains valid if instead of lattice animals we enumerate certain subspecies called interfaces. Enumerating interfaces leads to functional duality formulas that are tightly connected to percolation and are not valid for lattice animals, as well as to strict inequalities for the percolation threshold.Incidentally, we prove that the rate of the exponential decay of the cluster size distribution of Bernoulli percolation is a continuous function of$p\in (0,1)$.

Dual function of glucocorticoid hormones in the body and using this duality for preventing complications of glucocorticoid therapy

Glucocorticoid preparations are used in all areas of medicine for more than 70 years as the most effective anti-inflammatory drugs possessing also anti-allergic and immunosuppressive actions. However, the use of these preparations, unique in the combination and expression of therapeutic properties, is associated with nearly inevitable serious adverse effects. The complications of glucocorticoid therapy are caused by the duality of glucocorticoid hormone functions. Glucocorticoid hormones in the body act: · As the most universal regulators of virtually all metabolic and physiological processes and · As hormones mainly responsible for the organism behavior under stress conditions. In clinical practice, glucocorticoid preparations are used mainly as stress-responsible agents, and their regulatory activities are neglected, but they are manifested inevitably as complications. To prevent these complications, it is necessary to follow the regulatory properties of glucocorticoid preparations which are realized through regulation of activities of many enzymes. The hepatic tyrosine amino transferase seems to be, possibly, the best example of the regulatory activity of glucocorticoids. Based on the literature data and results of the author’s studies, it is proposed to use blood level of tyrosine as a promising laboratory parameter for monitoring glucocorticoid therapy.

Transcriptomic evidence for tumor-specific beneficial or adverse effects of TGFβ pathway inhibition on the prognosis of patients with liver cancer.

Therapeutic targeting of the Transforming Growth Factor beta (TGFβ) pathway in cancer represents a clinical challenge since TGFβ exhibits either tumor suppressive or tumor promoting properties, depending on the tumor stage. Thus, treatment with galunisertib, a small molecule inhibitor of TGFβ receptor type 1, demonstrated clinical benefits only in subsets of patients. Due to the functional duality of TGFβ in cancer, one can hypothesize that inhibiting this pathway could result in beneficial or adverse effects depending on tumor subtypes. Here, we report distinct gene expression signatures in response to galunisertib in PLC/PRF/5 and SNU-449, two cell lines that recapitulate human hepatocellular carcinoma (HCC) with good and poor prognosis, respectively. More importantly, integrative transcriptomics using independent cohorts of patients with HCC demonstrates that galunisertib-induced transcriptional reprogramming in SNU-449 is associated with human HCC with a better clinical outcome (i.e. increased overall survival), while galunisertib-induced transcriptional reprogramming in PLC/PRF/5 is associated with human HCC with a worse clinical outcome (i.e. reduced overall survival), demonstrating that galunisertib could indeed be beneficial or detrimental depending on HCC subtypes. Collectively, our study highlights the importance of patient selection to demonstrate a clinical benefit of TGFβ pathway inhibition and identifies Serpin Family F Member 2 (SERPINF2) as a putative companion biomarker for galunisertib in HCC.

Unfolding the Mystery Behind the Onset of Chondrocyte Hypertrophy during Chondrogenesis: Toward Designing Advanced Permanent Cartilage‐mimetic Biomaterials

AbstractSuccessful recapitulation of the anatomical microarchitecture and biomechanics of the native articular cartilage under in vitro culture conditions is still an elusive topic of research. The major roadblock lies in maintaining the stable chondrogenic phenotype in vivo or under long‐term in vitro conditions. Tissue engineers worldwide has coined this aberrant loss of permanent cartilage characteristics to transient cartilage form as “chondrocyte hypertrophy”. Although the following has been validated through the expression of a few known markers but very little is understood regarding the molecular mechanism that dwells underneath. This review summarizes the precise aetiology behind the development and progression of the hypertrophic phenotype in chondrocytes under in vitro chondrogenic conditions. Based on the current literature survey, it is deciphered that the type of cell utilized (chondrocytes or stem cells), the chondrogenic culture conditions (growth factors/biochemical mediators) and the culture microenvironment (oxygen tension, mechanical loading) during chondrogenesis have a direct correlation with the dysregulated activity of the chondrogenic signaling pathways corroborating the onset of hypertrophic maturation of chondrocytes. Furthermore, it is critically analyzed whether to completely inhibit these hypertrophy‐inducing signaling pathways or apply a brake in terms of time‐dependent dose due to their functional duality role in chondrogenesis.

Secondary metabolites interference on potential of Solanum lycopersicum grown under UV-B stress and its impact on developmental attributes of Capsicum annuum

Ultraviolet-B (UV–B) radiation contributes only a minor fraction of the solar radiation that shows functional duality. It can induce negative effects directly by degrading DNA and protein or can strengthen UV-light mediated stress acclimation responses through activation of series of secondary metabolic pathways. In this experiment, we examined the secondary metabolites profile of Solanum lycopersicum (tomato) grown in doses of 15 min, 30 min, 45 min and 60 min of UV-B and the effects of its extracts on growth and metabolism of Capsicum annuum (chilli). The chief secondary metabolites of the tomato plants were determined by using gas-chromatography mass spectroscopy. Several biophysical, biochemical and histochemical analyses were performed to evaluate the effects of UV-B on secondary metabolism of the tomato and impact of its extract on chilli plants. The results indicated that the chilli plant showed negative growth responses against the aqueous extracts of tomato. These decrease in growth parameters are related to enhanced effects of secondary metabolites found in extracts which induce oxidative stress in the chilli plants. Moreover, histochemical imaging of chilli leaves and roots also showed the increased generation of reactive oxygen species and lignin accumulation. In conclusion our results highlight the presence of miscellaneous secondary metabolites which increased under UV-B stress and improved its herbicidal potency against chilli plants.

Подходы к психологическим детерминантам профессионального становления педагога на этапе обучения в вузе

<p>The article provides an overview of psychological approaches to the concept of “professional development of a teacher at the stage of study at a university”. The vectors of studying the process of professional formation of a teacher in the process of studying at a university are presented. An integrated approach is considered, based on the category of professional suitability, the main indicators of which are success in professional activities and subjective satisfaction with work. The psychological determinants of the process of professional and personal development of the teacher have been allocated: analysis of the period of vocational training as an integral concept, which combines social, individual and age references in their close relationship and interdependence; functional duality of the educational process; understanding the interaction of the student, future teacher and teaching staff, as a subject-subject model of interaction; analysis of the educational space of the higher school as a public sphere and the matrices of professional and personal development of the student of the future teacher; analysis of professional development as secondary socialization of the student, future teacher.</p>

Duality and fluxes in the sen formulation of self-dual fields

In Sen's formulation of self-dual fields one finds two closed forms: H(g) and H(s). Only the former couples to sources and the spacetime metric. The latter has the wrong sign kinetic term but decouples and hence might be regarded as an unphysical artifact. In this letter we illustrate how an electromagnetic duality associated to the potential for H(s) gives rise to a T-like duality in the partition function for H(g). We then compute the partition function on a 4k+2-dimensional torus highlighting its dependence on the choice of flux of H(s). Lastly we compute the two-point function of Wilson Surface operators.