We investigate perovskite oxides from different aspects, namely their pseudoharmonic dynamical properties, their dynamical properties when strong anharmonicity exists and the intriguing functionalities arising from domain walls. Taking these viewpoints together yields a rather complex picture of this material class which was not anticipated in previous approaches. It opens pathways to novel applications and reveals the rich ground states beyond the fictitious belief in ‘simplicity of perovskites and such structures’.

Dielectric elastomers, such as thermoplastic polyurethanes (TPU), are widely used as dielectric layer, emulation layer and substrate of flexible and stretchable devices. To construct capacitors and actuators that work stably upon deformation, it has become an urgent need to investigate the evolution of dielectricity under stress and strain. However, the lack of effective methods for estimating the dielectric constant of elastomers under strain poses a big challenge. This article reports a device for in-situ measuring the dielectric constant of TPU under strain. It is found that upon stretching TPU to a strain of 400%, its dielectric constant decreases from 8.47 to 2.94. In addition, combined Fourier-transform infrared spectroscopy, X-ray scattering technique, and atomic force microscopy have been utilized to characterize the evolution of microstructure under strain. The investigation under tensile strain reveals that a decreased density and average size of polarized hard domains, along with a tendency of the molecular chains to align in parallel with the tensile stress. The evolution of the microstructures results in a reduction of the dielectric constant parallel to the electric field in TPU. Our work provides valuable experimental reference for improving the stability of flexible sensors and actuators based on dielectric elastomers.

We carry out in a thin heterogeneous porous layer, the multiscale analysis of Smoluchowski's discrete diffusion-coagulation equations describing the evolution density of diffusing particles that are subject to coagulate in pairs. Assuming that the thin heterogeneous layer is made of microstructures that are uniformly distributed inside, we obtain in the limit an upscaled model in lower space dimension. We also prove a corrector-type result very useful in numerical computations. In view of the thin structure of the domain, we appeal to a concept of two-scale convergence adapted to thin heterogeneous media to achieve our goal.

As synthetic/artificial life forms become more abundant and sophisticated, an increasing number of bizarre creatures - xenobots, robots, soft A-life entities, genetically engineered organisms, etc. - are invading our society. Therefore, we need to bring order to all this, to establish what is living and what is not. Here, I intend to classify all these non-natural entities and clarify their status with reference to their consideration or not as living beings, leaving the door open to an uncertain future in which perhaps we can see how "the artificial" and "the natural" merge to originate something new. To order all this "new biodiversity" and to also give entry to viruses (which are excluded of the three-domains tree of life), I propose the creation of a new domain, Lithbea (from the name: life-in-the-border entities), in which all these new human-made entities as well as the viruses will be included. Within this domain there would be two kingdoms, Virus and Humade (contraction of human-made), based on their origin, natural or human-made. A brief description of each component of Lithbea is included and the implications for society and biology of this “new biodiversity” is briefly discussed.

Fucosylated carbohydrates and glycoproteins from human breast milk are essential for the development of the gut microbiota in early life because they are selectively metabolized by bifidobacteria. In this regard, α-L-fucosidases play a key role in this successful bifidobacterial colonization allowing the utilization of these substrates. Although a considerable number of α-L-fucosidases from bifidobacteria have been identified by computational analysis, only a few of them have been characterized. Hitherto, α-L-fucosidases are classified into 3 families, GH29, GH95 and GH151 based on their catalytic structure. However, bifidobacterial α-L-fucosidases belonging to a particular family show significant differences in their sequence. Because this fact could underlie distinct phylogenetic evolves, here extensive similarity searches and comparative analyses of the bifidobacterial α-L-fucosidases identified were carried out with the assistance of previous physicochemical studies available. This work reveals 4 and 2 paralogue bifidobacterial fucosidase groups within GH29 and GH95 families, respectively. Moreover, Bifidobacterium logum subsp. infantis species exhibited the greatest number of phylogenetic lineages in their fucosidases clustered in every family GH29, GH95 and GH151. Since α-L-fucosidases phylogenetically descended from other glycosyl hydrolase families, we hypothesized that could exhibit additional glycosidase activities other than fucosidase, raising the possibility about their application to transfucosylate other substrates than lactose in order to synthesis novel prebiotics.

One of the bottlenecks to bringing new therapies to the clinic has been a lack of vectors for delivering novel therapeutics in a targeted manner. Cell penetrating peptides (CPPs) have received a lot of attention and have been the subject of numerous developments since their identification nearly 3 decades ago. Known for their transduction abilities, they have generally been considered inert vectors. In this review we present a schema for their classification, highlight what is known about their mechanism of transduction, and outline the existing literature, as well as our own experience, vis a vis the intrinsic anti-inflammatory properties that certain CPPs exhibit. Given the inflammatory responses associated with viral vectors, CPPs represent a viable alternative to these vectors; further, the anti-inflammatory properties of CPPs, mostly through inhibition of the NF-κB pathway, are encouraging. Much work in relevant animal models, toxicity studies in large animal models, and ultimately human trials are needed before their potential is fully realized.

The rapid changes in technology on a global scale, combined with the widespread adoption of business operations in cyberspace, have intensified the need for robust protection against escalating risks posed by cyber threats. This research paper aims to identify fundamental cyber resilience management attributes that enable organizations to manage cybersecurity, sustain, and adapt amidst evolving cyber risks and threats. By integrating resilience theory and security theory, this study establishes the attributes for resilience within cyber domains, making a novel contribution to cyber resilience management in organizations. The study introduces a model featuring seven main variables: Rationale, Reliable, Readiness, Resistance, Robust, Rebound, Reflective, and sub-variables across the Physical, Logical, and Social cyber domains, providing a converged framework for achieving cyber resilience. The findings of the study highlight the significance of fundamental attributes for enhancing cyber resilience management in organizations, such as clarity in purpose, vision, and values for security management, an empowered culture, availability of resources, avoidance of single points of failure, development, and coordination of resources to respond to threats and risks, promotion of continual improvement, and the sharing of information and knowledge. In conclusion, this research paper presents a model for managing cybersecurity in organizations by identifying key attributes for achieving cyber resilience.

Ubiquitin binding domains (UBDs) are modular elements that bind non-covalently to ubiquitin and act as downstream effectors and amplifiers of the ubiquitination signal. With few exceptions, UBDs recognize the hydrophobic path centered on Ile44 (Leu-8, Ile-44, Val-70). Nevertheless, a variety of different orientations, which can be attributed to specific contacts between each UBD and surface residues surrounding the hydrophobic patch, specify how each class of UBD recognizes ubiquitin. Here, we describe the structure of a novel ubiquitin-binding domain that we identified in NEDD4 binding protein 1 (N4BP1). By performing protein sequence analysis, mutagenesis and NMR spectroscopy of the ¹⁵N isotopically labelled protein, we demonstrate that a Phe-Pro motif in N4BP1 recognizes the canonical hydrophobic patch of ubiquitin. This recognition mode resembles the molecular mechanism evolved in the CUE (Coupling of ubiquitin conjugation to ER degradation) domain family, where an invariant proline, usually following a phenylalanine, is required for binding to ubiquitin. Interestingly, the UBD of N4BP1 is evolutionary related to CUBAN (Cullin binding domain associating with NEDD8) (40% identity and 47% similarity), a protein module that also recognizes the ubiquitin-like NEDD8, which is the closest relative of ubiquitin (58% identity and 80% similarity). By performing circular dichroism and ¹⁵N NMR chemical shift perturbation of N4BP1 in complex with ubiquitin, we demonstrate that the UBD of N4BP1 lacks the NEDD8 binding properties observed in CUBAN and it recognizes the Ile44-centered patch of ubiquitin through a dedicated binding site, which share some of the features observed in the CUE domain family. Moreover, we show that, in addition to mediating the interaction with ubiquitin and ubiquitinated substrates, both the CUBAN and the UBD of N4BP1 are poly-ubiquitinated in cells. This modification is dependent on the presence of a functional domain. We believe that the structural and functional characterization of this novel UBD will allow a deeper understanding of the molecular mechanisms governing N4BP1 function, while at the same time providing a valuable tool for clarifying how the discrimination between ubiquitin and the highly related NEDD8 is achieved.

In this paper, we establish certain Lp bounds for several classes of rough Marcinkiewicz integrals over surfaces of revolution on product spaces. By using these bounds and using an extrapolation argument, we obtain the Lp boundedness of these Marcinkiewicz integrals under very weak conditions on the kernel functions. Several previous results on Marcinkiewicz operators are essentially extended or improved. Our results represent natural extensions and improvements of several known results on Marcinkiewicz integrals over symmetric spaces.

Since their identification over twenty-five years ago, the plethora of cell penetrating peptides (CPP) and their applications has skyrocketed. These 5 to 30 amino acid long peptides have the unique property of breaching the cell membrane barrier while carrying cargoes larger then themselves into cells in an intact, functional form. CPPs can be conjugated to fluorophores, activatable probes, radioisotopes or contrast agents for imaging tissues, such as tumors. There is no singular mechanism for translocation of CPPs into a cell, and therefore, many CPPs are taken up by a multitude of cell types, creating the challenge of tumor specific translocation and hindering clinical effectiveness. Varying strategies have been developed to combat this issue and enhance their diagnostic potential by derivatizing CPPs for better targeting by constructing specific cell activated forms. These methods are currently being used to image integrin expressing tumors, breast cancer cells, human histiocytic lymphoma and protease secreting fibrosarcoma cells, to name a few. Additionally, identifying safe, effective therapeutics for malignant tumors has long been an active area of research. CPPs can circumvent many of the complications found in treating cancer with conventional therapeutics by targeted delivery of drugs into tumors, thereby decreasing off-target side effects, a feat not achievable by currently employed conventional chemotherapeutics. Myriad types of chemotherapeutics such as tyrosine kinase inhibitors, anti-tumor antibodies and nanoparticles can be functionally attached to these peptides leading to the possibility of delivering established and novel cancer therapeutics directly to tumor tissue. While much research is needed to overcome potential issues with these peptides, they offer a significant advancement over current mechanisms to treat cancer. In this review, we present a brief overview of the research leading to identification of CPPs with a comprehensive state of the art review on the role of these novel peptides in both cancer diagnostics as well as therapeutics.

We analyzed the affinity-proteomics data of saliva absorbed to plate-bound Spike protein of SARS-CoV-2, and identified major virus-binding proteins as MUC7, MUC5B, DMBT1, and neutrophil defensins. Furthermore, we found that saliva from healthy donors inhibited the binding of Spike-protein-specific polyclonal antibodies to Spike antigen. These data suggest that the Spike protein’s glycoprotein-binding domains (GBD) may be targeted to block virus adherence or entry of SARS-CoV-2.

Cell plasma membranes display a dramatically rich structural complexity characterized by functional sub-wavelength domains with specific lipid and protein composition. Under favorable experimental conditions, patterned morphologies can also be observed in vitro on model systems such as supported membranes or lipid vesicles. Lipid mixtures separating in liquid-ordered and liquid-disordered phases below a demixing temperature play a pivotal role in this context. Protein-protein and protein-lipid interactions also contribute to membrane shaping by promoting small domains or clusters. Such phase separations displaying characteristic length-scales falling in-between the nanoscopic, molecular scale on the one hand and the macroscopic scale on the other hand, are named mesophases in soft condensed matter physics. In this Review, we propose a classification of the diverse mechanisms leading to mesophase separation in biomembranes. We distinguish between mechanisms relying upon equilibrium thermodynamics and those involving out-of-equilibrium mechanisms, notably active membrane recycling. In equilibrium, we show that the mechanisms generically dwell on an up-down symmetry breaking between the upper and lower bilayer leaflets. Symmetry breaking is an ubiquitous mechanism in condensed matter physics at the heart of several important phenomena. In the present case, it can be either spontaneous (domain buckling) or explicit, i.e. due to an external cause (global or local vesicle bending properties). Whenever possible, theoretical predictions and simulation results are confronted to experiments on model systems or living cells, which enables us to identify the most realistic mechanisms from a biological perspective.

Impulsive buying is a growing problem of modern society with significant financial and psychological consequences, and it is necessary to examine the mechanisms underlying it. Understanding the mechanisms driving this behaviour is crucial. Impulsive buying consists of two key aspects: a cognitive aspect, characterised by a lack of planning and reflection, and an affective aspect, involving emotional responses that can occur before, during, or after a purchase. This study aimed to explore the relationship between personality traits, as measured by the HEXACO model, and tendencies toward impulsive buying. Specifically, it examined how the HEXACO traits differentially predict the cognitive and affective components of impulsive buying tendencies.

Lactococcus lactis is a potential bacterial cell factory to develop delivery systems for vaccines and therapeutic proteins. Large progress has been made in applications using engineered L. lactis against, e.g., inflammatory bowel disease and cervical cancer, but improvement of secretion and cell anchoring efficacy is still desirable. A double-labelling method based on biarsenical hairpin binding and nickel-polyhistidine affinity was used for visualization of protein trafficking and quantification of targeted proteins on the cell surface and in the cytoplasm. To investigate the importance of mature domain targeting signals (MTSs), we generated truncated constructs encoding 126, 66, and 26 amino acid residues from the N-terminus of the basic membrane protein A (BmpA) and fused those with the gene for the human papillomavirus serotype 16 (HPV16) E7 oncoprotein. Overexpression of fusion proteins was observed to come at a cost of cell proliferation. L. lactis cells produced and displayed the shortest fusion protein only with difficulty, suggesting that the entire absence of a homologous sequence containing MTSs significantly impedes export and surface anchoring of fusion proteins. With 40 amino acids following the signal peptide and containing one MTS, effective translocation was possible. Mutations of MTSs towards increased hydrophobicity resulted in an increase of secreted and surface-displayed fusion protein, suggesting the potential to design rationally improved constructs.

Within an amplicon-based metagenomic study of Archaea, Fungi, and Bacteria in Livingston Island, Maritime Antarctica, in many of the samples antagonisms between these three super kingdoms were observed under the form of an inversely proportional dependence of the richnesses of the three types of microorganisms. This was quantified - based on the observed numbers of the total tags and the numbers of the operational taxonomic units (OTUs), as well as based on four alpha diversity parameters – the Shannon, the Simpson, the Chao1, and the ACE indices. We found that the most discriminative results in the antagonism measuring were observed in the comparison of the numbers of the OTUs and the ACE community richness estimator. The antagonism between Archaea and Fungi was strongest, followed by that of Archaea and Bacteria. The Fungi-Bacteria antagonism was slightly detectable. Pearson and Spearman correlation analysis also showed a statistically significant negative correlation between the fungal and archaeal effective tags, while the correlation between archaeal and bacterial diversity was positive. Indications of the order of primary microbial succession in barren ecological niches were also observed, demonstrating that Archaea and Bacteria are the pioneers, followed by Fungi which in time would displace Archaea.

We prove Lp estimates of a class of generalized Marcinkiewicz integral operators with mixed homogeneity on product domains. By using these estimates along with an extrapolation argument we obtain the boundedness of our operators under very weak conditions on the kernel functions. Our results in this paper improve and extend several known results on both generalized Marcinkiewicz integrals and parabolic Marcinkiewicz integrals on product domains.

Zoos are increasingly putting in place formalized animal welfare assessment programs to allow monitoring of welfare over time, as well as to aid in resource prioritization. These programs tend to rely on assessment tools that incorporate resource-based and observational animal- focused measures since it is rarely feasible to obtain measures of physiology in zoo-housed animals. A range of assessment tools are available which commonly have a basis in the Five Domains framework. A comprehensive review of the literature was conducted to bring together recent studies examining welfare assessment methods in zoo animals. A summary of these methods is provided with advantages and limitations of the approach es presented. We then highlight practical considerations with respect to implementation of these tools into practice, for example scoring schemes, weighting of criteria, and innate animal factors for consideration. It is concluded that would be value in standardizing guidelines for development of welfare assessment tools since zoo accreditation bodies rarely prescribe these. There is also a need to develop taxon or species- specific assessment tools to inform welfare management.

As a complex system, our body acts as a whole system connected to the environmental incitements. It is ordered, coherent, and tries to maintain the least possible entropy, saving the greatest amount of energy. In order to explain the dynamics of the systemic regulative network, a theoretical and speculative model is proposed, with a comprehensive approach that allows seeing the entire regulative system as a continuous unicuum. This paper covers two themes: 1) the connections between the quantum level and the classical one, through some principles of the QFT and through the Coherence Domains. The system is modeled as a field described by the wave function, with synchronous and consistent events, driven in a global computing by the quantum potential Q. The quantum potential implies the non-locality, and it needs only ultra-weak waves to occur, so it may explain how the rapid and global activation of the organism in response to perturbation/punctiform information works. The initial hypothesis is that some consistent quantum phenomena are amplified through the systemic regulative network until they become macroscopic observable. This is possible because of Coherence Domains. 2) The reactions of the different systemic networks to perturbations/punctiform information, with the attempt to model and measure information in biology, going beyond the Shannon and Turing theories. Hopfield Networks and an informational point of view are used to address the crucial informational and organizational role of proteins and nucleic acids.

Apoptosis, also known as the programmed death of cells, is responsible for maintaining the homeostasis of tissues and this function is carried out by caspases. The process of apoptosis is carried out via two distinct pathways: the extrinsic pathway, which is governed by death receptors, and the intrinsic pathway, also known as the mitochondrial pathway. The BCL-2 protein family encoded by the BCL-2 gene, located at the 18q21.33 chromosomal location, is in charge of regulating the intrinsic pathway, which is responsible for inducing cell death via the permeabilization of the mitochondrial membrane and the release of apoptosis - inducing components. The BCL-2 homology (BH1, BH2, BH3, BH4) domains of this family proteins are crucial for their functioning and their common BH domains allow interactions between members of the same family and can also serve as indications of pro- or anti-apoptotic activity. A direct correlation may be shown between the overexpression of BCL-2 and the postponement of cell death. It has been determined that a change in the expression of BCL-2 is the root cause of a variety of malignancies, including lung, breast, melanoma, and chronic lymphocytic leukemia, Multiple Sclerosis, Diabetes. In this review, we discuss the therapeutic potential of regulating BCL-2 family connections and their relevance to health and disease.

Fifty years on from the classical fluid-mosaic model of Singer and Nicolson, current views of the plasma membrane portray a much more complex view of this interface region. Compartmentalization, together with transbilayer and lateral asymmetries, provide the structural foundation for functional specializations at the cell surface, including the active role of the lipid microenvironment in the modulation of membrane-bound proteins. The chemical synapse, the site where neurotransmitter-coded signals are decoded by neurotransmitter receptors, adds another layer of complexity to the plasma membrane architectural intricacy, mainly due to the need to accommodate a sizeable number of molecules in a minute subcellular compartment with dimensions barely reaching the micrometer. In this review, we discuss how Nature has developed suitable adjustments to accommodate different types of membrane-bound receptors and scaffolding proteins via membrane microdomains, and how this “efford-sharing” mechanism has evolved to optimize crosstalk or separation or coupling where/when appropriate. To this end, we use a fast ligand-gated neurotransmitter receptor, the nicotinic acetylcholine receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as paradigmatic example.

Abstract: The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of poly-PR/GR dipeptide repeats which are encoded by the C9orf72 gene. Recently, it was shown that poly-PR/GR alters chromatin accessibility which results in stabilization and enhancement of transcriptional activity of the tumor suppressor p53 in several neurodegenerative disease models. Reduction of p53 protein levels in cell and model organisms protects against neurotoxicity of poly-PR, and partially protects against neurotoxicity of poly-GR. Here, we aimed to study the detailed molecular mechanisms how p53 contributes to poly-PR/GR mediated neurodegeneration. Using a combination of biophysical techniques such as nuclear magnetic resonance (NMR) spectroscopy, fluorescence polarization, turbidity assays and differential interference contrast (DIC) microscopy, we found that p53 physically interacts with poly-PR/GR and triggers liquid-liquid phase separation of p53. We identified p53 transactivation domain 2 (TAD2) as the main binding site for PR25/GR25 and show that binding of poly-PR/GR to p53 is mediated by a network of electrostatic and/or hydrophobic interactions. Our findings might help to understand the mechanistic role of p53 in poly-PR/GR - associated neurodegeneration.

SARS-CoV-2 is mutating and creating divergent variants across the world. An in-depth investigation of the amino acid substitution in the genomic signature of SARS-CoV-2 proteins is highly essential for understanding its host adaptation and infection biology. A total of 9587 SARS-CoV-2 structural protein sequences collected from 49 different countries are used to characterize protein-wise variants, substitution pattern (type and location), and major substitution changes. The majority of the substitutions are distinct, occurred mostly in a particular location, and leads to a change in amino acid's biochemical properties. In terms of mutational changes, Envelope (E) and Membrane (M) proteins are relatively stable than Nucleocapsid (N) and Spike (S) proteins. Several co-occurrence substitutions are observed, particularly in S and N proteins. Substitution specific to active sub-domains reveals that Heptapeptide Repeat, Fusion peptides, Transmembrane in S protein, and N-terminal and C-terminal domains in N protein are remarkably mutated, and also found few deleterious mutations in these domains.

Attitudes and behaviours towards the natural environment have been extensively studied in certain cultural settings during the last 40 years. In education, the teacher's ability to grasp the fundamentals of an academic subject may define his or her own attitudes towards that discipline; certainly the reverse is also valid. The correlations between affective and cognitive domains appear to play a significant role in teaching-learning dynamics. In this study we seek to assess whether the affective posture towards school sciences of a cohort of teachers in rural communities shows an association with their cognitive competence in the disciplines. The results of this study provide evidence that there is a statistically significant correlation between the cognitive and affective domains for in-service teachers. The affective domain, therefore, could serve as a predictor for cognitive competency and self-efficacy expectancies with respect to both content and career fulfilment.

In this paper, several classes of rough Marcinkiewicz integral operators along surfaces of revolution on product spaces are investigated. We prove the Lp boundedness of these operators when their kernels functions belong to a class of functions related to a class of functions introduced by Grafakos-Stefanov. The results in this paper extend and improve several known results on Marcinkiewicz integrals.

Despite significant strides in prevention, diagnosis, and treatment, cardiovascular diseases remain the number one cause of mortality in the United States, with rates climbing at an alarming rate in the developing world. Targeted delivery of therapeutics to the heart has been a lofty goal to achieve with strategies ranging from direct intra-cardiac or intra-pericardial delivery, intra-coronary infusion, to adeno-associated viral vectors which have preference, if not complete cardio-selectivity, for cardiac tissue. Cell penetrating peptides (CPP) are 5-30 amino acid long peptides that are able to breach cell membrane barriers while carrying cargoes up to several times their size, in an intact functional form. Identified nearly three decades ago, the first of these CPPs came from the HIV coat protein transactivator of transcription. Although a highly efficient CPP, its clinical utility is limited by its robust ability to cross any cell membrane barrier, including crossing the blood-brain barrier and transducing neuronal tissue non-specifically. Several strategies have been utilized to identify cell or tissue specific CPPs, one of which is phage display. Using this latter technique, we identified a cardiomyocyte targeting peptide (CTP) more than a decade ago, a finding that has been corroborated by several independent labs across the world that have utilized CTP for myriad different purposes in pre-clinical animal models. The goal of this publication is to provide a comprehensive review of the identification, validation, and application of CTP, and outlining its potential in diagnostic and therapeutic applications especially in the field of targeted RNA interference.

Choanoflagellates are single-celled eukaryotes with complex signaling pathways. They are considered the closest non-metazoan ancestors to mammals and other metazoans, and form multicellular-like states called rosettes. The choanoflagellate Monosiga brevicollis contains over 150 PDZ domains, an important peptide-binding domain in all three domains of life (Archaea, Bacteria, and Eukarya). Therefore, an understanding of PDZ domain signaling pathways in choanoflagellates may provide insight into the origins of multicellularity. PDZ domains recognize the C-terminus of target proteins and regulate signaling and trafficking pathways, as well as cellular adhesion. Here, we developed a computational program, Domain Analysis and Motif Matcher (DAMM), that predicts target specificity in choanoflagellate PDZ domains by analyzing peptide-binding cleft sequence identity as compared to human PDZ domains. We used this program, protein biochemistry, fluorescence polarization, and structural analyses to characterize the specificity of A9UPE9_MONBE, a M. brevicollis PDZ domain-containing protein with no homology to any metazoan protein, finding that its PDZ domain is most similar to those of the DLG family. We then identified two endogenous sequences that bind A9UPE9 PDZ with <100 M affinity, a value commonly considered the threshold for cellular PDZ-peptide interactions. Taken together, this approach can be used to predict cellular targets of previously uncharacterized PDZ domains in choanoflagellates and other organisms. Our data contributes to investigations into choanoflagellate signaling and how it informs metazoan evolution.

The increasing detection of infections of Trypanosoma cruzi, the etiological agent of Chagas disease, in non-endemic regions beyond Latin America has risen to be a major public health issue. With an impact in the millions of people, current treatments rely on antiquated drugs that produce severe side effects and are considered nearly ineffective for the chronic phase. The minimal progress in the development of new drugs highlights the need for advances in basic research on crucial biochemical pathways in T. cruzi to identify new targets. Here, we report on the T. cruzi presenilin-like transmembrane aspartyl enzyme, a protease of the aspartic class in a unique phylogenetic subgroup with T. vivax separate from protozoans. Computational analyses suggests it contains 9 transmembrane domains and an active site with the characteristic PALP motif of the A22 family. Multiple linear B-cell epitopes were identified by SPOT synthesis analysis with Chagasic patient sera. Two were chosen to generate rabbit antisera, whose signal was primarily localized to the flagellar pocket, intracellular vesicles and endoplasmic reticulum in parasites by whole cell immunofluorescence. The results suggest that the parasitic presenilin-like enzyme could have a role in the secretory pathway and serve as a biomarker for infections.

Viruses are the most prevalent infectious agents, populating almost every ecosystem on earth. Most viruses carry only a handful of genes supporting their replication and the production of capsids. It came as a great surprise in 2003 when the first giant virus was discovered and found to have a >1Mbp genome encoding almost a thousand proteins. Following this first discovery, dozens of giant virus strains across several viral families have been reported. Here, we provide an updated quantitative and qualitative view on giant viruses and elaborate on their shared and variable features. We review the complexity of giant virus proteomes, which include functions traditionally associated only with cellular organisms. These unprecedented functions include components of the translation machinery, DNA maintenance, and metabolic enzymes. We discuss the possible underlying evolutionary processes and mechanisms that might have shaped the diversity of giant viruses and their genomes, highlighting their remarkable capacity to hijack genes and genomic sequences from their hosts and environments. This leads us to examine prominent theories regarding the origin of giant viruses. Finally, we present the emerging ecological view of giant viruses, found across widespread habitats and ecological systems, with respect to the environment and human health.

: Emaravirus (Order Bunyavirales; Family Fimoviridae) is a genus comprising over 20 emerging plant viruses with a worldwide distribution and economic impact. Emaraviruses infect a variety of host plants and have especially become prevalent in important long-living woody plants. These viruses are enveloped, with a segmented, single-stranded, negative-sense RNA genome and are transmitted by eriophyid mites or mechanical transmission. Emaraviruses have four core genome segments encoding an RNA-dependent RNA polymerase, a glycoprotein precursor, a nucleocapsid protein, and a movement protein. They also have additional genome segments, whose number varies widely. We report here that the proteins encoded by these segments form three main homology groups: a homolog of the sadwavirus Glu2 Pro glutamic protease; a protein involved in pathogenicity, which we named “ABC”; and a protein of unknown function, which we named “P55”. The distribution of these proteins parallels the emaravirus phylogeny and suggests, with other analyses, that emaraviruses should be split into at least two genera. Reliable diagnosis systems are urgently needed to detect emaraviruses, assess their economic and ecological importance, and take appropriate measures to prevent their spread (such as routine testing, hygiene measures, and control of mite vectors). Additional research needs include understanding the function of emaravirus proteins, breeding resistant plants and clarifying transmission modes.

We address weighted composition operators between Bers-type spaces on generalized Hua-Cartan-Hartogs domains and provide necessary and sufficient conditions for their boundedness and compactness. We then apply our results to study the boundedness and the compactness of weighted composition operators between Bers-type spaces on five different domains: generalized Hua domains, Cartan-Hartogs domains, generalized Cartan-Hartogs domains, generalized Cartan-Hartogs domains over different Cartan domains and generalized ellipsoidal-type domains.

This paper presents a comprehensive analysis of the scholarly footprint of ChatGPT, an AI language model, using bibliometric and scientometric methods. The study aims to understand the evolution of research output, citation patterns, collaborative networks, application domains, and future research directions related to ChatGPT. By analyzing data from the Scopus database, 533 relevant articles were identified for analysis. The findings reveal the prominent publication venues, influential authors, and countries contributing to ChatGPT research. Collaborative networks among researchers and institutions are visualized, highlighting patterns of co-authorship. The application domains of ChatGPT, such as customer support and content generation, are examined. Moreover, the study identifies emerging keywords and potential research areas for future exploration. The methodology employed includes data extraction, bibliometric analysis using various indicators, and visualization techniques such as Sankey diagrams. The analysis provides valuable insights into ChatGPT's influence in academia and offers researchers guidance for further advancements. This study stimulates discussions, collaborations and innovations to enhance ChatGPT's capabilities and impact across domains.

In this paper, a local meshless method (LMM) based on radial basis functions (RBFs) is utilized for the numerical solution of various types of PDEs, due to the flexibility with respect to geometry and high order of convergence rate. In case of global meshless methods, the two major deficiencies are the computational cost and the optimum value of shape parameter. Therefore, research is currently focus towards localized radial basis function approximations, as the local meshless method is proposed here. The local meshless procedures is used for spatial discretization whereas for temporal discretization different time integrators are employed. The proposed local meshless method is testified in terms of efficiency, accuracy and ease of implementation using regular and irregular domains.

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (Fth-1), ferritin light-chain (Ftl), and urinary F2-isoprostanes (uF2-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCI were evaluated by multivariable regression; correlations with uF2-isoPs were also assessed. Higher Ftl and Fth-1 associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% Confidence Interval (95% CI) 0.36-0.79 and 0.66, 95% CI 0.45-0.97, respectively). In women, higher Ftl and Fth-1 associated with better NPZ-4 (Ftl: adjusted beta (β)=0.15, 95% CI 0.02-0.29; Ftl-by-sex βinteraction=0.32, p=0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF2-isoPs in women (Ftl: rho=-0.47, p<0.001). Circulating Ftl and Fth-1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate underlying mechanisms.

The IgM and IgT classes were previously identified and characterized in the Antarctic teleost Trematomus bernacchii, a species belonging to the Perciform suborder Notothenoidei. Herein we characterized the gene encoding the polymeric immunoglobulin receptor (pIgR) in the same species and compared it to pIgR of multiple teleost species belonging to five perciform sub-orders, including 11 Antarctic and one non-Antarctic (Cottoperca gobio) notothenioid species, the latter living in less cold periantarctic sea. Antarctic pIgR genes displayed particularly long in-trons marked by sites of transposable elements and transcription factors. Furthermore, analysis of T. bernacchii pIgR cDNA unveiled multiple amino acid substitutions unique to Antarctic species, all introducing adaptive features, including N-glycosylation sequons. Interestingly, C. gobio shared most features with the other perciforms rather than with the cold adapted relatives. T. bernacchii pIgR transcripts were predominantly expressed in mucosal tissues, as indicated by q-PCR and in situ hybridization analysis. These results suggest that in cold adapted species pIgR preserved its fundamental role in mucosal immune defense, although remarkable gene structure modifications occurred.

KLHL genes and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in normal cell function and in disease (KLHL40, KLHL41, KBTBD13, KEAP1, and ENC1), previous studies that examined epigenetic factors affecting transcription were predominantly limited to promoter DNA methylation. Using diverse tissue and cell culture whole-genome profiles, we examined 17 KLHL or KBTBD genes preferentially expressed in skeletal muscle or brain to identify tissue-specific enhancer and promoter chromatin, open chromatin (DNaseI hypersensitivity), and DNA hypomethylation. Sixteen of the 17 genes displayed muscle- or brain-specific enhancer chromatin in their gene bodies, and most exhibited specific intergenic enhancer chromatin as well. Seven genes were embedded in a super-enhancer. The enhancer chromatin regions typically displayed foci of DNA hypomethylation at peaks of open chromatin. In addition, we found evidence that gene neighbors (HHATL and FBXO32) of KLHL40 and KLHL38 harbor enhancer chromatin that likely upregulates the adjacent KLHL gene. Many KLHL/KBTBD genes had tissue-specific promoter chromatin at their 5’ ends, but surprisingly, two (KBTBD11 and KLHL31) had constitutively unmethylated promoter chromatin in their 3’ exons that overlaps a retrotransposed KLHL gene. Our findings demonstrate the importance of expanding epigenetic analyses beyond the 5’ ends of genes in studies of normal and abnormal gene regulation.

Although phylogenetic analysis shows coronaviruses (CoV) share similar genome sequences, CoVs encode different number of proteins (5 to 14), which has implication on viral pathogenicity and infection. Here, we aimed to identify (in-silico) the similarities between different members of coronavirus family. The analysis included 50 coronavirus proteomes, including SARS-CoV-2 (COVID-19), to find the variation of the number of protein functional motifs and domain in each coronavirus. For this role, we used the experimentally validated domain (motif) that known to be crucial for viral infection. Although human CoVs are classified within one genus, we found variations among them. SARS-CoV-1, SARS-CoV-2 and MERS-CoV encode different type of domains, which has implications on the molecular interactions triggered by each virus within human cells. Secondly, we used functional motifs to reconstruct the potential molecular pathways or interactions triggered by SARS-CoV-2 proteins within human cell.

The architecture, organization and functioning of biocatalytic reaction networks, which are coded in the cell specific genome and which work together in the small space of biological cells, are a fascinating feature of life evolved over more than 3 billion years. The knowledge about the diversity of biocatalytic functions and metabolic pathways sustaining life on our planet is highly important, especially as the currently occurring loss of biodiversity is considered a planetary boundary which is at high risk, and knowledge about the life of current biological organisms should be gained before they become extinct. In addition to the well-known enzymatic reactions involved in biochemical pathways, the enzyme universe offers numerous opportunities for discovering novel functions and pathways. Maintaining thousands of molecules and reactions functioning properly within biological cells, which may be exposed to various kinds of external hazards, environmental stress, enzymatic side reactions or non-enzymatic chemical reactions, is key for keeping cellular life healthy. This review aims at outlining advances in assigning enzyme functions to protein sequences and the discovery of novel biocatalytic functions and pathways.

Complex modeling has received significant attention in recent years and is increasingly used to explain the statistical phenomenon with increasing and decreasing fluctuations such as the similarity or difference of spike protein charge patterns of coronaviruses. Different from the existing covariance or correlation coefficient methods in traditional integer dimension construction, this study proposes a simplified novel fractional dimension derivation with the exact Excel tool algorithm. It involves the fractional center moment extension to covariance, which ends up a complex covariance coefficient that is better than the Pearson correlation coefficient, in the sense that the nonlinearity relationship can be further depicted. The spike protein sequences of coronaviruses were obtained from the GenBank and GISAID database, including the coronaviruses from pangolin, bat, canine, swine (three variants), feline, tiger, SARS-CoV-1, MERS, and SARS-CoV-2 (including the strains of Wuhan, Beijing, New York, German, and UK variant B.1.1.7) were used as the representative examples in this study. By examining the values above and below the average/mean based on the positive and negative charge patterns of the amino acid residues of the spike proteins from coronaviruses, the proposed algorithm provides deep insights into the nonlinear evolving trends of spike proteins for understanding the viral evolution and identifying the protein characteristics associated with viral fatality. The calculation results demonstrate that the complex covariance coefficient analyzed by this algorithm is capable of distinguishing the subtle nonlinear differences in the spike protein charge patterns with reference to Wuhan strain SARS-CoV-2 for which the Pearson correlation coefficient may overlook. Our analysis reveals the unique convergent (positive correlative) to divergent (negative correlative) domain center positions of each virus. The convergent or conserved region may be critical to the viral stability or viability; while the divergent region is highly variable between coronaviruses suggesting high frequency of mutations in this region. The analyses show that the conserved center region of SARS-CoV-1 spike protein is located at amino acid residues 900, but shifted to the amino acid residues 700 in MERS spike protein, and then to amino acid residues 600 in SARS-COV-2 spike protein, indicating the evolvement of the coronaviruses. Interestingly, the conserved center region of the spike protein in SARS-COV-2 variant B.1.1.7 shifted back to amino acid residues 700, suggesting this variant is more virulent than the original SARS-COV-2 strain. Another important characteristic our study reveals is that the distance between the divergent mean and the maximal divergent point in each of the viruses (MERS>SARS-CoV-1>SARS-CoV-2) is proportional to viral fatality rate. This algorithm may help to understand and analyze the evolving trends and critical characteristics of SARS-COV-2 variants, other coronaviral proteins and viruses.

The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to 10e8 CAR T cells/ Kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here we tested CD8/4-1BB compared to CD28-based anti-CAIX CAR PBMCs cells-releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a 10e7 CAR PBMCs cells/ Kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, T cell exhaustion status in peripheral CD4 T cells, additionally to CD8 was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon administration of 10e7 CAR PMBCs cells/Kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.

Transcription factors must scan genomic DNA, recognize the cognate sequence of their control element(s), and bind tightly to them. The DNA recognition process is primarily carried out by their DNA binding domains (DBD), which interact with the cognate site with high affinity and more weakly with any other DNA sequence. DBDs are generally thought to bind to their cognate DNA without changing conformation (lock-and-key). Here we used nuclear magnetic resonance and circular dichroism to investigate the interplay between DNA recognition and DBD conformation in the Engrailed homeodomain (EnHD), as model case for the homeodomain family of eukaryotic DBDs. We found that the conformational ensemble of EnHD is rather flexible and becomes more structured as ionic strength increases following a Debye-Hückel’s dependence. Our analysis indicates that EnHD’s response to ionic strength is mediated by a built-in electrostatic spring-loaded latch that operates as conformational transducer. We also found that, at moderate ionic strengths, EnHD changes conformation upon binding to cognate DNA. This change is of larger amplitude and somewhat orthogonal to the response to ionic strength. As a consequence, very high ionic strengths (e.g. 700 mM) block the electrostatic-spring-loaded latch and binding to cognate DNA becomes lock-and-key. However, the interplay between EnHD conformation and cognate DNA binding is robust across a range of ionic strengths (i.e. 45 to 300 mM) that covers the most physiologically-relevant conditions. Therefore, our results demonstrate the presence of a mechanism for the conformational control of cognate DNA recognition on a eukaryotic DBD. This mechanism can function as a signal transducer that immediately locks the DBD in place upon encountering the cognate site during active DNA scanning. The electrostatic-spring-loaded latch of EnHD can also enable the fine control of DNA recognition in response to local/temporal changes in ionic strength induced by variate physiological processes.

Finding out how cells with the same genome change fates in differentiation commitment is a challenge of biology. We used MCF-7 breast cancer cells treated with the ErbB2 ligand heregulin (HRG), which induces differentiation, to address if and how the constitutive pericentromere-associated domains (PADs) may be involved in this process. PAD-specific repressive heterochromatin (H3K9me3) and active euchromatin (H3K4me3) marking, centromere (CENPA) labelling, qPCR, acridine-orange-DNA structural test, and microscopic image analysis were applied. We found a two-step DNA unfolding, at 15-20 min and 60 min after HRG treatment, coinciding with bi-phasic activation of the early response genes (c-FOS family) and two steps of critical phase transition which were revealed in transcriptome studies. In control, the distribution of PAD number and size displays a power-law scaling with a boundary at the nucleolus. PADs’ clustering correlates with centromere numbers. 15 min after HRG treatment, the unravelling of PADs occurs, coinciding with the first step of euchromatin unfolding. The second step is associated with transcription of long-non-coding-RNA from satellite III DNA. We hypothesize that splitting of the PAD clusters under the critical size threshold of the silencing domain abrupts position effect variegation. It allows the first genome transcription avalanche to occur, starting differentiation commitment.