Class Of Structures Research Articles

Conformation and binding of 12 Microcystin (MC) congeners to PPP1 using molecular dynamics simulations: A potential approach in support of an improved MC risk assessment.

Microcystins (MCs) occur frequently during cyanobacterial blooms worldwide, representing a group of currently about 300 known MC congeners, which are structurally highly similar. Human exposure to MCs via contaminated water, food or dietary supplements can lead to severe intoxications with ensuing high morbidity and in some cases mortality. Currently, one MC congener (MC-LR) is almost exclusively considered for risk assessment (RA) by the WHO. Many MC congeners co-occur during bloom events, of which MC-LR is not the most toxic. Indeed, MC congeners differ dramatically in their inherent toxicity, consequently raising question about the reliability of the WHO RA and the derived guidance values. Molecular dynamics (MD) simulation can aid in understanding differences in toxicity, as experimental validation for all known MC congeners is not feasible. Therefore, we present MD simulations of a total of twelve MC congeners, of which eight MC congeners were simulated for the first time. We show that depending on their structure and toxicity class, MCs adapt to different backbone conformations. These backbone conformations are specific to certain MC congeners and can change or shift to other conformations upon binding to PPP1, affecting the stability of the binding. Analysis of the interactions with PPP1 demonstrated that there are frequently occurring patterns for individual MC congeners, and that published PPP interactions could be reproduced. In addition, common but also unique patterns were found for individual MC congeners, suggesting differences in binding behaviour. The MD simulations presented here therefore enhance our understanding of MC congener-specific differences and demonstrated that congener-specific investigations are prerequisite for allowing characterisation of yet untested or even unknown MC congeners, thereby allowing for a novel potential approach in support of an improved RA of microcystins in humans.

Topological Analysis of Fractal Binary and Ternary Trees

Fractals are complex geometric objects that seem the same at different scales and have self-similarity. Because of this special characteristic, fractals can be used to simulate intricate biological processes. Fractal binary and ternary trees are novel data types that combine the productiveness of tree architectures with the ideas of fractal geometry. In addition to self-similarity and scalability, these trees have potential across a range of computer science and medical applications. The main goal of the study is to identify and analyze topological indices and graph entropy for fractal binary and fractal ternary trees. By examining indices such as the Randić index, Zagreb indices, and entropy measurements, the study aims to obtain a comprehensive knowledge of the structural complexity and information-theoretic properties of these fractal graphs. The study starts with the vertex and edge partitioning of fractal binary and ternary trees in order to distinguish different structural classes. Using these partitions, we obtained topological indices and graph entropy values for the fractal trees. Also, this study compares the topological indices for each fractal tree with the number of copies in the fractal dimension for a succession of graphs.

Resorcinol-based Bolaamphiphilic Quaternary Ammonium Compounds.

Quaternary ammonium compounds (QACs) play crucial disinfectant roles in healthcare, industry, and domestic settings. Most commercially utilized QACs like benzalkonium chloride have a common architectural theme, leading to a rise in bacterial resistance and urgent need for novel structural classes. Some potent QACs such as chlorhexidine (CHX) and octenidine (OCT) feature a bolaamphiphilic architecture, comprised of two cationic centers at the molecular periphery and a non-polar region connecting them; these compounds show promise to elude bacterial resistance mechanisms. Inspired by such structures, we synthesized a series of 43 biscationic amphiphilic compounds focused on a resorcinol core, featuring flexibility of linker lengths, alkyl tails, and relative substituent positioning, to study their structure activity relationships (SARs). Antibacterial activity evaluation against a panel of gram-positive and gram-negative strains, including ESKAPE pathogens (A. baumannii,P. aeruginosa), were encouraging, with minimum inhibitory concentrations (MICs) of 0.5-4 μM against all tested strains for select compounds. Ten prepared compounds bearing either 17 or 18 total side chain carbons demonstrated uniformly strong antibacterial activity againstP. aeruginosa(MIC 4-16 μM) and 6 other strains (MIC ≤4 μM), irrespective of cationic spacing.These findings promise to further extend the application of bolaamphiphilic QACs as a novel class of disinfectants.

Plant community and structural pattern analyses of Abraham Sacred Forest in Amhara Regional State, northwest Ethiopia.

Owing to its topographic variations, Ethiopia is a biodiversity-rich country. However, the long-term degradation of resources has resulted in isolated forest patches largely around sacred places. Thus, this work was aimed to evaluate the plant community formation and structural dynamics of the Abraham Sacred Forest patch. Data were collected from 60 plots located on transect lines. Five subplots (4 m2), four at each corner and center, were set to collect juveniles' data. Individuals of each species and cover abundance were recorded, and adults' stem girth was measured. Hierarchical cluster analysis was used to identify plant communities. A Kruskal-Wallis followed by Tukey's honestly significant difference test was performed to check the statistical significance among the plant communities. Shannon-Wiener diversity index, equitability index, and non-parametric species richness estimators were used to quantify species diversity, evenness, and richness, respectively. Structural parameters and size class ratios were used to analyze the vegetation structure and regeneration status. Seventy wood species, distributed in 62 genera and 38 families, were recorded. Fabaceae was the most species-rich (10 species) family. Three plant communities were identified. A Kruskal-Wallis test indicated that the community types showed significant differences (P < 0.05) with respect to altitude and slope. The density and basal area of the forest were 4580.4 ha-1 and 35.18 m2ha-1 respectively. The inverted J-shaped pattern in DBH classes implies a good reproduction status. However, importance value index and regeneration status analyses revealed that certain species, like Astropanax abyssinicum (Hochst. ex. A. Rich) Seem, Myrica salicifolia Hochst. ex. A. Rich and Dombeya torrida (G.F.Gmel) Bamps, require conservation priority.

An Analaysis of Category Shift and Its Equivalence in Tourism Promotion Video Subtitles

This study aims to identify the types of category shift defined by Catford theory (1965) and Nida’s for translation equivalence (1964). The descriptive qualitative method was used to analyze the data. This study used a secondary source from four videos. First, Badung Heaven of Dream, second, Pantai Melasti were posted in Jegeg Bagus Badung YouTube Channel. Third, Pungin puspa, and fourth, A Story of Sacred Bond from West Bali were posted on Jegeg Bagus Bali YouTube Channel. This study analyzed words, phrases, clauses, terms, and sentences. Total data were 33 data, which analyzed qualitatively. The analysis showed that there were four types of category shift. They were Structure shift (17), Class shift (1), Unit shift (10), and Intra-system shift (5). This study also found two types of translation equivalence. Namely Formal equivalence (21) and dynamic equivalence (12). The most dominant types of category shift that found is structure shift and the most dominant equivalence that found is formal equivalence.

A Formal 1,2-Stevens Rearrangement of Thioester Ylides as a Single-Atom Molecular Editing Tool.

A rhodium-catalyzed reaction of thioesters with diazo reagents was recognized as a powerful and unprecedented tool for single-atom molecular editing by the insertion of a single carbon atom into the C(O)─S thioester bond, thereby leading to various α-thioketones possessing a quaternary carbon atom. A selective and precise defunctionalization of the polyfunctionalized products further demonstrated the synthetic utility of the reaction for the synthesis of more common structural classes of compounds.

Interpenetrating Composites: A Nomenclature Dilemma.

Interpenetrating phase composites are a novel class of heterogeneous structures that have recently gained attention. In these types of composites, one of the phases is topologically continuous and can maintain its structural integrity even if the other phase is removed. These composites are generally fabricated by casting, where the reinforcement penetrates into the precursor matrix as a continuous phase. However, the following dilemma arises: if the same two phases are combined by other powder metallurgical routes (due to differences in the fabrication and interfacial conditions), can they still be called interpenetrating phase composites? The reinforcement is added to the precursor matrix, as in any of the conventional composite processing methods. Most importantly, the reinforcement does not interpenetrate the matrix phase. The present Review discusses the various fabrication routes employed for the fabrication of these interpenetrating phase composites and attempts to identify the correct nomenclature for these composites fabricated via the powder metallurgical approach.

A Review on Branched-Chain Amino Acid Aminotransferase (BCAT) Inhibitors: Current Status, Challenges and Perspectives.

Branched-chain amino acids (BCAAs) are essential amino acids for humans and play an indispensable role in many physiological and pathological processes. Branched-chain amino acid aminotransferase (BCAT) is a key enzyme that catalyzes the metabolism of BCAAs. BCAT is upregulated in many cancers and implicated in the development and progress of some other diseases, such as metabolic and neurological diseases; and therefore, targeting BCAT might be a potential therapeutic approach for these diseases. There are two isoforms of BCAT, i.e., cytoplasmic BCAT1 (or BCATc) and mitochondrial BCAT2 (or BCATm). The discovery of BCAT inhibitors was initiated by Warner-Lambert, a subsidiary of Pfizer, in 2000, followed by many other pharmaceutical companies, such as GlaxoSmithKline (GSK), Ergon, Icagen, Agios, and Bayer. Strategies of high-throughput screening (HTS), DNA-Encoded library technology (ELT), and fragment-based screening (FBS) have been employed for hit identification, followed by structural optimization. Despite low selectivity, both BCAT1 and BCAT2 selective inhibitors were individually developed, each with a few chemical structural classes. The most advanced BCAT1 inhibitor is BAY-069, discovered by Bayer, which has a potent enzymatic inhibitory activity against BCAT1 and a decent in vitro and in vivo pharmacokinetic profile but displayed weaker cellular inhibitory activity and almost no anti-proliferative activity. There are no BCAT inhibitors currently under investigation in clinical trials. Further studies are still needed to discover BCAT inhibitors with a more druggable profile for proof of concept. This review focuses on the latest progress of studies on the understanding of the physiology and pathology of BCAT and the discovery and development of BCAT inhibitors. The structure-activity relationship (SAR) and the druggability, and the challenges of BCAT inhibitors are discussed, with the aim of inspiring the discovery and development of BCAT inhibitors in the future.

Developing Chemical Signatures for Categories of Household Consumer Products Using Suspect Screening Analysis.

Consumer products are a major source of chemicals that may pose a health risk. It is important to understand what chemicals are in these products to evaluate risk and assess new products for uncommon ingredients. Suspect screening analysis (SSA) using two-dimensional gas chromatography-high-resolution-time-of-flight/mass spectrometry (GCxGC-HR-TOF/MS) was applied to 92 consumer products from 5 categories. 485 probable chemical structures were tentatively identified using the NIST 2017 spectral library across all products (109 confirmed). Chemicals were characterized by functional use and structural class. Fabric upholsteries contained the most chemicals (239) identifiable by GCxGC-HR-TOF/MS and silicone kitchen tools the least (64). Use of duplicate samples and repeat purchases of products allowed for a within-product category similarity assessment, which showed highest variability in baby soap and lowest in cotton clothing. Chemical ingredient signatures (including reported sample abundance ranges) for each product type were obtained by identifying chemicals occurring in ≥80% of product samples. These signatures provide a baseline set of chemical ingredients (that is, representative mixtures) across common consumer product types. The chemical signatures will help in evaluating new and existing products. Separating constituent chemicals into typical and atypical might inform exposure assessment, in vitro bioactivity screening, and ultimately the risk related to using such products.

Bird Species Detection Net: Bird Species Detection Based on the Extraction of Local Details and Global Information Using a Dual-Feature Mixer.

Bird species detection is critical for applications such as the analysis of bird population dynamics and species diversity. However, this task remains challenging due to local structural similarities and class imbalances among bird species. Currently, most deep learning algorithms focus on designing local feature extraction modules while ignoring the importance of global information. However, this global information is essential for accurate bird species detection. To address this limitation, we propose BSD-Net, a bird species detection network. BSD-Net efficiently learns local and global information in pixels to accurately detect bird species. BSD-Net consists of two main components: a dual-branch feature mixer (DBFM) and a prediction balancing module (PBM). The dual-branch feature mixer extracts features from dichotomous feature segments using global attention and deep convolution, expanding the network's receptive field and achieving a strong inductive bias, allowing the network to distinguish between similar local details. The prediction balance module balances the difference in feature space based on the pixel values of each category, thereby resolving category imbalances and improving the network's detection accuracy. The experimental results using two public benchmarks and a self-constructed Poyang Lake Bird dataset demonstrate that BSD-Net outperforms existing methods, achieving 45.71% and 80.00% mAP50 with the CUB-200-2011 and Poyang Lake Bird datasets, respectively, and 66.03% AP with FBD-SV-2024, allowing for more accurate location and species information for bird detection tasks in video surveillance.

A New Algebraic Approach of Neutrosophic Lie Algebra by AH Isometry

This paper introduces a novel approach to the concept of neutrosophic Lie algebra by leveraging the AH isometry framework. We establish foundational properties of neutrosophic Lie algebra, demonstrating that each neutrosophic algebra inherently fulfills the criteria of a Lie algebra. Moreover, we introduce distinct neutrosophic Lie algebraic structures, providing illustrative examples to support these constructs. By integrating neutrosophic logic, our approach effectively addresses indeterminacy, ambiguity, and imprecision, enhancing the classical algebraic structures with new dimensions of flexibility. The potential applications of neutrosophic Lie algebra are vast, particularly in fields requiring nuanced treatments of uncertainty.

Structure-resolved dynamics of type 2M von Willebrand disease.

Genetically determined amino acid substitutions in the platelet adhesive A1 domain alter von Willebrand factor's (VWF) platelet agglutination competence, resulting in both gain- (type 2B) and loss-of-function (type 2M) phenotypes of von Willebrand disease. Prior studies of variants in both phenotypes revealed defects in secondary structure that altered stability and folding of the domain. An intriguing observation was that loss of function arose from both misfolding of A1 and, in a few cases, hyperstabilization of the native structure. To fully understand the 2M phenotype, we thoroughly investigated the structure/function relationships of 15 additional type 2M variants and 2 polymorphisms in the A1 domain. These variants were characterized using circular dichroism, fluorescence, calorimetry, hydrogen-deuterium exchange mass spectrometry, surface plasmon resonance, and platelet adhesion under shear flow. Six variants were natively folded, with 4 being hyperstabilized. Nine variants disordered A1, causing a loss in α-helical structure and unfolding enthalpy. GPIbα binding affinity and platelet adhesion dynamics were highly correlated to helical structure. Hydrogen-deuterium exchange resolved specific C-terminal secondary structure elements that differentially diminish the GPIbα binding affinity of A1. These localized structural perturbations were highly correlated to GPIbα binding affinity and shear-dependent platelet adhesion. While hyperstabilized dynamics in A1 do impair stable platelet attachment to VWF under flow, variant-induced localized disorder in specific regions of the domain misfolds A1 and abrogates platelet adhesion. These 2 opposing conformational properties represent 2 structural classes of VWF that drive the loss-of-function phenotype that is type 2M von Willebrand disease.

Exploring dihydropyrimidone derivatives as modulators of carbohydrate catabolic enzyme to mitigate diabetes

Diabetes is a prevalent and serious metabolic disorder affecting millions globally, and it poses extensive health risks due to elevated blood glucose levels. One promising approach for managing diabetes is the inhibition of α-glucosidase, an enzyme that plays a crucial role in carbohydrate metabolism. Targeting α-glucosidase can help delay glucose absorption, thus controlling postprandial blood sugar spikes. Dihydropyrimidones, a core structural class present in various biologically active natural compounds, have been recognized for their diverse therapeutic potential, including anti-diabetic properties. In this study, we evaluated a library of previously synthesized 37 Dihydropyrimidone derivatives to assess their potential as α-glucosidase inhibitors. We identified 34 derivatives with significant inhibitory activity, exhibiting IC50 values in the range of 5.30–56.72 µM. Among these, compounds 2, 4–7, 9–11, 13–16, 31, 32, and 33 demonstrated high potency, with IC50 values below 20 µM; the most active compound, 5, achieved an IC50 of 5.30 µM. A detailed kinetic study on compound 5 revealed a competitive inhibition mode with a Ki value of 16.10 ± 0.0075 µM. Additionally, cytotoxicity assays confirmed that compound 5 is non-toxic to BJ cell lines, underscoring its safety for therapeutic use. The computational studies further supported the inhibitory potential by illustrating key interactions and binding affinities between the Dihydropyrimidone derivatives and the α-glucosidase, highlighting these compounds as promising candidates for diabetes management.

History of bridge architecture to the XVIIIth century

Abstract. Problem. Bridge construction and the warehouse history development of lighting architecture and living technology. The contribution to the material from this diet was based on the close interconnection of the design and the artistic appearance of the material. The history of the bridge development construction is laid out in the context of the foreign cultural and technical level of the analyzed era. Knowledge of the architectural design basics expands the professional and secluded look of future fachists, the creative taste of art, encourages developers to create constructively and artistically valuable disputes. The goal is to conduct further research and analysis of the development of the place and the development of culture from ancient Greece and classical structures of the post-beam type, simplifying the process of building arch crypts in Starodav the new Roman power, bridges between Central Europe and Asia. Behind the era of the Revival of Italy and the end of the 16th century. Priishov Baroque style. Its characteristic features were the use of dynamic compositions and rich architectural decor. Soon the baroque will emerge in France, but will not expand widely here. Beginning from the middle of the 17th century, classicism became a panicky style in France. before the tendency to create facade compositions that are not directly related to the constructive side of disputes in England. The analysis shows that bridge projects in the 18th century. consist of engineers who were either architects or practical bridge builders. Methodology. Simultaneously carrying out an analysis of the development of the theoretical field of engineering knowledge. To achieve the goal, it is necessary to reveal the sequence of road infrastructure, look at the materials in the geometric variety of sizes of stone materials, and identify their influences in the development of structural bridge systems. Results. Based on a comprehensive look at the bridges built before the 18th century, the main stages in the development of the place were revealed. Regardless of the actual costs of human and financial resources, it is possible to demonstrate the reliability of everyday structures and ensure the reliability of the designed architectural forms today. Originality. Before carrying out structural analysis, we follow the designs and methods of building places of architectural styles that developed significantly under the influx of changes in the aesthetic views of the era. Practical value. The unity of constructive and artistic solutions has been revealed. Conducting primer analysis of the main style-creating disputes (palaces, cathedrals, villas), their formal and expansive warehouse architecture, which develops independently, poses in connection with the development of the structure. The trends of park art, of which park architecture and bridges have become a special sphere, are looming for further development.

Project activities using creative technologies and artificial intelligence in classes in Russian as a foreign language

The article discusses the place of project activities in the practice of teaching foreign languages and the role of creative technologies and artificial intelligence in teaching Russian as a foreign language, analyzes scientific and educational literature on the implementation of project activities and the introduction of creative technologies and artificial intelligence into the educational process. A technological structure has been developed for a series of classes on Russian as a foreign language for foreign teachers, in which projects of educational media material for students based on storytelling were created using creative technologies and artificial intelligence. Practical experience is given in implementing the technological structure of classes with a group of teachers from different universities in Zimbabwe with a level of Russian language proficiency B1 and higher (11 people in total), who mastered the additional professional development program “Russian language as a language” at the Immanuel Kant Baltic Federal University. foreign for science, education, culture" (86 hours) from October 27 to November 7, 2023. The results of the pedagogical experiment showed that the use of creative technologies allowed foreign teachers to take a fresh look at their teaching activities, to present in a different way the process of teaching students in their country in the disciplines of natural sciences and engineering and technical profiles, and practical experience in working with neural networks and the chat constructor -bots allowed foreigners to make projects modern, bright, and interesting. The study showed that project activities using creative technologies and artificial intelligence in teaching Russian as a foreign language allow foreign speakers to comprehensively improve their professional and communicative competencies, as well as “soft skills.”

Integration of Structural Characteristics from GEDI Waveforms for Improved Forest Type Classification

Abstract: Forest types correspond to differences in structural characteristics and species composition that influence biomass and biodiversity values, which are essential measurements for ecological monitoring and management. However, differentiating forest types in tropical regions remains a challenge. This study aimed to improve forest type extent mapping by combining structural information from discrete full-waveform LiDAR returns with multitemporal images. This study was conducted in a tropical forest region over complex terrain in north-eastern Tanzania. First, structural classes were generated by applying time-series clustering algorithms. The results showed four different structural clusters corresponding to forest types, montane–humid forest, montane–dry forest, submontane forest, and non-forest, when using the Kshape algorithm. Kshape considers the shape of the full-sequence LiDAR waveform, requiring little preprocessing. Despite the overlap amongst the original clusters, the averages of structural characteristics were significantly different across all but five metrics. The labeled clusters were then further refined and used as training data to generate a wall-to-wall forest cover type map by classifying biannual images. The highest-performing model was a KNN model with 13 spectral and 3 terrain features achieving 81.7% accuracy. The patterns in the distributions of forest types provide better information from which to adapt forest management, particularly in forest–non-forest transitional zones.

What Can Be Learned by Knowing Only the Amino Acid Composition of Proteins?

The amino acid composition of proteins depends on many factors. It varies in organisms that are distant in taxonomic position. The amino acid composition of proteins depends on the localization of proteins in cells and tissues and the structure of proteins. The question arises: is it possible to separate different proteomes using only the amino acid composition of proteins? Is it possible to determine, considering only its amino acid composition, to what structural class the protein under study will belong? We have developed a method and a measure that maximally separate two sets of proteins. As a result, we assign each protein an R-value, positive values of which are more characteristic of the first set, and negative ones-of the second. By studying the distribution of R in two sets, we can determine how much these sets differ in composition. Also, when examining a new protein, we can determine if it is more similar to the first set or the second. In this paper, we show that using only amino acid composition, it is possible to separate sets of proteins belonging to different organisms, as well as proteins that differ in function or structure. In all cases, we assign to proteins a measure R that maximally separates the studied sets. This approach can be further used to annotate proteins with unknown functions.

A New Polymeric Hybrid Auxetic Structure Additively Manufactured by Fused Filament Fabrication 3D Printing: Machine Learning-Based Energy Absorption Prediction and Optimization.

The significance of this paper is an investigation into the design, development, and optimization of a new polymeric hybrid auxetic structure by additive manufacturing (AM). This work will introduce an innovative class of polymeric hybrid auxetic structure by the integration of an arrow-head unit cell into a missing rib unit cell, which will be fabricated using fused filament fabrication (FFF) technique, that is, one subset of AM. The auxetic performance of the structure is validated through the measurement of its negative Poisson's ratio, confirming its potential for enhanced energy absorption. A chain of regression, linear, and quadratic polynomial machine learning algorithms are used to predict and optimize the energy absorption capability at variant processing conditions. Amongst them, the polynomial regression model stands out with an R-squared value of 92.46%, reflecting an excellent predictive capability for energy absorption of additively manufactured polymeric hybrid auxetic structure. The optimization technique revealed that the printing speed of 80 mm/s and layer height of 200 µm were the critical values to achieve a maximum amount of energy absorption at 5.954 kJ/m2, achieved at a printing temperature of 244.65 °C. Such results also contribute to the development of AM, since they show not only the potential for energy absorption of polymeric hybrid auxetic structures but also how effective machine learning is in the optimization of the AM process.

Emergence and clonal dissemination of KPC-2- and NDM-1-coharboring Citrobacter freundii in China with an IncR plasmid.

The rise of carbapenem-resistant Enterobacteriaceae coharboring KPC-2 and NDM-1 poses a significant public health threat. KPC-2-NDM-1-Citrobacter freundii is rarely reported in clinical settings. In this study, we report the largest cohort of eight KPC-2-NDM-1-C. freundii isolated from children with urinary tract infections. Comprehensive characterization, including antimicrobial susceptibility testing, plasmid conjugation, whole-genome sequencing, and comparative genomics, was conducted for these clinical strains. Antimicrobial susceptibility testing indicated that all strains were resistant to meropenem [minimal inhibitory concentration (MICs) ≥ 8 µg/mL] and imipenem (MICs > 8 µg/mL). Genotyping and comparative genomics analyses identified the eight KPC-2-NDM-1- C. freundii belonging to ST523, exhibiting a close relationship characterized by 45 single nucleotide polymorphisms. Whole-genome sequencing and plasmid analysis confirmed the presence of blaKPC-2 and blaNDM-1 on an IncR plasmid named pC275-2 with 46,050 bp. The blaNDM-1 was integrated within the blaNDM-1 related region, which includes ΔISAba125, blaNDM-1, ble-MBL, trpF, dsbD, and ISCR1, while the blaKPC-2 gene was located on a novel non-Tn4401 genetic element. The blaKPC-2 genetic architectures containing blaKPC-2 differed from classical structures, underscoring the ongoing evolution of these genetic elements.IMPORTANCEOur study described the largest cohort to date of eight ST523 KPC-2-NDM-1-C. freundii isolated from children with urinary tract infections. The cooccurrence of KPC-2, a serine β-lactamases, and NDM-1, a metallo-β-lactamase on an IncR plasmid pC275-2 from a clinical carbapenem-resistant C. freundii. The conserved insertion structure mediated the blaNDM-1, and the propagation of blaKPC-2 gene with a new genetic background using IncR plasmid in clinical settings promotes the emergence of superbugs necessitating vigilant monitoring. Our research detected that ST523 KPC-2- NDM-1-C. freundii were disseminated in a children's hospital. The potential spread of an IncR plasmid within the hospital raises concerns about the pandemic potential of this clone that produces two carbapenemases: KPC-2 and NDM-1. Further investigations will be necessary to control and prevent the spread of KPC-2-NDM-1-C. freundiis.

Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression

BackgroundMECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.MethodsTo study the role of the genomic rearrangement structures on an individual’s clinical phenotypic variability, we employed a comprehensive genomics, transcriptomics, and deep phenotyping analysis approach on 137 individuals affected by MRXSL. Genomic structural information was correlated with transcriptomic and quantitative phenotypic analysis using Human Phenotype Ontology (HPO) semantic similarity scores.ResultsDuplication sizes in the cohort ranging from 64.6 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (48%), terminal duplications (22%), inverted triplications (20%), and other CGRs (10%). Most of the terminal duplication structures consist of translocations (65%) followed by recombinant chromosomes (23%). Notably, 65% of de novo events occurred in the Terminal duplication group in contrast with 17% observed in Tandem duplications. RNA-seq data from lymphoblastoid cell lines indicated that the MECP2 transcript quantity in MECP2 triplications is statistically different from all duplications, but not between other classes of genomic structures. We also observed a significant (p < 0.05) correlation (Pearson R = 0.6, Spearman p = 0.63) between the log-transformed MECP2 RNA levels and MECP2 protein levels, demonstrating that genomic aberrations spanning MECP2 lead to altered MECP2 RNA and MECP2 protein levels. Genotype–phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: Tandem duplications, Other complex duplications, Terminal duplications/Translocations, and Triplications encompassing MECP2.ConclusionIn aggregate, this combined analysis uncovers an interplay between MECP2 dosage, genomic rearrangement structure and phenotypic traits. Whereas the level of MECP2 is a key determinant of the phenotype, the DNA rearrangement structure can contribute to clinical severity and disease expression variability. Employing this type of analytical approach will advance our understanding of the impact of genomic rearrangements on genomic disorders and may help guide more targeted therapeutic approaches.