Unique Class Research Articles

Wear Study on Various Conditions of AA7075 Metal Matrix Composite with Silicon Carbide (SiC), Boron Carbide (B4C) as Reinforcement for Aerospace Applications

This study aims to investigate the wear behavior of AA7075 alloy with the reinforcement of Silicon carbide (SiC) and Boron carbide (B4C) particles. Process parameters are crucial for component quality improvement, particularly in metal matrix composites (MMCs), a unique class of materials used in a variety of technical applications, such as but not limited to automobiles, marine, and aeronautics.These are frequently utilized in challenging applications due to their significantly better strength to weight ratios, stiffness, and then standard materials. However, it has numerous disadvantages, including high weight ratios, high deformation and stresses, poor fatigue life cycle, early wear and friction, and so on. Up till now, numerous reinforcements have been employed to address these crucial problems. Due to its superior properties, aluminum matrix composites (AMCs) have been used in many different applications. This work attempts to examine the wear behavior of AA7075 alloy reinforced with silicon (SiC) and boron (B4C) particles utilizing the stir casting process AA 7075-(SiC)-(B4C) composites were produced by employing AA 7075 as the matrix material with silicon carbide (SiC) and boron carbide (B4C) particles as reinforcement in various percentages of weight (5%, 10%, and 15%). Parameters of the composites, including wear behavior, coefficient of friction, frictional force, and pin temperature were assessed through graphical representation.

Exploring Spin-Crossover Cobalt(II) Single-Ion Magnets as Multifunctional and Multiresponsive Magnetic Devices: Advancements and Prospects in Molecular Spintronics and Quantum Computing Technologies

Spin-crossover (SCO) and single-ion magnets (SIMs), or their mixed SCO-SIM derivatives, are a convenient solution in the evolution from molecular magnetism toward molecular spintronics and quantum computing. Herein, we report on the current trends and future directions on the use of mononuclear six-coordinate CoII SCO-SIM complexes with potential opto-, electro-, or chemo-active 2,6-pyridinediimine (PDI)- and 2,2′:6′,2′-terpyridine (TERPY)-type ligands as archetypical examples of multifunctional and multiresponsive magnetic devices for applications in molecular spintronics and quantum computing technologies. This unique class of spin-crossover cobalt(II) molecular nanomagnets is particularly well suited for addressing and scaling on different supports, like metal molecular junctions or carbon nanomaterials (CNMs) and metal–organic frameworks (MOFs) or metal-covalent organic frameworks (MCOFs), in order to measure the single-molecule electron transport and quantum coherence properties, which are two major challenges in single-molecule spintronics (SMS) and quantum information processing (QIP).

Classifying Female Sexual Homicide Offenders: A Latent Class Analysis of Murder Arrestees in the U.S.

ABSTRACTResearch on sexual homicides has primarily focused on male offenders, and thus little is known about female offenders who perpetrated sexual homicides. This study aimed to develop the first statistical classification of female single‐victim (SV) sexual homicide offenders (SHOs) using the U.S. FBI's Supplementary Homicide Reports database that spanned over a 47‐year period (1976–2022). A latent class analysis (LCA) was computed to detect subtypes of female SHOs in a sample of 158 offenders. Findings of the LCA identified two unique classes of female SHOs exist within the data: White intra‐familial offenders and Black extra‐familial offenders. The distinguishing features of these two classes were the offender's racial group, the victim's age and racial groups, the offender‐victim relationship, the geographical urbanness level of crime location, and weapon use. This empirically‐derived offender classification can be informative to law enforcement agents and security professionals in their investigative strategies.

PMN J1310–5552: A Gamma-Ray-emitting Blazar Candidate Harboring a Cosmic Monster

Relativistic jets manifest some of the most intriguing activities in the nuclear regions of active galaxies. Identifying the most powerful relativistic jets permits us to probe the most luminous accretion systems and, in turn, the most massive black holes. This paper reports the identification of one such object, PMN J1310−5552 (z = 1.56), a blazar candidate of uncertain type detected with the Fermi Large Area Telescope (LAT) and Swift Burst Alert Telescope. The detection of broad emission lines in its optical spectra taken with the X-Shooter and Goodman spectrographs classifies it to be a flat-spectrum radio quasar. The analysis of the Goodman optical spectrum has revealed PMN J1310−5552 harbors a massive black hole (log scale M BH = 9.90 ± 0.07, in M ⊙) and luminous accretion disk (log scale L disk = 46.86 ± 0.03, in erg s−1). The fitting of the observed big blue bump with the standard accretion disk model resulted in the log scale M BH =9.81−0.20+0.19 (in M ⊙) and L disk =46.86−0.09+0.09 (in erg s−1), respectively. These parameters suggest PMN J1310−5552 hosts one of the most massive black holes and the most luminous accretion disks among the blazar population. The physical properties of this enigmatic blazar were studied by modeling the broadband spectral energy distribution considering the data from NuSTAR, Swift, Fermi-LAT, and archival observations. Overall, PMN J1310−5552 is a powerful “MeV” blazar with physical parameters similar to other members of this unique class of blazars. These results provide glimpses of monsters lurking among the unknown high-energy emitters and demonstrate the importance of ongoing wide-field sky surveys to discover them.

A single-base deletion in exon 2 of Hd1 delineates monogenic recessive photoperiod insensitivity in aromatic Joha rice: a novel allele for seasonal adaptability

BackgroundAssam's aromatic Joha rice is a unique rice class famous for its aroma, taste, and nutritional benefits, which fetch high market prices in domestic and international markets. Joha landraces are inherently poor yielders due to their strong aroma and predominantly photoperiod sensitivity. Hybridization involving non-aromatic HYVs improves yield with concomitant loss of quality. In this context, mutation breeding, a sustainable approach where genetic mutations are induced to create desirable traits, often provides useful allelic variation in specific morpho-agronomic traits. The present study delves into the genetic characterization of a photoperiod-insensitive mutant. As part of our mutation breeding programme, this mutant was isolated from a gamma ray-induced M2 population of a Joha rice landrace, Kon Joha.ResultsThe mutant was unique, and a single recessive gene conditions the induced photoperiod insensitivity. Mutant gene tagging involved 402 SSR and InDel markers, and later polymorphic markers were used for bulk segregant analysis (BSA) in the F2 population of ‘mutant × Kalijeera (distant parent)’. BSA revealed an association between the SSR marker RM527 and this mutant trait. This marker is present on chromosome 6 of the rice genome. Using chromosome 6-specific SSR markers in polymorphic screening and BSA revealed another associated marker, RM19725, for the mutant trait. The genomic interval between RM527 and RM19725 harbors a photoperiod-insensitive gene, Hd1, on chromosome 6. Cloning and sequencing of Hd1 genomic fragments from the parents and mutants revealed a single-base deletion in exon 2, leading to a frameshift mutation in the Hd1 protein. This mutation in exon 2 leads to severe structural abnormalities in the CCT domain of the Hd1 protein that is critical for the interaction of the repressing complex with conserved response elements in the florigen gene under long-day conditions, thereby causing photoperiod insensitivity.ConclusionsThe mutant's pleasant aroma and other quality characteristics, comparable to those of the parent cultivar, hold significant promise. They expand its potential use in a structured breeding programme aimed at developing high-value aromatic Joha rice. This rice, resilient to winter- and summer-growing environments and with broad seasonal adaptability, could revolutionize the rice market. The practical value of our research is underscored by this exciting possibility.

The High-Resolution Structure of a Variable Lymphocyte Receptor From Petromyzon marinus Capable of Binding tothe Brain Extracellular Matrix.

Variable lymphocyte receptors (VLRs) are antigen receptors derived from the adaptive immune system of jawless vertebrates such as lamprey (Petromyzon marinus). First discovered in 2004, VLRs have been the subject of numerous biochemical and structural investigations. Due to their unique antigen binding properties, VLRs have been leveraged as possible drug delivery agents. One such VLR, previously identified and referred to as P1C10, was shown to bind to the brain extracellular matrix. Here, we present the high-resolution X-ray crystal structure of this VLR determined to 1.3 Å resolution. The fold is dominated by a six-stranded mixed β-sheet which provides a concave surface for possible antigen binding. Electron density corresponding to a 4-(2-hydroxyethyl)piperazine-1-propanesulfonic acid buffer molecule (HEPPS) was found in this region. By comparing the P1C10 molecular architecture and its buffer binding residues with those of other VLRs previously reported, it was possible to illustrate how this unique class of proteins can accommodate diverse binding partners. Additionally, we provide an analysis of the experimentally determined structure compared to the models generated by the commonly used AlphaFold and iTASSER structure prediction software packages.

A Direct Chemical Repair of Etheno-Type RNA Damages.

Etheno damages in RNA represent a unique class of structural alterations that arise from exposure to various environmental stressors or endogenous processes. They significantly distort the RNA structure and affect crucial biological functions, including RNA-protein interactions, ribosome function, and translation fidelity. However, repair mechanisms for those etheno damages in RNA are still being elucidated. Here, a synthetic flavin derivative PS9 has been identified as the first example of chemical repair approach for this type of RNA damages. It efficiently managed the removal of etheno-type εA and εC damages in nucleosides, oligonucleotides in vitro, and in E. coli RNA in vivo under blue light irradiation. The capacity of the chemical approach relies on a unique cycloaddition activation of the etheno-bridge with singlet oxygen, which is distinct from traditional epoxidation of the C=C double bonds by proteins from the AlkB family. The understanding and effective manipulation of etheno damages in RNA with chemical tools hold implications for deciphering their role in mutagenesis and RNA biology, potentially opening avenues for targeted therapeutic interventions and biomarker development.

A Direct Chemical Repair of Etheno‐Type RNA Damages

Etheno damages in RNA represent a unique class of structural alterations that arise from exposure to various environmental stressors or endogenous processes. They significantly distort the RNA structure and affect crucial biological functions, including RNA‐protein interactions, ribosome function, and translation fidelity. However, repair mechanisms for those etheno damages in RNA are still being elucidated. Here, a synthetic flavin derivative PS9 has been identified as the first example of chemical repair approach for this type of RNA damages. It efficiently managed the removal of etheno‐type εA and εC damages in nucleosides, oligonucleotides in vitro, and in E. coli RNA in vivo under blue light irradiation. The capacity of the chemical approach relies on a unique cycloaddition activation of the etheno‐bridge with singlet oxygen, which is distinct from traditional epoxidation of the C=C double bonds by proteins from the AlkB family. The understanding and effective manipulation of etheno damages in RNA with chemical tools hold implications for deciphering their role in mutagenesis and RNA biology, potentially opening avenues for targeted therapeutic interventions and biomarker development.

Immunoglobulin A Antibodies: From Protection to Harmful Roles.

Immunoglobulin A (IgA) is the most abundantly produced antibody in humans. IgA is a unique class of immunoglobulin due to its multiple molecular forms, and a defining difference between the two subclasses: IgA1 has a long hinge-region that is heavily O-glycosylated, whereas the IgA2 hinge-region is shorter but resistant to bacterial proteases prevalent at mucosal sites. IgA is essential for immune homeostasis and education. Mucosal IgA plays a crucial role in maintaining the integrity of the mucosal barrier by immune exclusion of pathobionts while facilitating colonization with certain commensals; a large part of the gut microbiota is coated with IgA. In the circulation, monomeric IgA that has not been engaged by antigen plays a discrete role in dampening inflammatory responses. Protective and harmful roles of IgA have been studied over several decades, but a new understanding of the complex role of this immunoglobulin in health and disease has been provided by recent studies. Here, we discuss the physiological and pathological roles of IgA with a special focus on the gut, kidneys, and autoimmunity. We also discuss new IgA-based therapeutic approaches.

Phage-Derived Endolysins Against Resistant Staphylococcus spp.: A Review of Features, Antibacterial Activities, and Recent Applications.

Antimicrobial resistance is a significant global public health issue, and the dissemination of antibiotic resistance in Gram-positive bacterial pathogens has significantly increased morbidity, mortality rates, and healthcare costs. Among them, Staphylococcus, especially methicillin-resistant Staphylococcus aureus (MRSA), causes a wide range of diseases due to its diverse pathogenic factors and infection strategies. These bacteria also present significant issues in veterinary medicine and food safety. Effectively managing staphylococci-related problems necessitates a concerted effort to implement preventive measures, rapidly detect the pathogen, and develop new and safe antimicrobial therapies. In recent years, there has been growing interest in using endolysins to combat bacterial infections. These enzymes, which are also referred to as lysins, are a unique class of hydrolytic enzymes synthesized by double-stranded DNA bacteriophages. They possess glycosidase, lytic transglycosylase, amidase, and endopeptidase activities, effectively destroying the peptidoglycan layer and resulting in bacterial lysis. This unique property makes endolysins powerful antimicrobial agents, particularly against Gram-positive organisms with more accessible peptidoglycan layers. Therefore, considering the potential benefits of endolysins compared to conventional antibiotics, we have endeavored to gather and review the characteristics and uses of endolysins derived from staphylococcal bacteriophages, as well as their antibacterial effectiveness against Staphylococcus spp. based on conducted experiments and trials.

Structural and hydrodynamic controls on fluid travel time distributions across fracture networks

Fracture networks are preferential flow paths playing a critical role in a wide range of environmental and industrial problems. Their complex multiscale structure leads to broad distributions of fluid travel times, affecting many biogeochemical processes. Yet, the relationship between the fracture network structures, their hydrodynamic properties, and the resulting anomalous transport dynamics remains unclear. We use a large database of fracture network models to investigate the factors controlling fluid velocity and travel-time distributions across a wide range of networks, from synthetic to field-calibrated models, with aperture variability at both fracture and network scales. Analysis reveals that transport statistics have generic properties across investigated networks, including notably heavy-tailed travel time distributions. Networks of increasing complexity and heterogeneity lead to broader velocity distributions and more channeled velocity fields, where flow concentrates in a narrow channel web in the three-dimensional (3D) fracture structure. While heterogeneity in point-velocity statistics increases travel-time variability, channeling tends to reduce it. This counterintuitive phenomenon challenges current theories, which assume that long travel time power law exponents are determined solely by point-velocity statistics. By analyzing velocity and travel time statistics for different flow structures, we develop a coupled Continuous Time Random Walk framework capturing the unexpected control of the velocity field's spatial structure on anomalous transport in fracture networks. This leads to a unique class of random walk models capturing the respective roles of velocity heterogeneity and spatial structure on transport in networks. These findings open a prospective for characterizing, modeling, and predicting transport dynamics in complex networks, with potential applications to geological, biological, and engineered networks.

Extracellular vesicles, including large translating vesicles called midbody remnants, are released during the cell cycle.

Extracellular vesicles (EVs) play crucial roles in cell-cell communication, but the biogenesis of large EVs has remained elusive. Here, we show that the biogenesis of large EVs (>800nm-2um) occurs predominantly through the completion of successful cytokinesis, and the majority of large extracellular vesicles are midbody remnants (MBRs) with translation activity, and the unique marker MKLP1. Blocking the cell cycle or cytokinesis, genetically or chemically, significantly decreases MBRs and large (800nm-2um), medium (500-800nm), and small (<300nm) EVs, suggesting that proliferative cells can also generate all sizes of EVs. The canonical EV markers including CD9, CD63, CD81 localize to the spindle midzone, midbody and MBRs, suggesting that these markers are not specific for detecting EVs exclusively. Importantly, all commonly used EV isolation methods isolate MBRs, confounding previous EV research. Lastly, isolated MBRs maintain translation activity regardless of the isolation method. We propose a model for the biogenesis of extracellular vesicles throughout the cell cycle and suggest that some large EVs are primarily generated from mitotic cells. The discovery of MBRs as a unique class of large, translating EVs has implications for using them as cancer diagnostic markers and for engineering them for therapeutic cargo delivery during mitosis.

CircFOXP1: a potential diagnostic and therapeutic target in human diseases.

Circular RNA (circRNA) are a unique class of non-coding RNAs characterized by their covalently closed loop structures, which grant them properties such as stability and conservation. Among these, circFOXP1 has been implicated in various diseases, including cancers, respiratory, skeletal, and cardiovascular disorders. This review systematically examines circFOXP1's role in disease progression, highlighting its involvement in critical biological processes, including cell proliferation, invasion, apoptosis, and autophagy. Mechanistically, circFOXP1 functions through miRNA sponging, protein interactions, and modulation of key signaling pathways such as Wnt and PI3K/AKT. We discuss its potential as a diagnostic and therapeutic target. Our analysis also identifies key unresolved questions, such as the precise regulatory networks involving circFOXP1 and its translation potential, offering pathways for future research.

Abstract 4134926: Association of Eicosanoid Metabolites with Body Mass Index

Introduction: The specific molecular pathways from obesity to inflammation to cardiovascular disease remain unclear. Eicosanoids are a unique class of bioactive lipids that govern the upstream initiation of pro- and anti-inflammatory activity. Objective: We leveraged a novel lipidomic platform to quantify &gt; 800 eicosanoid metabolites and examined their association with body mass index (BMI). Methods: We studied Multi-Ethnic Study of Atherosclerosis (MESA) participants with available samples for eicosanoid analysis. Eicosanoids and related metabolites were assessed using a directed, non-targeted mass spectrometry-based platform. We examined the cross-sectional association of eicosanoid metabolites with BMI using multivariable linear regression models. Analyses were considered significant at FDR q-value &lt;0.01. Results: A total of 5101 individuals (age 63 ± 10 years; 53% women, 60% non-Whites) were included. The mean BMI was 28.3 ± 5.1 kg/m2. Of 811 eicosanoids analyzed, 255 showed a significant association with BMI (see Figure for putative metabolite identities; FDR q-value &lt;0.01 for all). Derivatives of docosahexaenoic acid (DHA; 19,20 DiHDPA, β = - 0.206, standard error [SE] = 0.013) and eicosatetraenoic acid (11(S) HEPE, β = - 0.180, SE = 0.014) were associated with lower BMI. Linoleic acid derivatives (12,13 diHOME, an exercise-induced lipokine) had a similar association. Conversely, derivatives of linoleic acid (13-oxoODE, β = 0.241, SE = 0.01) and arachidonic acid (11-HETE, β = 0.236, SE = 0.017) were associated with higher BMI. Other derivatives of linoleic acid (15 (S) HETrE) and prostaglandin (11b PGF2α) were also associated with higher BMI. Conclusions: We found that specific eicosanoid metabolites, including DHA and linoleic acid derivatives with known anti-inflammatory, atheroprotective, and beneficial metabolic effects (e.g., 19,20 DiHDPA; 12,13 diHOME), were associated with lower BMI. By contrast, specific arachidonic acid and prostaglandin derivatives with known pro-inflammatory and adverse CV effects (e.g. oxylipin 11-HETE; PGF2α; 13-oxoODE) were associated with higher BMI. These findings further the understanding of specific inflammatory pathways underlying the development of obesity-related CVD.

Coupled Polymethine Dyes: Six Decades of Discoveries.

This review provides a comprehensive examination of the applications of the seminal coupling principle introduced by Siegfried Dähne and Dieter Leupold in 1966. Their heuristic and groundbreaking work proposed that combining multiple polymethine subunits within a single chromophore enables orbital coupling, consequently narrowing the HOMO-LUMO gap, and yielding redshifted optical properties. These outcomes are particularly valuable for developing organic dyes tailored for visible-to-near-infrared applications. Despite their potential, coupled polymethines remain relatively underexplored, with most reported instances being serendipitous discoveries over the last six decades. In light of this, our review compiles and discusses the reported coupled polymethine structures, covering synthetic, spectroscopic, theoretical and applicative aspects, offering insights into the structure-property relationships of this unique class of dyes and perspectives for their future applications.

Photo-induced hydroxypentafluorosulfanylation of alkenes with SF5Cl and oxygen gas and their further derivatization

Fluorinated or fluoroalkylated alcohols are common structural motifs in biologically active molecules, natural products, and pharmaceuticals. However, pentafluorosulfanyl (SF5) alcohols, a unique class of SF5 compounds that serve as synthetically valuable building blocks, are difficult to prepare with current methodologies. In this article, we present a single-step, metal-free, and photo-induced hydroxypentafluorosulfanylation of styrenes or α,β-unsaturated esters/amide, producing a series of structurally diverse pentafluorosulfanyl alcohols with up to 89% yields. This reaction is mild and operationally simple, using molecular oxygen as the hydroxy source. The protocol is suitable for a wide range of alkenes, including natural products and drug molecule derivatives. The formed SF5 alcohol units can be readily converted into diverse functionalized SF5 compounds, such as α-SF5 ketones, SF5 diols, and SF5 cyclic carbonates. The potential applications of these SF5 compounds in pharmaceutical and material sciences are vast, making this research a step forward in the field.

Evolution of g-type lysozymes in metazoa: insights into immunity and digestive adaptations.

Exploring the evolutionary dynamics of lysozymes is critical for advancing our knowledge of adaptations in immune and digestive systems. Here, we characterize the distribution of a unique class of lysozymes known as g-type, which hydrolyze key components of bacterial cell walls. Notably, ctenophores, and choanoflagellates (the sister group of Metazoa), lack g-type lysozymes. We reveal a mosaic distribution of these genes, particularly within lophotrochozoans/spiralians, suggesting the horizontal gene transfer events from predatory myxobacteria played a role in their acquisition, enabling specialized dietary and defensive adaptations. We further identify two major groups of g-type lysozymes based on their widespread distribution in gastropods. Despite their sequence diversity, these lysozymes maintain conserved structural integrity that is crucial for enzymatic activity, underscoring independent evolutionary pathways where g-type lysozymes have developed functionalities typically associated with different lysozyme types in other species. Specifically, using Aplysia californica as a reference species, we identified three distinct g-type lysozyme genes: two are expressed in organs linked to both feeding and defense, and the third exhibits broader distribution, likely associated with immune functions. These findings advance our understanding of the evolutionary dynamics shaping the recruitment and mosaic functional diversification of these enzymes across metazoans, offering new insights into ecological physiology and physiological evolution as emerging fields.

Extraction, characterization and antioxidative potentials of UV-screening compound, mycosporine-like amino acids from epilithic cyanobacterium Lyngbya sp. HKAR - 15.

Mycosporine-like amino acids (MAAs) are a unique class of UV-screening bioactive molecules with potent antioxidants and photoprotective properties, synthesized by various species of cyanobacteria in different habitats. The cyanobacterial biofilms play a crucial driver in the development of ecological communities. The current study examined the existence of the photoprotective MAAs in a novel epilithic cyanobacterium Lyngbya sp. strain HKAR-15 isolated from cyanobacterial biofilms on the rock surface. The isolated MAAs were identified, purified and characterized using UV-Vis spectroscopy, HPLC (High-Performance Liquid Chromatography), ESI-MS (Electrospray Ionization-Mass Spectrometry), FTIR (Fourier Transform Infrared Spectroscopy) and NMR (Nuclear Magnetic Resonance). The compounds were recognized as palythine (retention time (RT): 2.7min; UV λmax: 320nm; m/z: 245.02) and porphyra-334 (RT: 3.6min; UV λmax: 334nm; m/z: 347.1). FTIR spectroscopy analyses also revealed the presence of functional groups of both compounds. NMR spectroscopy analyses confirmed the presence of both palythine and porphyra-334. The UV-induced production of both MAAs was visualized under ultraviolet radiation (UVR) in contrast to the photosynthetically active radiation (PAR). The MAAs (palythine and porphyra-334) had a significant dose-dependent free radical scavenging capacity. The findings show that MAAs perform a dynamic role in the survival and photoprotection of cyanobacteria in hostile environments under high solar UV irradiances. These photoprotective compounds may have various biotechnological applications as well as role in the development of natural sunscreens.

Structurally Diverse Limonoids from Trichilia connaroides and Their Antitumor Activities

Comprehensive SummaryTwelve new limonoids (1—12), named trichilitins A—L, were isolated from the leaves and twigs of Trichilia connaroides, together with ten known compounds (13—22). The structures were elucidated by extensive spectroscopic investigations, X‐ray diffraction analyses, and ECD calculations. Compound 1, which belongs to a unique class of ring B‐seco limonoid, has been identified as 6/7/6/5 tetracyclic due to a key Baeyer‐Villiger oxidation. Compounds 2—7 were identified as ring intact limonoids, while compounds 8—10 were established as ring D‐seco ones, and 11 and 12 were determined to be rearranged ones. All of the compounds were tested for cytotoxicity against three human tumor cell lines (HCT‐116, NCl‐H1975, and SH‐SY5Y). Compounds 6, 7, 13, 14, and 19 exhibited significant cytotoxic effects, especially 7 exhibited significant cytotoxic effects against HCT‐116 with an IC50 value of 0.035 μmol·L–1 and was more active than the positive control, doxorubicin with an IC50 value of 0.20 μmol·L–1. Compound 7 effectively induced apoptosis of HCT‐116, which was associated with S‐phase cell cycle arrest. Furthermore, the Western blot analysis showed that compound 7 could induce cell cycle arrest by promoting the expression levels of p53 and p21.

Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial

IntroductionSubjects with amyotrophic lateral sclerosis (ALS) treated with Radicava® (edaravone) IV (intravenous; Mitsubishi Tanabe Pharma America [MTPA], hereafter “MTPA IV edaravone”) in Study MCI186‐19 had a significantly slower physical functional decline vs placebo-treated subjects as measured by the revised ALS Functional Rating Scale (ALSFRS-R) and analyzed by the linear mixed model for repeated measures (MMRM). This Study 19 post hoc analysis of MTPA IV edaravone-treated and placebo-treated subjects evaluated linear and nonlinear latent class mixed models defining trajectories based on identifying the model with the lowest Bayesian information criterion. The best model differentiated 4 nonlinear trajectories in ALS subjects. ALSFRS-R total score in MTPA IV edaravone-treated and placebo-treated subjects was evaluated for these 4 nonlinear latent class trajectory groups. MethodsDisease trajectories of MCI186‐19 MTPA IV edaravone-treated or placebo-treated ALS subjects who completed the double-blind period were investigated using latent class analysis (LCA) statistical models to identify potential unique nonlinear ALSFRS-R disease trajectories. ResultsALSFRS-R trajectories revealed 4 unique nonlinear trajectory latent classes per treatment group in MTPA IV edaravone-treated and placebo-treated ALS subjects completing the MCI186‐19 double-blind period. Latent classes 2‐4 had statistically significant slowing of ALSFRS-R total score decline in the predicted nonlinear trajectories of MTPA IV edaravone-treated vs placebo-treated ALS subjects. ConclusionsThis post hoc analysis suggests MTPA IV edaravone treatment results in slower ALSFRS-R decline vs placebo in most predicted nonlinear trajectories. LCA is a novel approach that may benefit future trial analyses.