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Fibroblasts are a dynamic cell type that achieve selective differentiated states to mediate acute wound healing and long-term tissue remodeling with scarring. With myocardial infarction injury, cardiomyocytes are replaced by secreted extracellular matrix proteins produced by proliferating and differentiating fibroblasts. Here, we employed 3 different mouse lineage-tracing models and stage-specific gene profiling to phenotypically analyze and classify resident cardiac fibroblast dynamics during myocardial infarction injury and stable scar formation. Fibroblasts were activated and highly proliferative, reaching a maximum rate within 2 to 4 days after infarction injury, at which point they expanded 3.5-fold and were maintained long term. By 3 to 7 days, these cells differentiated into myofibroblasts that secreted abundant extracellular matrix proteins and expressed smooth muscle α-actin to structurally support the necrotic area. By 7 to 10 days, myofibroblasts lost proliferative ability and smooth muscle α-actin expression as the collagen-containing extracellular matrix and scar fully matured. However, these same lineage-traced initial fibroblasts persisted within the scar, achieving a new molecular and stable differentiated state referred to as a matrifibrocyte, which was also observed in the scars of human hearts. These cells express common and unique extracellular matrix and tendon genes that are more specialized to support the mature scar.

Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction (MI) and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell type in terms of their origins and functional effects in vivo . Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen-inducible Cre for cellular lineage-tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Lineage tracing with four additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin + myofibroblasts reduces collagen production and scar formation after MI. Periostin-traced myofibroblasts also revert back to a less-activated state upon injury resolution. Our results define the myofibroblast as a periostin-expressing cell type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21 + tissue-resident fibroblasts. The origin and fate of myofibroblasts, the cells responsible for cardiac remodelling and fibrosis, is controversial. Here the authors show that cardiac myofibroblasts express periostin, derive exclusively from tissue-resident fibroblasts, are necessary for scar formation after injury, and can revert back to a less-activated state upon injury resolution.

Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. While Thbs4 is known to protect striated muscle from disease by enhancing sarcolemmal stability through increased integrin and dystroglycan attachment complexes, here we show that Thbs3 antithetically promotes sarcolemmal destabilization by reducing integrin function, augmenting disease-induced decompensation. Deletion of Thbs3 in mice enhances integrin membrane expression and membrane stability, protecting the heart from disease stimuli. Transgene-mediated overexpression of α7β1D integrin in the heart ameliorates the disease predisposing effects of Thbs3 by augmenting sarcolemmal stability. Mechanistically, we show that mutating Thbs3 to contain the conserved RGD integrin binding domain normally found in Thbs4 and Thbs5 now rescues the defective expression of integrins on the sarcolemma. Thus, Thbs proteins mediate the intracellular processing of integrin plasma membrane attachment complexes to regulate the dynamics of cellular remodeling and membrane stability. Thrombospondin 4 has been shown to protect the heart and the skeletal muscle by enhancing matrix secretion and membrane stability thanks to its intracellular function. Here the authors show that thrombospondin 3 exacerbates injury-induced cardiomyopathy and promotes destabilization of the cardiomyocyte membrane by impairing integrin trafficking to the sarcolemma.

Neurodegenerative diseases (NDDs) have received considerable interest from scientists for a long time due to their multifactorial nature. Alzheimer’s disease (AD) is of particular importance among pathologies, and despite approved drugs for its treatment, there is no effective pharmacological therapy to stop, halt, or repair neurodegeneration. The U.S. Food and Drug Administration (FDA) has approved certain medications to treat AD, including galantamine, donepezil, rivastigmine, memantine, tacrine, suvorexant, brexpiprazole, butein, and Licochalcone A. Topological indices and quantitative structure‐property relationships (QSPRs) are indispensable in drug discovery. They allow researchers to analyze, compare, and predict the properties of chemical compounds, thereby expediting the identification of promising drug candidates while minimizing experimental costs and efforts. Regression models are vital in QSPR analysis, especially when dealing with topological indices. They facilitate quantifying the relationship between chemical structure and properties, thereby facilitating drug design, material discovery, and other chemistry‐related applications. The objective of this study is to examine the efficacy of descriptors in correlating the physicochemical features of molecules associated with Alzheimer’s disease. We will use the computational method to calculate degree‐related, distance‐related, and eccentricity‐based topological indices for any chemical graph. QSPR models are developed utilizing degree‐based, distance‐based, and eccentricity‐based topological indices to estimate some physicochemical properties of AD drugs, including molecular weight (MW), boiling point (BP), topological polar surface area (TPSA), complexity (C), polarizability (P), and refractive index ( R ). The QSPRS studies are obtained using the linear regression technique. The present study found that the topological indices Randic index R , first Zagreb index M 1 , and atom‐bond connectivity index ABC provide valuable insights into the structure‐activity relationships of different drugs and help in designing more effective combinations for treating Alzheimer’s disease.

Hemodynamic stress on the mammalian heart results in compensatory hypertrophy and activation of the unfolded protein response through activating transcription factor 6α (ATF6α) in cardiac myocytes, but the roles of ATF6α or the related transcription factor ATF6β in regulating this hypertrophic response are not well-understood. Here we examined the effects of loss of ATF6α or ATF6β on the cardiac response to pressure overload. Mice gene-deleted for Atf6 or Atf6b were subjected to 2 weeks of transverse aortic constriction, and each showed a significant reduction in hypertrophy with reduced expression of endoplasmic reticulum (ER) stress-associated proteins compared with controls. However, with long-term pressure overload both Atf6 and Atf6b null mice showed enhanced decompensation typified by increased heart weight, pulmonary edema and reduced function compared to control mice. Our subsequent studies using cardiac-specific transgenic mice expressing the transcriptionally active N-terminus of ATF6α or ATF6β revealed that these factors control overlapping gene expression networks that include numerous ER protein chaperones and ER associated degradation components. This work reveals previously unappreciated roles for ATF6α and ATF6β in regulating the pressure overload induced cardiac hypertrophic response and in controlling the expression of genes that condition the ER during hemodynamic stress.

This paper is concerned with the novel exact solitons for the truncated M-fractional (1+1)-dimensional nonlinear generalized Bretherton model with arbitrary constants. This model is used to explain the resonant nonlinear interaction between the waves in different phenomena, including fluid dynamics, plasma physics, ocean waves, and many others. A series of exact solitons, including bright, dark, periodic, singular, singular–bright, singular–dark, and other solitons are obtained by applying the extended sinh-Gordon equation expansion (EShGEE) and the modified (G′/G2)-expansion techniques. A novel definition of fractional derivative provides solutions that are distinct from previous solutions. Mathematica software was used to obtain and verify the solutions. The solutions are shown through 2D, 3D, and density plots. A stability process was conducted to verify that the solutions are exact and accurate. Modulation instability was used to determine the steady-state results for the corresponding equation.

This paper presents a novel framework for introducing generalized 1-parameter 3-variable Hermite polynomials. These polynomials are characterized through generating functions and series definitions, elucidating their fundamental properties. Moreover, utilising a factorisation method, this study establishes recurrence relations, shift operators, and various differential equations, including differential, integro-differential, and partial differential equations.

In its crystalline state, the α ‐icosahedral nanosheet of boron demonstrates superconductivity and thermal electronic properties. Mathematical research on a graph’s structure yields a graph descriptor, a numerical measure. Chemical graph theory employs connectivity descriptors to analyze molecular structures, providing crucial insights into many chemical compounds’ chemical and biological characteristics. These characteristics benefit physicists, chemists, and medical and pharmaceutical specialists. In this paper, the idea of reverse degree–based ‐polynomial is initiated, and differential and integral operators are computed. We formulate reverse degree–based topological descriptors based on this concept. In this paper, we examine the boron α ‐icosahedral nanosheet for this technique. We looked at the physicochemical properties of boron α ‐icosahedral nanosheets using reverse degree–based topological descriptors and best‐fit linear regression models to get an idea of what they are. Researchers are hoping that this strategy will lead them into new areas where they can investigate related studies.

The first Zagreb eccentricity index E 1 (℧) is the sum of square of eccentricities of the vertices, and the second Zagreb eccentricity index E 2 (℧) is the sum of product squares of the eccentricities of the vertices. A linked graph G is called a cactus if any two of its cycles share only one vertex. In other words, there are no two independent cycles that share an edge. Cactus graphs are also known as “block graphs” or “sensitized graphs.” They are closely related to chordal graphs and can be used to represent various types of networks, including communication networks and road networks. In this contribution, E 1 (℧) and E 2 (℧) values of cacti with k pendant vertices and k cycles, respectively, are considered. We determine the minimum E 1 , E 2 indices for n order cacti with k pendant vertices and k cycles.

The correct derivation of integral inequalities on fuzzy-number-valued mappings depends on applying fractional calculus to fuzzy number analysis. The purpose of this article is to introduce a new class of convex mappings and generalize various previously published results on the fuzzy number and interval-valued mappings via fuzzy-order relations using fuzzy coordinated ỽ-convexity mappings so that the new version of the well-known Hermite–Hadamard (H-H) inequality can be presented in various variants via the fractional integral operators (Riemann–Liouville). Some new product forms of these inequalities for coordinated ỽ-convex fuzzy-number-valued mappings (coordinated ỽ-convex FNVMs) are also discussed. Additionally, we provide several fascinating non-trivial examples and exceptional cases to show that these results are accurate.