Differentiation Matrix Research Articles

Enhancing Fracture Healing with 3D Bioprinted Hif1a-Overexpressing BMSCs Hydrogel: A Novel Approach to Accelerated Bone Repair.

Addressing the urgent need for effective fracture treatments, this study investigates the efficacy of a 3D bioprinted biomimetic hydrogel, enriched with bone marrow mesenchymal stem cells (BMSCs) and targeted hypoxia-inducible factor 1 alpha (Hif1a) gene activation, in enhancing fracture healing. A photocross-linkable bioink, gelatin methacryloyl bone matrix anhydride (GBMA) is developed, and selected its 5% concentration for bioink formulation. Rat BMSCs are isolated and combined with GBMA to create the GBMA@BMSCs bioink. This bioink is then used in 3D bioprinting to fabricate a hydrogel for application in a rat femoral fracture model. Through transcriptome sequencing, WGCNA, and Venn analysis, the hypoxia-inducible factor Hif1a is identified as a critical gene in the fracture healing process. In vitro studies showed that Hif1a promoted BMSC proliferation, chondrogenic differentiation, and cartilage matrix stability. The in vivo application of the GBMA@BMSCs hydrogel with Hif1a overexpression significantly accelerated fracture healing, evidenced by early and enhanced cartilage callus formation. The study demonstrates that 3D bioprinting of GBMA@BMSCs hydrogel, particularly with Hif1a-enhanced BMSCs, offers a promising approach for rapid and effective fracture repair.

Spectral scheme for atomic structure calculations in density functional theory

We present a spectral scheme for atomic structure calculations in pseudopotential Kohn-Sham density functional theory. In particular, after applying an exponential transformation of the radial coordinates, we employ global polynomial interpolation on a Chebyshev grid, with derivative operators approximated using the Chebyshev differentiation matrix, and integrations using Clenshaw-Curtis quadrature. We demonstrate the accuracy and efficiency of the scheme through spin-polarized and unpolarized calculations for representative atoms, while considering local, semilocal, and hybrid exchange-correlation functionals. In particular, we find that O(200) grid points are sufficient to achieve an accuracy of 1 microhartree in the eigenvalues for optimized norm conserving Vanderbilt pseudopotentials spanning the periodic table from atomic number Z=1 to 83.

Indole-3-acetic acid attenuates pulmonary fibrosis by modulating lung microbiota, inhibiting fibroblast activation, and alleviating alveolar epithelial cell senescence

AimPulmonary fibrosis (PF) is a relentlessly progressive disorder characterized by high mortality and limited effective therapeutic options. Indole-3-acetic acid (IAA), originally recognized as a plant hormone, is also identified as a tryptophan-derived metabolite catabolized from microbiota in mammals. IAA has exhibited antioxidative, anti-inflammatory, and anti-tumor effects in various disorders, yet its role in PF remains elusive. Main methodsBleomycin (BLM) was employed to induce PF in a mouse model. TGF-β1 was utilized in primary mouse lung fibroblasts (pMLFs) to establish a pro-fibrotic in vitro cellular model, and in A549 cells to create an in vitro cellular senescence model. The therapeutic effects of IAA on PF were evaluated using hematoxylin-eosin staining, immunofluorescence staining, western blotting, SA-β-gal assay, and network pharmacology analysis. Additionally, the effect of IAA on lung microbiota of PF was investigated using 16S rRNA gene sequencing analysis. Key findingswe observed a significant reduction in IAA levels in both PF patients and mouse models. Moreover, we demonstrated the therapeutic potential of IAA in alleviating PF in BLM-induced mouse models, showing a dose-dependent response. Mechanistically, we delineated three perspectives. Firstly, IAA promoted autophagic flux by inhibiting the PI3K/AKT/mTOR pathway, thereby suppressing lung fibroblast differentiation and extracellular matrix (ECM) deposition. Secondly, IAA attenuated alveolar epithelial cell senescence by modulating the PI3K/AKT and HIF-1 pathways. Lastly, IAA displayed the ability to mitigate PF by modulating the structure and composition of lung microbiota. SignificanceOur study demonstrates that IAA alleviates PF through multiple pathways, highlighting its potential as a therapeutic agent.

An unexpected role of Nogo-A as regulator of tooth enamel formation

Neurite outgrowth inhibitor A (Nogo-A) is a major player in neural development and regeneration and the target of clinical trials aiming at promoting the regeneration of the central nervous system upon traumatic and ischemic injury. In this work, we investigated the functions of Nogo-A during tooth development to determine its role in dental physiology and pathology. Using immunohistochemistry and in situ hybridization techniques, we showed that Nogo-A is highly expressed in the developing mouse teeth and, most specifically, in the ameloblasts that are responsible for the formation of enamel. Using both Nogo-A knockout and K14-Cre;Nogo-A fl/fl transgenic mice, we showed that Nogo-A deletion in the dental epithelium leads to the formation of defective enamel. This phenotype is associated with overexpression of a set of specific genes involved in ameloblast differentiation and enamel matrix production, such as amelogenin, ameloblastin and enamelin. By characterising the interactome of Nogo-A in the dental epithelium of wild-type and mutant animals, we found that Nogo-A directly interacts with molecules important for regulating gene expression, and its deletion disturbs their cellular localisation. Furthermore, we demonstrated that inhibition of the intracellular, but not cell-surface, Nogo-A is responsible for gene expression modulation in ameloblasts. Taken together, these results reveal an unexpected function for Nogo-A in tooth enamel formation by regulating gene expression and cytodifferentiation events.

Bioenergetic-active exosomes for cartilage regeneration and homeostasis maintenance.

Cartilage regeneration relies on adequate and continuous bioenergy supply to facilitate cellular differentiation and extracellular matrix synthesis. Chondrocytes frequently undergo energy stress under pathological conditions, characterized by disrupted cellular metabolism and reduced adenosine triphosphate (ATP) levels. However, there has limited progress in modulating energy metabolism for cartilage regeneration thus far. Here, we developed bioenergetic-active exosomes (Suc-EXO) to promote cartilage regeneration and homeostasis maintenance. Suc-EXO exhibited a 5.42-fold increase in ATP content, enabling the manipulation of cellular energy metabolism by fueling the TCA cycle. With continuous energy supply, Suc-EXO promoted BMSC chondrogenic differentiation via the P2X7-mediated PI3K-AKT pathway. Moreover, Suc-EXO improved chondrocyte anabolism and mitochondrial homeostasis via the P2X7-mediated SIRT3 pathway. In a rabbit cartilage defect model, the Suc-EXO-encapsulated hydrogel notably promoted cartilage regeneration and maintained neocartilage homeostasis, leading to 2.26 and 1.53 times increase in Col2 and ACAN abundance, respectively. These findings make a remarkable breakthrough in modulating energy metabolism for cartilage regeneration, offering immense potential for clinical translation.

Delivery Strategies of Growth Factors in Cartilage Tissue Engineering.

Cartilage plays an important role in supporting soft tissues, reducing joint friction, and distributing pressure. However, its self-repair capacity is limited due to the lack of blood vessels, nerves, and lymphatic systems. Tissue engineering offers a potential solution to promote cartilage regeneration by combining scaffolds, seed cells, and growth factors. Among these, growth factors play a critical role in regulating cell proliferation, differentiation, and extracellular matrix remodeling. However, their instability, susceptibility to degradation and potential side effects limit their effectiveness. This article reviews the main growth factors used in cartilage tissue engineering and their delivery strategies, including affinity-based delivery, carrier-assisted delivery, stimuli-responsive delivery, spatial structure-based delivery, and cell system-based delivery. Each method shows unique advantages in enhancing the delivery efficiency and specificity of growth factors but also faces challenges such as cost, biocompatibility, and safety. Future research needs to further optimize these strategies to achieve more efficient, safe, and economical delivery of growth factors, thereby advancing the clinical application of cartilage tissue engineering.

Three-Dimensional Printed Silk Fibroin/Hyaluronic Acid Scaffold with Functionalized Modification Results in Excellent Mechanical Strength and Efficient Endogenous Cell Recruitment for Articular Cartilage Regeneration.

Treatment of articular cartilage remains a great challenge due to its limited self-repair capability. In tissue engineering, a scaffold with both mechanical strength and regenerative capacity has been highly desired. This study developed a double-network scaffold based on natural biomaterials of silk fibroin (SF) and methacrylated hyaluronic acid (MAHA) using three-dimensional (3D) printing technology. Structural and mechanical characteristics of the scaffold was first investigated. To enhance its ability of recruiting endogenous bone marrow mesenchymal stem cells (BMSCs), the scaffold was conjugated with a proven BMSC-specific-affinity peptide E7, and its biocompatibility and capacity of cell recruitment were assessed in vitro. Animal experiments were conducted to evaluate cartilage regeneration after transplantation of the described scaffolds. The SF/HA scaffolds exhibited a hierarchical macro-microporous structure with ideal mechanical properties, and offered a 3D spatial microenvironment for cell migration and proliferation. In vitro experiments demonstrated excellent biocompatibility of the scaffolds to support BMSCs proliferation, differentiation, and extracellular matrix production. In vivo, superior capacity of cartilage regeneration was displayed by the SF/MAHA + E7 scaffold as compared with microfracture and unconjugated SF/MAHA scaffold based on macroscopic, histologic and imaging evaluation. In conclusion, this structurally and functionally optimized SF/MAHA + E7 scaffold may provide a promising approach to repair articular cartilage lesions in situ.

CCKR signaling map, G-Protein bindings, hormonal regulation, and neural mechanisms may influence the osteogenic/cementogenic differentiation potential of hPDLSCs

ObjectivePeriodontal regeneration poses challenges due to the periodontium's complexity, relying on mesenchymal cells from the periodontal ligament (hPDLSCs) to regenerate hard tissues like bone and cementum. While some hPDLSCs have high regeneration potential (HOP-hPDLSCs), most are low potential (LOP-hPDLSCs). This study analyzed hPDLSCs from a single donor to minimize inter-individual variability and focus on key differences in differentiation potentials. DesignThis study used RNA-seq, genomic databases, and bioinformatics tools to explore signaling pathways (SPs), biological processes (BPs), and molecular functions (MFs) guiding HOP cells to mineralized matrix production. It also investigated limitations of LOP cells and strategies for enhancing their osteo/cementogenesis. ResultsIn basal conditions, HOP exhibited a multifunctional gene network with higher expression of genes related to osteo/cementogenesis, cell differentiation, immune modulation, stress response, and hormonal regulation. In contrast, LOP focused on steroid hormone biosynthesis and nucleic acid maintenance. During osteo/cementogenic induction, HOP showed strong modulation of genes related to angiogenesis, cell division, mesenchymal differentiation, and extracellular matrix production. LOP demonstrated neural synaptic-related processes and preserved cellular cytoskeleton integrity. CCKR map signaling and G-protein receptor bindings gained significance during osteo/cementogenesis in HOP-hPDLSCs. Both HOP and LOP shared common BPs related to gastrointestinal and reproductive system development. ConclusionThe osteo/cementogenic differentiation of HOP cells may be regulated by CCKR signaling, G-protein bindings, and specific hormonal regulation. LOP cells seem committed to neural mechanisms. This study sheds light on hPDLSCs' complex characteristics, offering a deeper understanding of their differentiation potential for future periodontal regeneration research and therapies.

Fibroblast growth factor 2 promotes osteo/odontogenic differentiation in stem cells from the apical papilla by inhibiting PI3K/AKT pathway

Fibroblast growth factor 2 (FGF2) is a crucial factor in odontoblast differentiation and dentin matrix deposition, which facilitates pulpodentin repair and regeneration. Nevertheless, the specific biological function of FGF2 in odontoblastic differentiation remains unclear because it is controlled by complex signalling pathways. This study aimed to investigate the mechanism underlying the effect of FGF2 on osteo/odontogenic differentiation of stem cells from the apical papilla (SCAP). SCAP were pretreated with conditioned media containing FGF2 for 1 week, followed by culturing in induced differentiation medium for another week. RNA sequencing (RNA-seq) combined with quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to evaluate the pathways affected by FGF2 in SCAP. Osteo/odontogenic differentiation of SCAP was determined using Alizarin red S staining, alkaline phosphatase staining, RT-qPCR, and western blotting. Pretreatment with FGF2 for 1 week increased the osteo/odontogenic differentiation ability of SCAP. RNA-seq and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that phosphatidylinositol 3-kinase (PI3K)/AKT signalling is involved in the osteogenic function of FGF2. RT-qPCR results indicated that SCAP expressed FGF receptors, and western blotting showed that p-AKT was reduced in FGF2-pretreated SCAP. The activation of the PI3K/AKT pathway partially reversed the stimulatory effect of FGF2 on osteo/odontogenic differentiation of SCAP. Our findings suggest that pretreatment with FGF2 enhances the osteo/odontogenic differentiation ability of SCAP by inhibiting the PI3K/AKT pathway.

NLRP3 inflammasome activation contributes to the development of the pro-fibrotic phenotype of lung fibroblasts

Idiopathic pulmonary fibrosis (IPF) is an irreversible progressive interstitial lung disease of unknown cause. The poorly understood pathophysiology of IPF poses substantial challenges to the development of effective anti-lung fibrotic drugs. The NLRP3 inflammasome, a key component of the innate immune system, has recently been linked to the pathogenesis of lung fibrosis. However, the specific contributions of NLRP3 inflammasomes to determination of the pro-fibrotic phenotype of lung fibroblasts, which play a central role in the production of extracellular matrix protein, remain to be investigated. Therefore, the present study was performed to elucidate the involvement of NLRP3 inflammasome signalling pathways in modulation of lung fibroblast proliferation and differentiation. We found that activation of NLRP3 inflammasomes increased in lung fibroblasts derived from individuals with pulmonary fibrosis and in normal lung fibroblasts stimulated with transforming growth factor β and platelet-derived growth factor. Importantly, blockage of NLRP3 inflammasome signalling, either by gene silencing of NLRP3 or using pharmacological inhibitors of NLRP3, caspase-1, or IL-1 receptor, inhibited the proliferation, differentiation, and extracellular matrix protein synthesis of activated lung fibroblasts. Moreover, induction of the reactive oxygen species/thioredoxin-interacting protein axis, an upstream signalling pathway of NLRP3 inflammasomes, was essential for maintenance of the pro-fibrotic phenotype of lung fibroblasts. Interestingly, treatments with pharmacological inhibitors of NLRP3 inflammasomes prevented the progression of bleomycin-induced pulmonary fibrosis in mice. Collectively, these findings suggest that aberrant activation of NLRP3 inflammasomes is a critical event in the pathogenesis of IPF and that targeting NLRP3 inflammasomes may serve as a therapeutic strategy for IPF.

Local photo-crosslinking of native tissue matrix regulates cell function.

Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study cell function. However, the initiation of fibrosis has largely been overlooked, due to the challenges in recapitulating early fibrotic lesions within the native extracellular microenvironment. Using visible light mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo murine and human tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell spreading, differentiation and extracellular matrix remodeling. However, inhibition of cytoskeletal tension or integrin engagement reduced epithelial cell spreading and differentiation, resulting in alveolar epithelial cell dedifferentiation and reduced extracellular matrix deposition. Our findings emphasize the role of local extracellular matrix crosslinking and remodeling in early-stage tissue fibrosis and have implications for ex vivo disease modeling and applications to other tissues.

Advancement of DDR1 and DDR2 Inhibitors: Therapeutic Potential of Bioactive Compounds, Designing Strategies, and Structure‐Activity Relationship (SAR)

AbstractDDR1 and DDR2 are nonintegrin collagen receptors in the receptor tyrosine kinase family. Both DDRs bind to various collagen types and perform crucial functions in embryo development. DDRs are different from other receptor tyrosine kinases due to their interaction with extracellular matrix components and unusual activation kinetics. DDR regulates cell migration, survival, proliferation, differentiation, and extracellular matrix remodeling. Dysregulated DDR function is linked to the advancement of several human illnesses, including fibrosis, arthritis, neurodegenerative diseases, and cancer. DDRs play a vital role in disease progression and development. Therefore, the use of DDR inhibitors represents a promising therapeutic strategy, particularly for disorders with limited therapy alternatives. In recent years, DDRs have been regarded as attractive targets for drug development, as evidenced by a significant rise in research in this field. The current review illustrates about recent advancement of small molecules, their designing strategies and structure‐activity relationship. The DDR inhibitors can contain various core structures such as pyrimidine, phthalazine, pyrazole, pyrazine, imidazo[1,2‐a]sspyrazine, quinazoline, and thieno[3,2‐b]pyridin‐7‐yl derivatives. Furthermore, based on the constructive analysis of the published derivatives, we found that the majority of the powerful compounds have a similar scaffold (amide linker, hydrophobic tail, hinge binder with or without spacer). Among the different literature, the most potent compounds 4 (imidazo[1,2‐a]pyrazine), 5 (pyridine), 19 (pyridine), and 24 (quinazoline) displayed potent activity against DDR1 with IC50 values ranging from 2.26 – 4.67 nM, while DDR2 IC50 values ranging from 3.2 – 7.29 nM. This approach will help medicinal chemists to refine and develop novel small molecules targeting DDR1 and DDR2.

An approximate solution of the Blasius problem using spectral method

This paper aims at finding the numerical approximation of a classical Blasius flat plate problem using spectral collocation method. This technique is based on Chebyshev pseudospectral approach that involves the solution is approximated using Chebyshev polynomials, which are orthogonal polynomials defined on the interval [−1, 1]. The Chebyshev pseudospectral method employs Chebyshev- Gauss- Lobatto points, the extrema of the Chebyshev polynomials. The differential equation is approximated as a sum of Chebyshev polynomials. A differentiation matrix, based on these polynomials and their derivatives at the collocation points, transforms the differential equation into a system of algebraic equations. By evaluating the differential equation at these points and applying boundary conditions, the original boundary value problem reduced the solution to the solution of a system of algebraic equations. Solving for the coefficients of the polynomials yields the numerical approximation of the solution. The implementation of this method is carried out in Mathematica and its validity is ensured by comparing it with a built in MATLAB numerical routine called bvp4c.

Guizhi Fuling Wan attenuates tetrachloromethane-induced hepatic fibrosis in rats via PTEN/AKT/mTOR signaling pathway

Ethnopharmacological relevanceTreatment options for hepatic fibrosis, a prevalent liver condition closely linked to cirrhosis, are currently limited. While Guizhi Fuling Wan (GFW), a pill derived from traditional Chinese herbs, has been reported to possess hepatoprotective properties, its therapeutic effect and mechanism in hepatic fibrosis remain elusive. Aim of the studyThis study aimed to evaluate the anti-fibrotic impact of GFW and its underlying mechanisms in both in vivo and in vitro settings. Materials and methodsTetrachloromethane (CCl4) was used to induce hepatic fibrosis in male rats. In vitro, activation of hepatic stellate cells (HSCs) was triggered by platelet-derived growth factor-BB (PDGF-BB). In vivo, liver function, pathological alterations, and HSC activation were evaluated. Additionally, the impact of GFW on the activated phenotypes of Lieming Xu-2 (LX-2) cells was examined in vitro. Network pharmacology was employed to identify the potential targets of GFW in hepatic fibrosis. Lastly, the impact of GFW on the PTEN/AKT/mTOR pathway and PTEN ubiquitination in HSCs was investigated. ResultsGFW alleviated CCl4-induced liver damage and scarring in rats in a dose-dependent manner and suppressed HSC activation in vivo. Moreover, GFW inhibited the proliferation, migration, differentiation, and extracellular matrix (ECM) production of activated HSCs in vitro. GFW also promoted autophagy and apoptosis of HSCs. Meanwhile, network pharmacology and in vitro studies suggested that GFW inhibits the AKT/mTOR pathway by preventing PTEN degradation by suppressing ubiquitination. ConclusionGFW attenuates Ccl4-induced hepatic fibrosis in male rats by regulating the PTEN/AKT/mTOR signaling pathway, positioning it as a potential candidate for the treatment of hepatic fibrosis.

Meniscal Repair with ArthroZheal® an Autologous Bioactive Fibrin Scaffold. A New Technique and Treatment Option.

Injuries of the meniscus often lead to changes in joint biomechanics, which affect the load distribution and contact stresses. The menisci consist of a peripheral vascular region (red zone) and an inner avascular region (white zone). The blood supply plays an important role in the healing of meniscal tears. Surgical treatment of such lesions includes meniscectomy/meniscoplasty and repair, depending on the type of injury, where "meniscoplasty" refers to the treatment modality that occurs under coblation. The application of Autologous Bioactive Matrix (ABM) has been shown to promote healing in such lesions. In addition, a special type of PRF (ArthroZheal®, Vivostat A/S, Allerød, Denmark) has been demonstrated to have healing effects in extracellular matrix synthesis and cell proliferation, as well as regenerative and remodeling effects. This autologous product can be applied directly at the meniscal repair site. We performed a prospective study on meniscus repair with ArthroZheal® alone (plus meniscoplasty) and ArthroZheal® together with an all-inside suturing technique using the STAR AccurFix Meniscal Repair Device system (STAR Sports Medicine, Beijing, China), depending on the type and the site of the lesion. One hundred twenty knees (110 patients) were identified through the use of clinical examination and MRI scan. The study took place between January 2023 and August 2023. Two groups were created: GROUP A was treated only with ArthroZheal®(plus meniscoplasty) and GROUP B was treated with a combination of ArthroZheal® and an all-inside suturing technique (STAR AccurFix). Pre- and postoperative grading was performed with the International Knee Documentation Committee (IKDC) score and the Tegner Activity Level Scale (Tegner Score). The results with both treatment methods were excellent and meniscus restoration has been documented on MRIs conducted 6 months post-op. In 15 patients, 2nd-look arthroscopy was performed through a nanoscope on an outpatient basis, and showed meniscal healing and remodeling. Tegner scores and IKDC scores in both groups showed significant improvement. Meniscal repair should be performed at all costs to maintain meniscal integrity and prevent long-term degenerative changes. New treatment methods include orthobiologics and all-inside suturing techniques. The main idea is to apply an autologous biological scaffold which is able to carry cells into the meniscal lesion and to allow their differentiation, proliferation, and extracellular matrix synthesis to produce a meniscal-like tissue. Our results suggest that the application of autologous ABM (ArthroZheal®) for the treatment of such lesions by means of dry arthroscopy results in better MRI, pain management and functional results at 3 months post-op, and these improvements can persist for up to 6 months.

Comprehensive analysis of the REST transcription factor regulatory networks in IDH mutant and IDH wild-type glioma cell lines and tumors

The RE1-silencing transcription factor (REST) acts either as a repressor or activator of transcription depending on the genomic and cellular context. REST is a key player in brain cell differentiation by inducing chromatin modifications, including DNA methylation, in a proximity of its binding sites. Its dysfunction may contribute to oncogenesis. Mutations in IDH1/2 significantly change the epigenome contributing to blockade of cell differentiation and glioma development. We aimed at defining how REST modulates gene activation and repression in the context of the IDH mutation-related phenotype in gliomas. We studied the effects of REST knockdown, genome wide occurrence of REST binding sites, and DNA methylation of REST motifs in IDH wild type and IDH mutant gliomas. We found that REST target genes, REST binding patterns, and TF motif occurrence proximal to REST binding sites differed in IDH wild-type and mutant gliomas. Among differentially expressed REST targets were genes involved in glial cell differentiation and extracellular matrix organization, some of which were differentially methylated at promoters or gene bodies. REST knockdown differently impacted invasion of the parental or IDH1 mutant glioma cells. The canonical REST-repressed gene targets showed significant correlation with the GBM NPC-like cellular state. Interestingly, results of REST or KAISO silencing suggested the interplay between these TFs in regulation of REST-activated and repressed targets. The identified gene regulatory networks and putative REST cooperativity with other TFs, such as KAISO, show distinct REST target regulatory networks in IDH-WT and IDH-MUT gliomas, without concomitant DNA methylation changes. We conclude that REST could be an important therapeutic target in gliomas.

Construction of Fractional Pseudospectral Differentiation Matrices with Applications

Differentiation matrices are an important tool in the implementation of the spectral collocation method to solve various types of problems involving differential operators. Fractional differentiation of Jacobi orthogonal polynomials can be expressed explicitly through Jacobi–Jacobi transformations between two indexes. In the current paper, an algorithm is presented to construct a fractional differentiation matrix with a matrix representation for Riemann–Liouville, Caputo and Riesz derivatives, which makes the computation stable and efficient. Applications of the fractional differentiation matrix with the spectral collocation method to various problems, including fractional eigenvalue problems and fractional ordinary and partial differential equations, are presented to show the effectiveness of the presented method.

A new strategy based on the logarithmic Chebyshev cardinal functions for Hadamard time fractional coupled nonlinear Schrödinger–Hirota equations

In this research, the Hadamard fractional derivative is used to define the time fractional coupled nonlinear Schrödinger–Hirota equations. The logarithmic Chebyshev cardinal functions, as a new category of cardinal functions, are introduced to build a numerical method to solve this system. To do this, the Hadamard fractional differentiation matrix of these functions is obtained. In the developed method, by considering a hybrid approximation of the problem’s solution using the logarithmic Chebyshev cardinal functions (for the temporal variable) and classical Chebyshev cardinal polynomials (for the spatial variable), and employing the interpolation property of these basis functions, along with the expressed derivative matrix, solving the fractional system turns into obtaining the solution of an algebraic system of equations. Two numerical examples are investigated to acknowledge the high accuracy of the introduced procedure.

Meta-analysis of differential gene expression in lower motor neurons isolated by laser capture microdissection from post-mortem ALS spinal cords.

ALS is a fatal neurodegenerative disease for which underlying mechanisms are incompletely understood. The motor neuron is a central player in ALS pathogenesis but different transcriptome signatures have been derived from bulk analysis of post-mortem tissue and iPSC-derived motor neurons (iPSC-MNs). This study performed a meta-analysis of six gene expression studies (microarray and RNA-seq) in which laser capture microdissection (LCM) was used to isolate lower motor neurons from post-mortem spinal cords of ALS and control (CTL) subjects. Differentially expressed genes (DEGs) with consistent ALS versus CTL expression differences across studies were identified. The analysis identified 222 ALS-increased DEGs (FDR <0.10, SMD >0.80) and 278 ALS-decreased DEGs (FDR <0.10, SMD < -0.80). ALS-increased DEGs were linked to PI3K-AKT signaling, innate immunity, inflammation, motor neuron differentiation and extracellular matrix. ALS-decreased DEGs were associated with the ubiquitin-proteosome system, microtubules, axon growth, RNA-binding proteins and synaptic membrane. ALS-decreased DEG mRNAs frequently interacted with RNA-binding proteins (e.g., FUS, HuR). The complete set of DEGs (increased and decreased) overlapped significantly with genes near ALS-associated SNP loci (p < 0.01). Transcription factor target motifs with increased proximity to ALS-increased DEGs were identified, most notably DNA elements predicted to interact with forkhead transcription factors (e.g., FOXP1) and motor neuron and pancreas homeobox 1 (MNX1). Some of these DNA elements overlie ALS-associated SNPs within known enhancers and are predicted to have genotype-dependent MNX1 interactions. DEGs were compared to those identified from SOD1-G93A mice and bulk spinal cord segments or iPSC-MNs from ALS patients. There was good correspondence with transcriptome changes from SOD1-G93A mice (r ≤ 0.408) but most DEGs were not differentially expressed in bulk spinal cords or iPSC-MNs and transcriptome-wide effect size correlations were weak (bulk tissue: r ≤ 0.207, iPSC-MN: r ≤ 0.037). This study defines a robust transcriptome signature from LCM-based motor neuron studies of post-mortem tissue from ALS and CTL subjects. This signature differs from those obtained from analysis of bulk spinal cord segments and iPSC-MNs. Results provide insight into mechanisms underlying gene dysregulation in ALS and highlight connections between these mechanisms, ALS genetics, and motor neuron biology.

A Review of Stem Cell Attributes Derived from the Oral Cavity

Oral cavity stem cells (OCSCs) have been the focus of intense scientific efforts due to their accessibility and stem cell properties. The present work aims to compare the different characteristics of 6 types of dental stem cells derived from the oral cavity: dental pulp stem cells (DPSC), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSC), stem cells from the apical papilla (SCAP), bone marrow mesenchymal stem cells (BMSC), and gingival mesenchymal stem cells (GMSC). Using immunofluorescence and real-time polymerase chain reaction techniques, we analysed the cells for stem cell, differentiation, adhesion, and extracellular matrix markers; the ability to proliferate in vitro; and multilineage differentiation potential. Markers such as vimentin, CD44, alkaline phosphatase, CD146, CD271, CD49f, Oct 3/4, Sox 9, FGF7, nestin, and BMP4 showed significant differences in expression levels, highlighting the heterogeneity and unique characteristics of each cell type. At the same time, we confirmed that all cell types successfully differentiated into osteogenic, chondrogenic, or adipose lineages, with different readiness. In conclusion, our study reveals the distinct properties and potential applications of various dental-derived stem cells. These findings contribute to a deeper understanding of OCSCs and their significance in future clinical applications.