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This article is a tribute to Lewis Wolpert and his ideas on the occasion of the recent 50th anniversary of the publication of his article 'Positional Information and the Spatial Pattern of Differentiation'. This tribute relates to another one of his ideas: his early 'Progress Zone' timing model for limb development. Recent evidence is reviewed showing a mechanism sharing features with this model patterning the main body axis in early vertebrate development. This tribute celebrates the golden era of Developmental Biology.

Ergosterol peroxide is a natural compound of the steroid family found in many fungi, and it possesses antioxidant, anti-inflammatory, anticancer and antiviral activities. The anti-obesity activity of several edible and medicinal mushrooms has been reported, but the effect of mushroom-derived ergosterol peroxide on obesity has not been studied. Therefore, we analyzed the effect of ergosterol peroxide on the inhibition of triglyceride synthesis at protein and mRNA levels and differentiation of 3T3-L1 adipocytes. Ergosterol peroxide inhibited lipid droplet synthesis of differentiated 3T3-L1 cells, expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAT/enhancer-binding protein alpha (C/EBPα), the major transcription factors of differentiation, and also the expression of sterol regulatory element-binding protein-1c (SREBP-1c), which promotes the activity of PPARγ, resulting in inhibition of differentiation. It further inhibited the expression of fatty acid synthase (FAS), fatty acid translocase (FAT), and acetyl-coenzyme A carboxylase (ACC), which are lipogenic factors. In addition, it inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) involved in cell proliferation and activation of early differentiation transcription factors in the mitotic clonal expansion (MCE) stage. As a result, ergosterol peroxide significantly inhibited the synthesis of triglycerides and differentiation of 3T3-L1 cells, and is, therefore, a possibile prophylactic and therapeutic agent for obesity and related metabolic diseases., Competing Interests: The authors declare no conflict of interest.

Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system capable of killing virus-infected cells and/or cancer cells. The commonly used NK cells for therapeutic applications include primary NK cells and immortalized NK cell lines. However, primary NK cell therapy faces limitations due to its restricted proliferation capacity and challenges in stable storage. Meanwhile, the immortalized NK-92 cell line requires irradiation prior to infusion, which reduces its cytotoxic activity, providing a ready-made alternative and overcoming these bottlenecks. Recent improvements in differentiation protocols for iPSC-derived NK cells have facilitated the clinical production of iPSC-NK cells. Moreover, iPSC-NK cells can be genetically modified to enhance tumor targeting and improve the expansion and persistence of iPSC-NK cells, thereby achieving more robust antitumor efficacy. This paper focuses on the differentiation-protocols efforts of iPSC-derived NK cells and the latest progress in iPSC-NK cell therapy. Additionally, we discuss the current challenges faced by iPSC-NK cells and provide an outlook on future applications and developments.

The extracellular matrix is an organized three-dimensional network of protein-based molecules and other macromolecules that provide structural and biochemical support to tissues. Depending on its biochemical and structural properties, the extracellular matrix influences cell adhesion and signal transduction and, in general, can influence cell differentiation and proliferation through specific mechanisms of chemical and mechanical sensing. The development of body tissues during ontogenesis is accompanied by changes not only in cells but also in the composition and properties of the extracellular matrix. Similarly, tumor development in carcinogenesis is accompanied by a continuous change in the properties of the extracellular matrix of tumor cells, called 'oncomatrix', as the tumor matures, from the development of the primary focus to the stage of metastasis. In this paper, the characteristics of the composition and properties of the extracellular matrix of tumor tissues are considered, as well as changes to the composition and properties of the matrix during the evolution of the tumor and metastasis. The extracellular matrix patterns of tumor tissues can be used as biomarkers of oncological diseases as well as potential targets for promising anti-tumor therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: High-grade serous ovarian cancer (HGSC) has a high heterogeneity both among patients and within a single tumor. Four molecular subtypes of HGSC were previously described. These studies were based on analysis of several types of microarrays. Then, classifiers were created based on these results to determine the molecular subtype. When developing these classifiers, the application to high-throughput sequencing data, especially single-cell data, was not considered. In this paper, we created OVsignGenes, a neural network model for determining the HGSC subtype that can process bulk RNA-Seq or single-cell RNA-Seq data, including spatial transcriptomic data. Background/Objectives: High-grade serous carcinomas (HGSCs) are highly heterogeneous tumors, both among patients and within a single tumor. Differences in molecular mechanisms significantly describe this heterogeneity. Four molecular subtypes have been previously described by the Cancer Genome Atlas Consortium: differentiated, immunoreactive, mesenchymal, and proliferative. These subtypes may have varying degrees of progression, relapse-free survival, and overall survival, as well as response to therapy. The precise determination of these subtypes is certainly necessary both for diagnosis and future development of targeted therapies within personalized medicine. Methods: In this study, we analyzed gene expression data based on bulk RNA-seq, scRNA-seq, and spatial transcriptomic data from six cohorts (totaling 535 samples, including 60 single-cell samples). Differential expression analysis was performed using the edgeR package. The KEGG database and GSVA package were used for pathways enrichment analysis. As a predictive model, a deep neural network was created using the keras and tensorflow libraries. Results: We identified 357 differentially expressed genes among the four subtypes: 96 differentiated, 33 immunoreactive, 91 mesenchymal, and 137 proliferative. Based on these, we created OVsignGenes, a neural network model resistant to the effects of platform (test dataset AUC = 0.969). We then ran data from five more cohorts through our model, including scRNA-seq and spatial transcriptomics. Conclusions: Because the differentiated subtype is located at the intersection of the other three subtypes based on PCA and does not have a unique profile of differentially expressed genes or enriched pathways, it can be considered an initiating subtype of tumor that will develop into one of the three other subtypes. [ABSTRACT FROM AUTHOR]

The debate about what causes the generation of form and structure in embryological development goes back to antiquity. Most recently, it has focused on the divergent views as to whether the generation of patterns and form in development is a largely self-organized process or is mainly determined by the genome, in particular, complex developmental gene regulatory processes. This paper presents and analyzes pertinent models of pattern formation and form generation in a developing organism in the past and the present, with a special emphasis on Alan Turing's 1952 reaction–diffusion model. I first draw attention to the fact that Turing's paper remained, at first, without a noticeable impact on the community of biologists because purely physical–chemical models were unable to explain embryological development and often also simple repetitive patterns. I then show that from the year 2000 and onwards, Turing's 1952 paper was increasingly cited also by biologists. The model was updated to include gene products and now seemed able to account for the generation of biological patterns, though discrepancies between models and biological reality remained. I then point out Eric Davidson's successful theory of early embryogenesis based on gene-regulatory network analysis and its mathematical modeling that not only was able to provide a mechanistic and causal explanation for gene regulatory events controlling developmental cell fate specification but, unlike reaction–diffusion models, also addressed the effects of evolution and organisms' longstanding developmental and species stability. The paper concludes with an outlook on further developments of the gene regulatory network model. [ABSTRACT FROM AUTHOR]

Vascular smooth muscle cells (SMCs) can transition between a quiescent contractile or "differentiated" phenotype and a "proliferative-dedifferentiated" phenotype in response to environmental cues, similar to what in occurs in the wound healing process observed in fibroblasts. When dysregulated, these processes contribute to the development of various lung and cardiovascular diseases such as Chronic Obstructive Pulmonary Disease (COPD). Long non-coding RNAs (lncRNAs) have emerged as key modulators of SMC differentiation and phenotypic changes. In this study, we examined the expression of lncRNAs in primary human pulmonary artery SMCs (hPASMCs) during cell-to-cell contact-induced SMC differentiation. We discovered a novel lncRNA, which we named Differentiation And Growth Arrest-Related lncRNA ( DAGAR ) that was significantly upregulated in the quiescent phenotype with respect to proliferative SMCs and in cell-cycle-arrested MRC5 lung fibroblasts. We demonstrated that DAGAR expression is essential for SMC quiescence and its knockdown hinders SMC differentiation. The treatment of quiescent SMCs with the pro-inflammatory cytokine Tumor Necrosis Factor (TNF), a known inducer of SMC dedifferentiation and proliferation, elicited DAGAR downregulation. Consistent with this, we observed diminished DAGAR expression in pulmonary arteries from COPD patients compared to non-smoker controls. Through pulldown experiments followed by mass spectrometry analysis, we identified several proteins that interact with DAGAR that are related to cell differentiation, the cell cycle, cytoskeleton organization, iron metabolism, and the N-6-Methyladenosine (m6A) machinery. In conclusion, our findings highlight DAGAR as a novel lncRNA that plays a crucial role in the regulation of cell proliferation and SMC differentiation. This paper underscores the potential significance of DAGAR in SMC and fibroblast physiology in health and disease.

Stem cells possess the ability to differentiate into different lineages and the ability to self-renew, thus representing an excellent tool for regenerative medicine. They can be isolated from different tissues, including the adipose tissue. Adipose tissue and human adipose-derived stem cells (hADSCs) are privileged candidates for regenerative medicine procedures or other plastic reconstructive surgeries. The cellular environment is able to influence the fate of stem cells residing in the tissue. In a previous study, we exposed hADSCs to an exhausted medium of a breast cancer cell line (MCF-7) recovered at different days (4, 7, and 10 days). In the same paper, we inferred that the medium was able to influence the behaviour of stem cells. Considering these results, in the present study, we evaluated the expression of the major genes related to adipogenic and osteogenic differentiation. To confirm the gene expression data, oil red and alizarin red colorimetric assays were performed. Lastly, we evaluated the expression of miRNAs influencing the differentiation process and the proliferation rate, maintaining a proliferative state. The data obtained confirmed that cells exposed to the medium maintained a stem and proliferative state that could lead to a risky proliferative phenotype.

Stem cells are widely used in scientific research because of their ability to self-renew and differentiate into a variety of specialized cell types needed for body functions. However, the self-renewal and differentiation of stem cells are regulated by various stimuli, with mechanical stimulation being particularly notable due to its ability to mimic the physical environment in the body. This study systematically collected 2638 research papers published between 1994 and 2024, employing tools such as VOSviewer, CiteSpace, and GraphPad Prism to uncover research hotspots, publication trends, and collaboration networks. The results indicate a yearly increase in global research on the shear stress stimulation of stem cells, with significant contributions from the United States and China in terms of research investment and output. Future research directions include a deeper understanding of the mechanisms underlying mechanical stimulation's effects on stem cell differentiation, the development of new materials and scaffold designs to better replicate the natural cellular environment, and advancements in regenerative medicine. Despite considerable progress, challenges remain in translating basic research findings into clinical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Biliary tract malignancies, including cholangiocarcinoma (CCA) and gallbladder neoplasms, present intricate challenges in diagnosis and treatment. This comprehensive overview highlights the diversity of CCA subtypes, their genetic underpinnings, and the pivotal role of etiological factors. Despite diagnostic complexities, advancements in genomic sequencing reveal promising therapeutic targets, such as FGFR2 alterations and IDH1 mutations. Dr. James Cleary's insights underscore the potential of these targets in reshaping the treatment landscape. This paper provides insights into the conventional understanding of biliary tract malignancies and emphasizes the critical need for ongoing research to optimize outcomes in this challenging cancer subtype. By elucidating diverse FGFR2 alterations and the potential of IDH1 inhibition, the aim is to pave the way for targeted therapeutic interventions. As we delve deeper into understanding the intricate complexities of biliary tract malignancies, this research seeks to drive precision medicine forward, offering hope for improved treatment strategies and outcomes in the face of this formidable cancer. This paper provides insights into the conventional understanding of biliary tract malignancies, with a specific focus on cholangiocarcinoma (CCA). We then delve into the groundbreaking ideas presented by Dr. James Cleary. CCA, originating from biliary tree cells, manifests diverse subtypes contingent upon anatomical localization and differentiation status. These variants exhibit discrete genetic aberrations, yielding disparate clinical phenotypes and therapeutic modalities. Intrahepatic, perihilar, and distal CCAs intricately involve distinct segments of the biliary tree, further categorized as well-differentiated, moderately differentiated, or poorly differentiated adenocarcinomas based on their histological differentiation. Understanding the etiological factors contributing to CCA development assumes paramount importance. Stratifying these factors into two groups, those unrelated to fluke infestations (e.g., viral hepatitis and fatty liver conditions) and those associated with fluke infestations (e.g., chronic liver inflammation), facilitates predictive modeling. The epidemiology of CCA exhibits global variability, with Southeast Asia notably displaying higher incidences attributed primarily to liver fluke infestations. Jaundice resulting from bile duct obstruction constitutes a prevalent clinical manifestation of CCA, alongside symptoms like malaise, weight loss, and abdominal pain. Diagnostic challenges arise due to the symptomatic overlap with other biliary disorders. Employing comprehensive liver function tests and imaging modalities such as computed tomography assumes a pivotal role in ensuring accurate diagnosis and staging. However, the definitive confirmation of CCA necessitates a biopsy. Treatment modalities, predominantly encompassing surgical resection and radiation therapy, hold curative potential, although a considerable subset of patients is deemed unresectable upon exploration. Challenges intensify, particularly in cases classified as cancer of unknown origin, underscoring the imperative for early intervention. Advancements in genomic sequencing have revolutionized precision medicine in CCA. Distinct genomic markers, including fibroblast growth factor receptor 2 (FGFR2) alterations and isocitrate dehydrogenase 1 (IDH1) mutations, have emerged as promising therapeutic targets. FGFR2 alterations, encompassing mutations and rearrangements, play pivotal roles in oncogenesis, with FGFR inhibitors demonstrating promise despite identified resistance mechanisms. Similarly, IDH1 inhibitors face challenges with resistance, despite encouraging early clinical trial results, prompting exploration of novel irreversible inhibitors. Dr. James Cleary's illuminating discourse underscores the significance of diverse FGFR2 alterations and the potential of IDH1 inhibition in reshaping the treatment landscape for CCA. These findings unveil critical avenues for targeted therapeutic interventions, emphasizing the critical need for ongoing research to optimize outcomes in this challenging cancer subtype, incorporating innovative insights from Dr. Cleary. [ABSTRACT FROM AUTHOR]

In exploring the challenges of bone repair and regeneration, this review evaluates the potential of bone tissue engineering (BTE) as a viable alternative to traditional methods, such as autografts and allografts. Key developments in biomaterials and scaffold fabrication techniques, such as additive manufacturing and cell and bioactive molecule-laden scaffolds, are discussed, along with the integration of bio-responsive scaffolds, which can respond to physical and chemical stimuli. These advancements collectively aim to mimic the natural microenvironment of bone, thereby enhancing osteogenesis and facilitating the formation of new tissue. Through a comprehensive combination of in vitro and in vivo studies, we scrutinize the biocompatibility, osteoinductivity, and osteoconductivity of these engineered scaffolds, as well as their interactions with critical cellular players in bone healing processes. Findings from scaffold fabrication techniques and bio-responsive scaffolds indicate that incorporating nanostructured materials and bioactive compounds is particularly effective in promoting the recruitment and differentiation of osteoprogenitor cells. The therapeutic potential of these advanced biomaterials in clinical settings is widely recognized and the paper advocates continued research into multi-responsive scaffold systems. [ABSTRACT FROM AUTHOR]

The Bursa of Fabricius, an avian unique humoral immune organ, is instrumental to B cell development. Bursal-derived peptide BP9 fosters B-cell development and formation. Yet, the exact mechanism wherein BP9 impacts B cell differentiation and antigenic presentation remains undefined. In this paper, B cell activation and differentiation in the spleen cells from mice immunized with the AIV vaccine and BP9 were detected following flow cytometry (FCM) analysis. Furthermore, the molecular mechanism of BP9 in B cell differentiation in vivo was investigated with RNA sequencing technology. To verify the potential functional mechanism of BP9 in the antigenic presentation process, the transcriptome molecular basis of chicken macrophages stimulated by BP9 was measured via high-throughput sequencing technology. The results proved that when given in experimental dosages, BP9 notably accelerated total B cells, and enhanced B-cell differentiation and plasma cell production. The gene expression profiles of B cells from mice immunized with 0.01 mg/mL BP9 and AIV vaccine disclosed that 0.01 mg/mL BP9 initiated the enrichment of several biological functions and significantly stimulated key B-cell pathways in immunized mice. Crucially, a total of 4093 differentially expressed genes were identified in B cells with BP9 stimulation, including 943 upregulated genes and 3150 downregulated genes. Additionally, BP9 induced various cytokine productions in the chicken macrophage HD11 cells and activated 9 upregulated and 20 downregulated differential miRNAs, which were involved in various signal and biological processes. Furthermore, BP9 stimulated the activation of multiple transcription factors in HD11 cells, which was related to antigen presentation processes. In summary, these results suggested that BP9 might promote B cell differentiation and induce antigen presentation, which might provide the valuable insights into the mechanism of B cell differentiation upon bursal-derived immunomodulating peptide stimulation and provide a solid experimental groundwork for enhancing vaccine-induced immunity. [ABSTRACT FROM AUTHOR]

During their biosynthesis, Sonic hedgehog (Shh) morphogens are covalently modified by cholesterol at the C-terminus and palmitate at the N-terminus. Although both lipids initially anchor Shh to the plasma membrane of producing cells, it later translocates to the extracellular compartment to direct developmental fates in cells expressing the Patched (Ptch) receptor. Possible release mechanisms for dually lipidated Hh/Shh into the extracellular compartment are currently under intense debate. In this paper, we describe the serum-dependent conversion of the dually lipidated cellular precursor into a soluble cholesteroylated variant (ShhC) during its release. Although ShhC is formed in a Dispatched- and Scube2-dependent manner, suggesting the physiological relevance of the protein, the depalmitoylation of ShhC during release is inconsistent with the previously postulated function of N-palmitate in Ptch receptor binding and signaling. Therefore, we analyzed the potency of ShhC to induce Ptch-controlled target cell transcription and differentiation in Hh-sensitive reporter cells and in the Drosophila eye. In both experimental systems, we found that ShhC was highly bioactive despite the absence of the N-palmitate. We also found that the artificial removal of N-terminal peptides longer than eight amino acids inactivated the depalmitoylated soluble proteins in vitro and in the developing Drosophila eye. These results demonstrate that N-depalmitoylated ShhC requires an N-peptide of a defined minimum length for its signaling function to Ptch. [ABSTRACT FROM AUTHOR]

Simple Summary: There are three subfamilies of human PDZ-LIM family proteins with a total of 10 protein molecules, and PDZ-LIM family proteins serve as a class of scaffolding proteins that assume the function of signal transduction. In this paper, we describe the signature structural domains and major regulatory signals of PDZ-LIM family proteins and provide an overview and discussion of their functions in various tumors and major diseases, aiming to provide directions for future disease (mainly tumor) prevention and drug development. PDZ-LIM family proteins (PDLIMs) are a kind of scaffolding proteins that contain PDZ and LIM interaction domains. As protein–protein interacting molecules, PDZ and LIM domains function as scaffolds to bind to a variety of proteins. The PDLIMs are composed of evolutionarily conserved proteins found throughout different species. They can participate in cell signal transduction by mediating the interaction of signal molecules. They are involved in many important physiological processes, such as cell differentiation, proliferation, migration, and the maintenance of cellular structural integrity. Studies have shown that dysregulation of the PDLIMs leads to tumor formation and development. In this paper, we review and integrate the current knowledge on PDLIMs. The structure and function of the PDZ and LIM structural domains and the role of the PDLIMs in tumor development are described. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Nomogram for Predicting Recurrence-Free Survival of Primary Localized Gastrointestinal Stromal Tumor." The correction states that there were mistakes in Table 2 and Figure 3 of the original publication. The corrected versions of Table 2 and Figure 3 are provided in the document. The authors of the article state that these corrections do not significantly impact the overall findings and conclusions of the paper. [Extracted from the article]

Simple Summary: Androgen receptor-negative prostate cancer is one of the important mechanisms of castration resistant prostate cancer. The application of next generation androgen receptor signaling pathway inhibitors (ARPIs) has led to a gradual increase of AR-negative prostate cancer in the clinic. In this paper, we demonstrated the potential promotional role of ID2 in androgen receptor-negative prostate cancer through extensive bioinformatics analysis and experimental studies. Through transcriptome sequencing and downstream functional enrichment analysis, we found that ID2 can activate neuroendocrine or stemness-related pathways and inhibit androgen receptor signaling pathways. ID2 can activate JAK/STAT signaling pathway as well as FGFR signaling pathway to promote the acquisition of prostate cancer lineage plasticity, which in turn leads to androgen receptor-negative prostate cancer. Through cell function experiments and mouse experiments, we reveal that ID2 can promote prostate cancer evolution. Using transcriptome sequencing and publicly available clinical data, we generated ID2-related gene signatures to help determine clinical prognosis. The use of androgen receptor pathway inhibitors (ARPIs) has led to an increase in the proportion of AR-null prostate cancer, including neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC), but the mechanism underlying this lineage transition has not been elucidated. We found that ID2 expression was increased in AR-null prostate cancer. In vitro and in vivo studies confirmed that ID2 promotes PCa malignancy and can confer resistance to enzalutamide in PCa cells. We generated an ID2 UP50 signature, which is capable of determining resistance to enzalutamide and is valuable for predicting patient prognosis. Functional experiments showed that ID2 could activate stemness-associated JAK/STAT and FGFR signaling while inhibiting the AR signaling pathway. Our study indicates a potentially strong association between ID2 and the acquisition of a stem-like phenotype in adenocarcinoma cells, leading to resistance to androgen deprivation therapy (ADT) and next-generation ARPIs in prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Appendiceal neuroendocrine neoplasms are very rare in pediatric populations; thus, there are no common guidelines or consensus for the management in children and adolescents, and adult protocols are usually adopted. In the present study, we report on 17 patients that underwent appendectomy for appendicitis with incidental diagnosis of a neuroendocrine tumor revealed upon histologic examination. Patients' characteristics, tumor histology, follow-up and outcome are described and compared to data from the literature, with similar results being reported in various studies. Analysis of previous scientific publications on children with appendiceal neuroendocrine neoplasms was performed and recommendations for treatment and follow-up were reviewed. This tumor displays benign behavior and an excellent outcome in children and adolescents; thus, many authors agree that aggressive surgery after the patient's first appendectomy is not necessary and follow-ups can be reduced. Background/Objectives: Appendiceal neuroendocrine neoplasms (ANENs) are usually found incidentally during histology examination after appendectomy for appendicitis. Due to their rarity in pediatric populations, there is no consensus on treatment or follow-up. The analysis of patients with ANENs of our and other studies will increase the understanding of this tumor. Methods: Pediatric patients with ANENs were uniformly managed at our center between 1998 and 2023. Patients' presenting symptoms, surgery, tumor histology, post-surgical work-up, follow-up and outcome were analyzed. Results: Our report describes 17 patients with a diagnosis of ANEN after appendectomy. The median age was 14 years (range of 4–17 years). Tumors were located at the tip of the appendix in 58.8% of cases and only one had a diameter >1 cm. All were well-differentiated tumors with free resection margins. The submucosa was invaded in five cases, muscularis propria in eight and subserosa in four. Post-appendectomy work-up included tumor marker measurement, abdominal ultrasound and computed tomography or magnetic resonance imaging, chest X-ray and octreotide scintigraphy. No residual tumors or metastases were detected. Additional surgery was not necessary. Follow-up was carried out for a median duration of 6 years (range of 1–10 years). Only one patient was lost to follow-up and all other patients are alive without tumor recurrence. Conclusions: The tumor characteristics of our patients confirmed data from the literature. With the lack of a sufficient number of large prospective trials, it is important to add more information to confirm the benign nature and excellent outcome of this tumor, even without additional surgery. Consensus guidelines are needed for ANENs in pediatric populations. [ABSTRACT FROM AUTHOR]

Recent developments in stem cell technologies have made significant advancements in the field of in vitro gametogenesis. In vitro gametogenesis (IVG) is a promising technology where functional gametes (sperm or egg cells) can be generated from stem cells. Scientists have made continuous advancements in the field and successfully derived fully functional sperm from stem cells in mice. Two recent papers generated excitement in IVG by generating bi-maternal and bi-paternal mice from embryonic stem cells (ESCs) and pluripotent stem cells (PSCs). IVG is a promising technology with potential applications that include infertility treatment, fertility preservation, same-sex reproduction, bypassing oocyte depletion in women with advanced age, conservation biology, genetic disorder prevention, and research into human germ cell development. In vitro spermatogenesis (IVS) is the attempt to recreate the process of spermatogenesis in a culture system. Spermatogenesis is essential for male fertility and reproductive health, but it can be impaired by various factors such as genetic defects, environmental toxicants, infections, aging, or medical therapies. Spermatogenesis is a complex and highly regulated process involving multiple cell proliferation, differentiation, and maturation stages. The main challenges of IVS are to provide a suitable microenvironment that mimics the testis in vivo, to support the survival and development of all the cell types involved in spermatogenesis, and to achieve complete and functional spermatogenesis. Therefore, there is a great interest in developing methods to study spermatogenesis in vitro, both for basic research and clinical applications. This review covers recent developments in in vitro spermatogenesis in the past two years. Advances in tissue engineering and regenerative medicine have introduced techniques like ex vivo tissue culture and technologies such as bioreactors, microfluidic systems, and organoids. Bioreactors and microfluidic systems replicate physiological conditions for tissue and cell cultivation, while organoids model organ functionality. Meanwhile, scaffolds, made from various materials, provide essential structural support, guiding the growth and organization of cells into functional tissues. [ABSTRACT FROM AUTHOR]

In response to different degrees of mechanical injury, certain plant cells re-enter the division cycle to provide cells for tissue replenishment, tissue rejoining, de novo organ formation, and/or wound healing. The intermediate tissue formed by the dividing cells is called a callus. Callus formation can also be induced artificially in vitro by wounding and/or hormone (auxin and cytokinin) treatments. The callus tissue can be maintained in culture, providing starting material for de novo organ or embryo regeneration and thus serving as the basis for many plant biotechnology applications. Due to the biotechnological importance of callus cultures and the scientific interest in the developmental flexibility of somatic plant cells, the initial molecular steps of callus formation have been studied in detail. It was revealed that callus initiation can follow various ways, depending on the organ from which it develops and the inducer, but they converge on a seemingly identical tissue. It is not known, however, if callus is indeed a special tissue with a defined gene expression signature, whether it is a malformed meristem, or a mass of so-called "undifferentiated" cells, as is mostly believed. In this paper, I review the various mechanisms of plant regeneration that may converge on callus initiation. I discuss the role of plant hormones in the detour of callus formation from normal development. Finally, I compare various Arabidopsis gene expression datasets obtained a few days, two weeks, or several years after callus induction and identify 21 genes, including genes of key transcription factors controlling cell division and differentiation in meristematic regions, which were upregulated in all investigated callus samples. I summarize the information available on all 21 genes that point to the pre-meristematic nature of callus tissues underlying their wide regeneration potential. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of small agents targeting the B-cell receptor (BCR) pathway revolutionized the treatment of chronic lymphocytic leukemia (CLL). BCR-dependent leukemic cell proliferation is governed by phosphoinositide 3-kinase (PI3K) signaling. The selective PI3Kδ inhibitor idelalisib and dual PI3Kδ/γ inhibitor duvelisib are currently approved by the Food and Drug Administration and European Medicine Agency (only idelalisib) for CLL treatment. Umbralisib, a selective PI3Kδ and casein kinase-1ε (CK1ε) inhibitor, has a different chemical structure and a more favorable safety profile than other PI3K inhibitors (PiK3is); this has enabled its use in combination regimens in clinical trials in first-line and relapsed/refractory CLL. This paper summarizes the development of PI3Kis, their current role and future perspectives in the treatment of patients with CLL. Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is the most important for the development, differentiation and activation of B and T cells. Four isoforms are distinguished within class I (PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ). PI3Kδ expression is limited mainly to the B cells and their precursors, and blocking PI3K has been found to promote apoptosis of chronic lymphocytic leukemia (CLL) cells. Idelalisib, a selective PI3Kδ inhibitor, was the first-in-class PI3Ki introduced into CLL treatment. It showed efficacy in patients with del(17p)/TP53 mutation, unmutated IGHV status and refractory/relapsed disease. However, its side effects, such as autoimmune-mediated pneumonitis and colitis, infections and skin changes, limited its widespread use. The dual PI3Kδ/γ inhibitor duvelisib is approved for use in CLL patients but with similar toxicities to idelalisib. Umbralisib, a highly selective inhibitor of PI3Kδ and casein kinase-1ε (CK1ε), was found to be efficient and safe in monotherapy and in combination regimens in phase 3 trials in patients with CLL. Novel PI3Kis are under evaluation in early phase clinical trials. In this paper we present the mechanism of action, efficacy and toxicities of PI3Ki approved in the treatment of CLL and developed in clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Nc-RNA are microRNA, long-coding RNA, and circulating-RNA. In this review we report most recent data regarding the role of nc-RNA in airway diseases, with a particular attention to microRNA. They are short, endogenously initiated non-coding RNAs involved in post-transcriptionally control gene expression via either translational repression or mRNA degradation. MiRNAs play significant roles in control of cell mechanisms involved in developmental timing and host-pathogen interactions as well as cell differentiation, proliferation, apoptosis, and tumorigenesis. Today the knowledge of the functions of the micro-RNA are of fundamental importance to define the subtypes of inflammatory diseases of the lung and to understand the effectiveness of the treatment. Inflammation of the human lung is mediated in response to different stimuli (e.g., physical, radioactive, infective, pro-allergenic, or toxic) such as cigarette smoke and environmental pollutants. These stimuli often promote an increase in different inflammatory activities in the airways, manifesting themselves as chronic diseases (e.g., allergic airway diseases, asthma chronic bronchitis/chronic obstructive pulmonary disease, or even lung cancer). Non-coding RNA (ncRNAs) are single-stranded RNA molecules of few nucleotides that regulate the gene expression involved in many cellular processes. ncRNA are molecules typically involved in the reduction of translation and stability of the genes of mRNAs s. They regulate many biological aspects such as cellular growth, proliferation, differentiation, regulation of cell cycle, aging, apoptosis, metabolism, and neuronal patterning, and influence a wide range of biologic processes essential for the maintenance of cellular homeostasis. The relevance of ncRNAs in the pathogenetic mechanisms of respiratory diseases has been widely established and in the last decade many papers were published. However, once their importance is established in pathogenetic mechanisms, it becomes important to further deepen the research in this direction. In this review we describe several of most recent knowledge concerning ncRNA (overall miRNAs) expression and activities in the lung. [ABSTRACT FROM AUTHOR]

In this paper, we want to refute the notion that the microbiota should be considered an organ, given that an organ comprises tissue of similar or different embryological origin, while the microbiota is a pool of different microbial species originating individually from single replications and not from a common ancestral cellular element. Hence, we would like to propose a new morphological interpretation of its nature, based on the comprehensive context in which these microbes live: a muco-microbiotic layer of hollow organs, such as the airways and the bowel. The above concept should represent not only a new terminological annotation but also a more accurate portrayal of the physiology and pathophysiology of these organs. Indeed, a better understanding of the biological nature of this part of the human body can help scientists develop more specific experimental protocols, potentially leading to the establishment of better therapeutic strategies. [ABSTRACT FROM AUTHOR]

Multiple studies have demonstrated that various nanoparticles (NPs) stimulate osteogenic differentiation of mesenchymal stem cells (MSCs) and inhibit adipogenic ones. The mechanisms of these effects are not determined. The aim of this paper was to estimate Wharton's Jelly MSCs phenotype and humoral factor production during tri-lineage differentiation per se and in the presence of silicon-gold NPs. Silicon (SiNPs), gold (AuNPs), and 10% Au-doped Si nanoparticles (SiAuNPs) were synthesized by laser ablation, characterized, and studied in MSC cultures before and during differentiation. Humoral factor production ( n = 41) was analyzed by Luminex technology. NPs were nontoxic, did not induce ROS production, and stimulated G-CSF, GM-CSF, VEGF, CXCL1 (GRO) production in four day MSC cultures. During MSC differentiation, all NPs stimulated CD13 and CD90 expression in osteogenic cultures. MSC differentiation resulted in a decrease in multiple humoral factor production to day 14 of incubation. NPs did not significantly affect the production in chondrogenic cultures and stimulated it in both osteogenic and adipogenic ones. The major difference in the protein production between osteogenic and adipogenic MSC cultures in the presence of NPs was VEGF level, which was unaffected in osteogenic cells and 4-9 times increased in adipogenic ones. The effects of NPs decreased in a row AuNPs > SiAuNPs > SiNPs. Taken collectively, high expression of CD13 and CD90 by MSCs and critical level of VEGF production can, at least, partially explain the stimulatory effect of NPs on MSC osteogenic differentiation.

The sika deer is one type of seasonal breeding animal, and the growth of its antler is affected by light signals. Melatonin (MLT) is a neuroendocrine hormone synthesized by the pineal gland and plays an important role in controlling the circadian rhythm. Although the MLT/MT1 (melatonin 1A receptor) signal has been identified during antler development, its physiological function remains almost unknown. The role of MLT on antler growth in vivo and in vitro is discussed in this paper. In vivo, MLT implantation was found to significantly increase the weight of antlers. The relative growth rate of antlers showed a remarkable increased trend as well. In vitro, the experiment showed MLT accelerated antler mesenchymal cell differentiation. Further, results revealed that MLT regulated the expression of Collage type II (Col2a) through the MT1 binding mediated transcription of Yes-associated protein 1 (YAP1) in antler mesenchymal cells. In addition, treatment with vascular endothelial growth factor (VEGF) promoted chondrocytes degeneration by downregulating the expression of Col2a and Sox9 (SRY-Box Transcription Factor 9). MLT effectively inhibited VEGF-induced degeneration of antler chondrocytes by inhibiting the Signal transducers and activators of transcription 5/Interleukin-6 (STAT5/IL-6) pathway and activating the AKT/CREB (Cyclin AMP response-element binding protein) pathway dependent on Sox9 expression. Together, our results indicate that MLT plays a vital role in the development of antler cartilage.

The active form of vitamin D 3 (D 3 ), 1a,25-dihydroxyvitamn D 3 (1,25D 3 ), plays a central role in calcium and bone metabolism. Many structure-activity relationship (SAR) studies of D 3 have been conducted, with the aim of separating the biological activities of 1,25D 3 or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D 3 derivatives with alkoxy groups at C2, by means of the Julia-Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon. The effect of C2 substituents on the stereoselectivity of the coupling reaction was evaluated. The biological activities of the synthesized derivatives were evaluated in an HL-60 cell-based assay. The a-methoxy-substituted C2α-7a was found to show potent cell-differentiating activity, with an ED 50 value of 0.38 nM, being 26-fold more potent than 1,25D 3 .

Glycosylation is a common post-translational modification process of proteins. Mucin-type O-glycosylation is an O-glycosylation that starts from protein serine/threonine residues. Normally, it is involved in the normal development and differentiation of cells and tissues, abnormal glycosylation can lead to a variety of diseases, especially cancer. This paper reviews the normal biosynthesis of mucin-type O-glycans and their role in the maintenance of body health, followed by the mechanisms of abnormal mucin-type O-glycosylation in the development of diseases, especially tumors, including the effects of Tn, STn, T antigen, and different glycosyltransferases, with special emphasis on their role in the development of gastric cancer. Finally, tumor immunotherapy targeting mucin-type O-glycans was discussed. [ABSTRACT FROM AUTHOR]

The medical field has undergone constant development in recent years, and a segment of this development is occupied by biodegradable alloys. The most common alloys in this field are those based on Mg, their main advantage being the ability to degrade gradually, without affecting the patient, and also their ability to be fully absorbed by the human body. One of their most important conditions is the regeneration and replacement of human tissue. Tissue can be engineered in different ways, one being tissue regeneration in vivo, which can serve as a template. In vivo remodeling aims to restore tissue or organs. The key processes of tissue formation and maturation are: proliferation (sorting and differentiation of cells), proliferation and organization of the extracellular matrix, biodegradation of the scaffold-remodeling, and potential tissue growth. In the present paper, the design of the alloys in the Mg-Ca-Y system is formed from the beginning using high-purity components, Mg-98.5%, master-alloys: Mg-Y (70 wt.%–30 wt.%) and Mg-Ca (85 wt.%–15 wt.%). After 8 weeks of implantation, the degradation of the implanted material is observed, and only small remaining fragments are found. At the site of implantation, no inflammatory reaction is observed, but it is observed that the process of integration and reabsorption, over time, accentuates the prosaic surface of the material. The aim of the work is to test the biocompatibility of magnesium-based alloys on laboratory rats in order to use these alloys in medical applications. The innovative parts of these analyses are the chemical composition of the alloys used and the tests performed on laboratory animals. [ABSTRACT FROM AUTHOR]

Over the last few decades, polymers and their composites have shown a lot of promises in providing more viable alternatives to surgical procedures that require scaffolds and implants. With the advancement in biomaterial technologies, it is possible to overcome the limitations of current methods, including auto-transplantation, xeno-transplantation, and the implantation of artificial mechanical organs used to treat musculoskeletal conditions. The risks associated with these methods include complications, secondary injuries, and limited sources of donors. Three-dimensional (3D) printing technology has the potential to resolve some of these limitations. It can be used for the fabrication of tailored tissue-engineering scaffolds, and implants, repairing tissue defects in situ with cells, or even printing tissues and organs directly. In addition to perfectly matching the patient's damaged tissue, printed biomaterials can have engineered microstructures and cellular arrangements to promote cell growth and differentiation. As a result, such biomaterials allow the desired tissue repair to be achieved, and could eventually alleviate the shortage of organ donors. As such, this paper provides an overview of different 3D-printed polymers and their composites for orthopedic applications reported in the literature since 2010. For the benefit of the readers, general information regarding the material, the type of manufacturing method, and the biomechanical tests are also reported. [ABSTRACT FROM AUTHOR]

Simple Summary: Thyroid cancer is the most common endocrine cancer. As tumor-suppressor genes (TSGs) are implicated in many different functions in the organism, their loss in cells in a normal tissue may drive their transformation into cancer cells. TSGs are generally classified into three subclasses: (i) gatekeepers that encode proteins involved in the control of cell cycle and apoptosis; (ii) caretakers that produce proteins implicated in maintaining genomic stability; and (iii) landscapers that, when mutated, create a suitable environment for neoplastic growth. Different inactivation mechanisms may suppress TSG function. Understanding these mechanisms and TSG alterations in thyroid tumors is of great importance for thyroid cancer prognosis, diagnosis, and therapy. The present review paper discusses TSG inactivation mechanisms and alterations in order to help to identify more efficient therapeutic modalities for thyroid cancer management. Thyroid cancer is the most frequent endocrine malignancy and accounts for approximately 1% of all diagnosed cancers. A variety of mechanisms are involved in the transformation of a normal tissue into a malignant one. Loss of tumor-suppressor gene (TSG) function is one of these mechanisms. The normal functions of TSGs include cell proliferation and differentiation control, genomic integrity maintenance, DNA damage repair, and signaling pathway regulation. TSGs are generally classified into three subclasses: (i) gatekeepers that encode proteins involved in cell cycle and apoptosis control; (ii) caretakers that produce proteins implicated in the genomic stability maintenance; and (iii) landscapers that, when mutated, create a suitable environment for malignant cell growth. Several possible mechanisms have been implicated in TSG inactivation. Reviewing the various TSG alteration types detected in thyroid cancers may help researchers to better understand the TSG defects implicated in the development/progression of this cancer type and to find potential targets for prognostic, predictive, diagnostic, and therapeutic purposes. Hence, the main purposes of this review article are to describe the various TSG inactivation mechanisms and alterations in human thyroid cancer, and the current therapeutic options for targeting TSGs in thyroid cancer. [ABSTRACT FROM AUTHOR]

This paper proposes a rapid, label-free, and non-invasive approach for identifying murine cancer cells (B16F10 melanoma cancer cells) from non-cancer cells (C2C12 muscle cells) using machine-learning-assisted Raman spectroscopic imaging. Through quick Raman spectroscopic imaging, a hyperspectral data processing approach based on machine learning methods proved capable of presenting the cell structure and distinguishing cancer cells from non-cancer muscle cells without compromising full-spectrum information. This study discovered that biomolecular information–nucleic acids, proteins, and lipids—from cells could be retrieved efficiently from low-quality hyperspectral Raman datasets and then employed for cell line differentiation. [ABSTRACT FROM AUTHOR]

In this brief Opinion paper, the term "muco-microbiotic layer" is introduced to describe the innermost layer of the intestinal wall. This layer may contribute not only to the overall health of the bowel, but also to that of extraintestinal organs. Its constituents, in terms of soluble molecules and nanovesicles, need to be studied further. Moreover, one can hypothesize the existence of an analogous layer in other organs, such as the airways or some parts of the genital tracts. Further studies on it are needed. [ABSTRACT FROM AUTHOR]

Background: Recently a greater interest in tissue engineering for the treatment of large bone defect has been reported. The aim of the present systematic review and meta-analysis was to investigate the effectiveness of dental pulp stem cells and synthetic block complexes for bone defect treatment in preclinical in vivo articles., Methods: The electronic database and manual search was conducted on Pubmed, Scopus, and EMBASE. The papers identified were submitted for risk-of-bias assessment and classified according to new bone formation, bone graft characteristics, dental pulp stem cells (DPSCs) culture passages and amount of experimental data. The meta-analysis assessment was conducted to assess new bone formation in test sites with DPSCs/synthetic blocks vs. synthetic block alone., Results: The database search identified a total of 348 papers. After the initial screening, 30 studies were included, according to the different animal models: 19 papers on rats, 3 articles on rabbits, 2 manuscripts on sheep and 4 papers on swine. The meta-analysis evaluation showed a significantly increase in new bone formation in favor of DPSCs/synthetic scaffold complexes, if compared to the control at 4 weeks (Mean Diff: 17.09%, 95% CI: 15.16-18.91%, p < 0.01) and at 8 weeks (Mean Diff: 14.86%, 95% CI: 1.82-27.91%, p < 0.01) in rats calvaria bone defects., Conclusion: The synthetic scaffolds in association of DPSCs used for the treatment of bone defects showed encouraging results of early new bone formation in preclinical animal studies and could represent a useful resource for regenerative bone augmentation procedures.

Mesenchymal stem cells (MSCs) have two characteristics of interest for this paper: the ability to self-renew, and the potential for multiple-lineage differentiation into various cells. MSCs have been used in cardiac tissue regeneration for over a decade. Adult cardiac tissue regeneration ability is quite low; it cannot repair itself after injury, as the heart cells are replaced by fibroblasts and lose function. It is therefore important to search for a feasible way to repair and restore heart function through stem cell therapy. Stem cells can differentiate and provide a source of progenitor cells for cardiomyocytes, endothelial cells, and supporting cells. Studies have shown that the concentrations of blood lipids and lipoproteins affect cardiovascular diseases, such as atherosclerosis, hypertension, and obesity. Furthermore, the MSC lipid profiles, such as the triglyceride and cholesterol content, have been revealed by lipidomics, as well as their correlation with MSC differentiation. Abnormal blood lipids can cause serious damage to internal organs, especially heart tissue. In the past decade, the accumulated literature has indicated that lipids/lipoproteins affect stem cell behavior and biological functions, including their multiple lineage capability, and in turn affect the outcome of regenerative medicine. This review will focus on the effect of lipids/lipoproteins on MSC cardiac regenerative medicine, as well as the effect of lipid-lowering drugs in promoting cardiomyogenesis-associated MSC differentiation.

Elucidation of the genomic mechanism that guides the cell-fate change is one of the fundamental issues of biology. We previously demonstrated that whole genome expression is coordinated by the emergence of a critical point at both the cell-population and single-cell levels through the physical principle of self-organized criticality. In this paper, we further examine the genomic mechanism that determines the cell-fate changes from embryo to cancer development. The state of the critical point, acting as the organizing center of the cell fate, determines whether the genome resides in a super- or sub-critical state. In the super-critical state, a specific stochastic perturbation can spread over the entire system through the "genome engine", an autonomous critical-control genomic system, whereas in the sub-critical state, the perturbation remains at a local level. The cell-fate changes when the genome becomes super-critical. We provide a consistent framework to develop a time-evolutional transition theory for the biological regulation of the cell-fate change.

Strontium (Sr) and Magnesium (Mg) are bioactive ions that have been proven to exert a beneficial effect on bone; therefore, their incorporation into bone substitutes has long been viewed as a possible approach to improve tissue integration. However, the thermal instability of Mg-substituted hydroxyapatites has hitherto limited development. We previously described the creation of thermally consolidated porous constructs of Mg,Sr co-substituted apatites with adequate mechanical properties for their clinical use. The present paper describes the biocompatibility of Mg,Sr co-substituted granules using an alveolar-bone-derived primary model of human osteoblasts. Cells were cultured in the presence of different amounts of hydroxyapatite (HA), Sr-substituted HA, or MgSrHA porous macrogranules (with a size of 400–600 microns, obtained by grinding and sieving the sintered scaffolds) for three and seven days, and their viability was measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Protein content was measured using the Lowry assay at the same time points. Cell viability was not impaired by any of the tested compounds. Indirect and direct biocompatibility of these macrogranules was assessed by culturing cells in a previously conditioned medium with HA, SrHA, or MgSrHA, or in the presence of material granules. Osteoblasts formed larger and more numerous nodules around SrHA or MgSrHA granules. Furthermore, cell differentiation was evaluated by alkaline phosphatase staining of primary cells cultured in the presence of HA, SrHA, or MgSrHA granules, confirming the increased osteoconductivity of the doped materials. [ABSTRACT FROM AUTHOR]

This Special Issue of IJMS is devoted to regulation by non-coding RNAs and contains both original research and review articles. An attempt is made to provide an up-to-date analysis of this very fast moving field and cover regulatory roles of both microRNAs and long non-coding RNAs. Multifaceted functions of these RNAs in normal cellular processes, as well as in disease progression, are highlighted. [ABSTRACT FROM AUTHOR]

Lithium-ion cells with a silicon-graphite (SiC) anode and a nickel-rich cathode are potential candidates for use in electric vehicles (EVs) as this material combination offers high energy densities and low costs. Another desired cell specification that results from an intended short charging time for EVs is the robustness against high charge rates. However, high charge rates can lead to the critical aging mechanism of lithium plating, especially at low temperatures. Investigating this issue, this paper presents a test series on cyclic aging with varying charge rates from 0.2C to 1.5C at ambient temperatures of 0 °C and 10 °C applied to a nickel-rich SiC cell candidate. The resulting effects on cell aging are analyzed with a stripping method, whereby reversible lithium plating can be detected, and a differential voltage analysis (DVA), whereby the overall loss of capacity can be attributed to changes in individual characteristic capacities. The results indicate a degradation sensitivity of SiC anodes at elevated charge rates, evidenced by the loss in the silicon-related characteristic capacity, and question the aging robustness of this material combination. [ABSTRACT FROM AUTHOR]

Aspirin (ASA) is one of the most used medications worldwide and has shown various effects on cellular processes, including stem cell differentiation. However, the effect of ASA on adipogenesis of adipose tissue-derived stem cells (ASCs) remains largely unknown. Considering the potential application of ASCs in regenerative medicine and cell-based therapies, this study investigates the effects of ASA on adipogenic differentiation in human ASCs. ASCs were exposed to varying concentrations of ASA (0 µM, 400 µM, and 1000 µM) and evaluated for changes in morphology, migration, and adipogenic differentiation. While ASA exposure did not affect self-renewal potential, migration ability, or cell morphology, it significantly reduced lipid vacuole formation at 1000 µM after 21 days of adipogenic differentiation (p = 0.0025). This visible inhibition correlated with decreased expression of adipogenic markers (PPARG, ADIPOQ, and FABP4) and the proliferation marker MKi67 under ASA exposure in comparison to the control (ns). Overall, the findings demonstrate that ASA inhibits adipogenic differentiation of human ASCs in a dose-dependent manner in vitro, contrasting its known role in promoting osteogenic differentiation. This research highlights ASA's complex effects on ASCs and emphasizes the need for further investigation into its mechanisms and potential therapeutic applications in obesity and metabolic diseases. The inhibitory effects of ASA on adipogenesis should be considered in cell-based therapies using ASCs. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms are central to the regulation of all biological processes. This manuscript reviews the current understanding of diverse epigenetic modifications and their role in the establishment and maintenance of normal skin functions. In healthy skin, these mechanisms allow for the precise control of gene expression, facilitating the dynamic balance between cell proliferation and differentiation necessary for effective barrier function. Furthermore, as the skin ages, alterations in epigenetic marks can lead to impaired regenerative capacity and increased susceptibility to environmental stressors. The interaction between skin microbiota and epigenetic regulation will also be explored, highlighting how microbial communities can influence skin health by modulating the host gene expression. Future research should focus on the development of targeted interventions to promote skin development, resilience, and longevity, even in an ever-changing environment. This underscores the need for integrative approaches to study these complex regulatory networks. [ABSTRACT FROM AUTHOR]

Background and Objectives: Insulin-like growth factor-1 (IGF-1) plays a vital role in various cellular processes, including those involving stem cells. This study evaluated the effects of IGF-1 on cell survival, osteogenic differentiation, and mRNA expression in gingiva-derived mesenchymal stem cell spheroids. Materials and Methods: Using concave microwells, spheroids were generated in the presence of IGF-1 at concentrations of 0, 10, and 100 ng/mL. Cellular vitality was qualitatively assessed using microscopy, while a water-soluble tetrazolium salt–based assay kit quantified cellular viability. Osteogenic differentiation was evaluated via alkaline phosphatase activity and an anthraquinone dye test to measure calcium deposition. Additionally, quantitative polymerase chain reaction (qPCR) analysis was performed to determine the expression of RUNX2 and COL1A1. Results: By day 1, the stem cell spheroids had successfully formed, and their morphology remained stable over the following 7 days. The IGF-1 concentrations tested showed no significant differences in cell viability. Similarly, alkaline phosphatase activity on day 7 revealed no observable changes. However, on day 7, the incorporation of IGF-1 led to an increase in Alizarin Red staining, indicative of enhanced calcium deposition. Notably, an IGF-1 concentration of 100 ng/mL significantly upregulated the expression of COL1A1. Conclusions: These findings suggest that IGF-1 supports the maintenance of cell viability and promotes the expression of COL1A1 in gingiva-derived mesenchymal stem cell spheroids, highlighting its potential role in enhancing osteogenic differentiation. Future research should include long-term studies to evaluate the sustainability of IGF-1-induced effects on stem cell spheroids. [ABSTRACT FROM AUTHOR]

Simple Summary: Everyday use of breast MRI led to an increase in the number of visualized non-mass enhancement whose characterization is still a clinical problem. The aim of this retrospective study was to show whether the visualized non-mass enhancement can be more precisely characterized with the help of delineating non-mass enhancement on subtraction, where it is best seen, and transferring the marked section to the apparent diffusion coefficient map, where it can be quantified. Objectives: This study aimed to investigate whether the apparent diffusion coefficient (ADC) maps values of breast lesions presenting as non-mass enhancement (NME) on MRI could predict benign or malignant pathohistological findings. Materials and Methods: This retrospective single-center study included 136 female patients with NME and corresponding ultrasound correlate and a subsequent ultrasound-guided core needle biopsy. The patients were subdivided into benign or malignant subgroups based on pathology reports, which served as the gold standard. Blinded to the pathological results, two radiologists independently measured the ADC values of the depicted NME using punctate, 10 mm and whole tumor regions of interest (ROIs) wherever applicable. The mean of all measurements was also analyzed and compared with the pathologic subdivision. Results: The sensitivity of whole tumor ROI in detecting benign NME is 91% compared to 74% for 10 mm ROI and 78% for punctate ROI. No significant differences in ADC values were observed when comparing fatty breast tissue and dense breast tissue. Conclusions: There were differences in ADC values between benign and malignant findings using all types of measurements, where the whole tumor ROI was the most sensitive. [ABSTRACT FROM AUTHOR]

Simple Summary: CD79b, a B-cell-specific antigen, is highly expressed in mature B-cell lymphomas, making it a promising therapeutic target. This study employs flow cytometry to assess CD79b in lymph node biopsies from 127 cases of large B-cell lymphomas (LBCLs), compared to benign reactive hyperplasia. We found that LBCLs exhibited lower and heterogeneous CD79b expression, with 18% of cases showing almost exclusively intracellular positivity and, in particular, low surface expression in primary mediastinal B-cell lymphomas. A positive correlation was observed between CD79b expression and surface immunoglobulin light chains. Patients over 60 years old and those with high-risk disease (Revised International Prognostic Index of 3–5) demonstrated higher surface CD79b expression. These findings align with results from the POLARIX study, where the addition of a CD79b-ADC (antibody–drug conjugate) to first-line therapy improved outcomes for patients with similar characteristics. Flow cytometry on tissue biopsies may offer valuable insights into target antigen expression, including CD79b. Background: CD79b is a B-cell-specific antigen that is crucial to the B-cell receptor and is considered a key target for treatment in aggressive B-cell lymphomas. Methods: While immunohistochemical studies have shown widespread expression of CD79b in mature B-cell-derived lymphomas, flow cytometry allows for precise measurement and differentiation between surface and intracellular localization. Results: In our comparative analysis, we discovered that CD79b expression percentages and mean fluorescence intensity (MFI) were lower in a group of 127 cases of aggressive B-cell lymphomas compared to a control group of benign reactive hyperplasia. We also observed significant variability in the surface expression of CD79b among lymphoma cases, with 18% showing predominantly intracellular positivity. There was a strong correlation between the surface expression of CD79b and clonal light chains. Notably, primary mediastinal B-cell lymphomas exhibited significantly lower surface CD79b expression compared to other lymphoma subtypes (median 0.8% IQR 0–48.5 vs. 80% IQR 24–97, p = 0.0005). Furthermore, patients over 60 years old and those with a higher Revised International Prognostic Index (R-IPI) had significantly higher CD79b expression, both of which are associated with a significant benefit from adding an anti-CD79b drug conjugate to first-line chemotherapy in diffuse large B-cell lymphomas. Conclusions: In conclusion, the quantitative flow cytometric analysis of CD79b surface expression in aggressive B-cell lymphomas provides clinically relevant information, highlighting its potential usefulness in guiding therapeutic decisions. [ABSTRACT FROM AUTHOR]

In the fourth paper of this Special Issue, we bridge the theoretical debate on the role of memory and criticality discussed in the three earlier manuscripts, with a review of key concepts in biology and focus on cell-to-cell communication in organismal development. While all living organisms are dynamic complex networks of organization and disorder, most studies in biology have used energy and biochemical exchange to explain cell differentiation without considering the importance of information (entropy) transfer. While all complex networks are mixtures of patterns of complexity (non-crucial and crucial events), it is the crucial events that determine the efficiency of information transfer, especially during key transitions, such as in embryogenesis. With increasing multicellularity, emergent relationships from cell-to-cell communication create reaction–diffusion exchanges of different concentrations of biochemicals or morphogenetic gradients resulting in differential gene expression. We suggest that in conjunction with morphogenetic gradients, there exist gradients of information transfer creating cybernetic loops of stability and disorder, setting the stage for adaptive capability. We specifically reference results from the second paper in this Special Issue, which correlated biophotons with lentil seed germination to show that phase transitions accompany changes in complexity patterns during development. Criticality, therefore, appears to be an important factor in the transmission, transfer and coding of information for complex adaptive system development. [ABSTRACT FROM AUTHOR]

ECM stiffness significantly influences the differentiation of adipose-derived stem cells (ADSCs), with YAP—a key transcription factor in the Hippo signaling pathway—playing a pivotal role. This study investigates the effects of ECM stiffness on ADSC differentiation and its relationship with YAP signaling. Various hydrogel concentrations were employed to simulate different levels of ECM stiffness, and their impact on ADSC differentiation was assessed through material properties, adipocyte-specific gene expression, lipid droplet staining, YAP localization, and protein levels. Our results demonstrated that increasing hydrogel stiffness enhanced adipocyte differentiation in a gradient manner. Notably, inhibiting YAP signaling further increased lipid droplet accumulation, suggesting that ECM stiffness influences adipogenesis by modulating YAP signaling and its cytoplasmic phosphorylation. This study elucidates the molecular mechanisms underlying ECM stiffness-dependent lipid deposition, highlighting YAP's regulatory role in adipogenesis. These findings provide valuable insights into the regulation of cell differentiation and have important implications for tissue engineering and obesity treatment strategies. [ABSTRACT FROM AUTHOR]

The human genome involves six functional arachidonic acid (AA) lipoxygenase (ALOX) genes, and the corresponding enzymes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3, ALOX5) have been implicated in cell differentiations and in the pathogenesis of inflammatory, hyperproliferative, metabolic, and neurological disorders. Humans express two different AA 15-lipoxygenating ALOX isoforms, and these enzymes are called ALOX15 (15-LOX1) and ALOX15B (15-LOX2). Chromosomal localization, sequence alignments, and comparison of the enzyme properties suggest that pig and mouse ALOX15 orthologs (leukocyte-type 12-LOX) on the one hand and rabbit and human ALOX15 orthologs on the other (reticulocyte-type 15-LOX1) belong to the same enzyme family despite their different reaction specificities with AA as a substrate. In contrast, human ALOX12 (platelet-type 12-LOX), as well as pig and mouse ALOX15 (leukocyte-type 12-LOX), belong to different enzyme families, although they exhibit a similar reaction specificity with AA as a substrate. The complex multiplicity of mammalian ALOX isoforms and the controversial enzyme nomenclatures are highly confusing and prompted us to summarize the current knowledge on the biological functions, enzymatic properties, and allosteric regulation mechanisms of mammalian ALOX15, ALOX15B, and ALOX12 orthologs that belong to three different enzyme sub-families. [ABSTRACT FROM AUTHOR]

Autophagy maintains the stability of eukaryotic cells by degrading unwanted components and recycling nutrients and plays a pivotal role in muscle regeneration by regulating the quiescence, activation, and differentiation of satellite cells. Effective muscle regeneration is vital for maintaining muscle health and homeostasis. However, under certain disease conditions, such as aging, muscle regeneration can fail due to dysfunctional satellite cells. Dysregulated autophagy may limit satellite cell self-renewal, hinder differentiation, and increase susceptibility to apoptosis, thereby impeding muscle regeneration. This review explores the critical role of autophagy in muscle regeneration, emphasizing its interplay with apoptosis and recent advances in autophagy research related to diseases characterized by impaired muscle regeneration. Additionally, we discuss new approaches involving autophagy regulation to promote macrophage polarization, enhancing muscle regeneration. We suggest that utilizing cell therapy and biomaterials to modulate autophagy could be a promising strategy for supporting muscle regeneration. We hope that this review will provide new insights into the treatment of muscle diseases and promote muscle regeneration. [ABSTRACT FROM AUTHOR]

Normal neuronal cell differentiation and migration is critical to brain formation, is rapidly occurring as the fetal brain develops, and peaks at the time of the routine ultrasound anatomic survey. Abnormalities in cortical migration can signify an underlying genetic abnormality or other fetal injury that can have a profound impact on future development. Although cortical migration peaks at 20–22 weeks, cortical migration abnormalities are rarely diagnosed at the time of the anatomic survey. We describe three cases of fetal cortical abnormalities in which prenatal ultrasound imaging was instrumental to making a prompt and accurate diagnosis in the mid-trimester and for guiding clinical counseling. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is one of the most commonly diagnosed cancers worldwide and is the second leading cause of cancer-related deaths. In the last decade, significant advances have been made in the development of cell-based models of disease, including for culturing and expanding cells derived from patient biopsy tissue. These advances have led to the development of intestinal organoids, 3D cellular models of the colon, that more accurately represent the disease state and hold the potential to improve our understanding of disease processes. Furthermore, increasing the complexity of these models to include important components, such as the gut microbiome and the stromal compartment with immune cells and vasculature, will provide deeper insight into individual drug responses and lead to better patient outcomes in the future. Despite improvements in participation in population-based screening programme, colorectal cancer remains a major cause of cancer-related mortality worldwide. Targeted interventions are desirable to reduce the health and economic burden of this disease. Two-dimensional monolayers of colorectal cancer cell lines represent the traditional in vitro models for disease and are often used for diverse purposes, including the delineation of molecular pathways associated with disease aetiology or the gauging of drug efficacy. The lack of complexity in such models, chiefly the limited epithelial cell diversity and differentiation, attenuated mucus production, lack of microbial interactions and mechanical stresses, has driven interest in the development of more holistic and physiologically relevant in vitro model systems. In particular, established ex vivo patient-derived explant and patient-derived tumour xenograft models have been supplemented by progress in organoid and microfluidic organ-on-a-chip cultures. Here, we discuss the applicability of advanced culturing technologies, such as organoid systems, as models for colorectal cancer and for testing chemotherapeutic drug sensitivity and efficacy. We highlight current challenges associated with organoid technologies and discuss their future for more accurate disease modelling and personalized medicine. [ABSTRACT FROM AUTHOR]

The epidermis of the skin and skin appendages, such as nails, hair and sebaceous glands, depend on a balance of cell proliferation and terminal differentiation in order to fulfill their functions at the interface of the body and the environment. The differentiation of epithelial cells of the skin, commonly referred to as keratinocytes, involves major remodeling processes that generate metabolically inactive cell remnants serving as building blocks of the epidermal stratum corneum, nail plates and hair shafts. Only sebaceous gland differentiation results in cell disintegration and holocrine secretion. A series of studies performed in the past decade have revealed that the lysosome-dependent intracellular degradation mechanism of autophagy is active during keratinocyte differentiation, and the blockade of autophagy significantly alters the properties of the differentiation products. Here, we present a model for the autophagy-mediated degradation of organelles and cytosolic proteins as an important contributor to cellular remodeling in keratinocyte differentiation. The roles of autophagy are discussed in comparison to alternative intracellular degradation mechanisms and in the context of programmed cell death as an integral end point of epithelial differentiation. [ABSTRACT FROM AUTHOR]

As with all new fields of discovery, work on the biological role of G-quadruplexes (GQs) has produced a number of results that at first glance are quite baffling, sometimes because they do not fit well together, but mostly because they are different from commonly held expectations. Like other classes of flipons, those that form G-quadruplexes have a repeat sequence motif that enables the fold. The canonical DNA motif (G3N1–7)3G3, where N is any nucleotide and G is guanine, is a feature that is under active selection in avian and mammalian genomes. The involvement of G-flipons in genome maintenance traces back to the invertebrate Caenorhabditis elegans and to ancient DNA repair pathways. The role of GQs in transcription is supported by the observation that yeast Rap1 protein binds both B-DNA, in a sequence-specific manner, and GQs, in a structure-specific manner, through the same helix. Other sequence-specific transcription factors (TFs) also engage both conformations to actuate cellular transactions. Noncoding RNAs can also modulate GQ formation in a sequence-specific manner and engage the same cellular machinery as localized by TFs, linking the ancient RNA world with the modern protein world. The coevolution of noncoding RNAs and sequence-specific proteins is supported by studies of early embryonic development, where the transient formation of G-quadruplexes coordinates the epigenetic specification of cell fate. [ABSTRACT FROM AUTHOR]