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Summary: The flowering plant life cycle is completed by an alternation of diploid and haploid generations. The diploid sporophytes produce initial cells that undergo meiosis and produce spores. From haploid spores, male or female gametophytes, which produce gametes, develop. The union of gametes at fertilization restores diploidy in the zygote that initiates a new cycle of diploid sporophyte development. During this complex process, cell fate determination occurs at each of the critical stages and necessarily underpins successful plant reproduction. Here, we summarize available knowledge on the regulatory mechanism of cell fate determination at these critical stages of sexual reproduction, including sporogenesis, gametogenesis, and early embryogenesis, with particular emphasis on regulatory pathways of both male and female gametes before fertilization, and both apical and basal cell lineages of a proembryo after fertilization. Investigations reveal that cell fate determination involves multiple regulatory factors, such as positional information, differential distribution of cell fate determinants, cell‐to‐cell communication, and cell type‐specific transcription factors. These factors temporally and spatially act for different cell type differentiation to ensure successful sexual reproduction. These new insights into regulatory mechanisms underlying sexual cell fate determination not only updates our knowledge on sexual plant reproduction, but also provides new ideas and tools for crop breeding. [ABSTRACT FROM AUTHOR]

T cells develop in the thymus by expressing a diverse repertoire of either αβ‐ or γδ‐T cell receptors (TCR). While many studies have elucidated how TCR signaling and gene expression control T cell ontogeny, the role of nutrient metabolism is just emerging. Here, we discuss how metabolic reprogramming and nutrient availability impact the fate of developing thymic T cells. We focus on how the PI3K/mTOR signaling mediates various extracellular inputs and how this signaling pathway controls metabolic rewiring during highly proliferative and anabolic developmental stages. We highlight the role of the hexosamine biosynthetic pathway that generates metabolites that are utilized for N‐ and O‐linked glycosylation of proteins and how it impacts TCR expression during T cell ontogeny. We consider the dichotomy in metabolic needs during αβ‐ versus γδ‐T cell lineage commitment as well as how metabolism is also coupled to molecular signaling that controls cell fate. [ABSTRACT FROM AUTHOR]

ABSTRACT Mitochondria perform multiple functions within the cell, including the production of ATP and a great deal of metabolic intermediates, while also contributing to the cellular stress response. The majority of mitochondrial proteins are encoded by nuclear genomes, highlighting the importance of mitonuclear communication for sustaining mitochondrial homeostasis and functional. As a crucial part of the intracellular signalling network, mitochondria can impact stem cell fate determinations. Considering the essential function of stem cells in tissue maintenance, regeneration and aging, it is important to understand how mitochondria influence stem cell fate. This review explores the significant roles of mitonuclear communication and mitochondrial proteostasis, highlighting their influence on stem cells. We also examine how mitonuclear interactions contribute to cellular homeostasis, stem cell therapies, and the potential for extending lifespan. [ABSTRACT FROM AUTHOR]

Summary: The root epidermis of tracheophytes consists of hair‐forming cells (HCs) and nonhair cells (NCs). The HC distribution pattern is classified into three types: random (Type I), vertically alternating (Type II), and radial (Type III). Type III is found only in core eudicots and is known to be position‐dependent in superrosids with HCs positioned between two underlying cortical cells. However, the evolution of Type III and the universality of its position dependency in eudicots remain unclear.We surveyed the HC distribution in basal and Type III‐exhibiting core eudicots and conducted genomic analyses to get insight into whether eudicots share the same genetic network to establish Type III.Our survey revealed no canonical Type III in basal eudicots but a reverse Type III, with NCs between two cortical cells and HCs on a single cortical cell, in Papaveraceae of basal eudicots. Type III‐exhibiting species from both superrosids and superasterids showed the canonical position dependency of HCs. However, some key components for Type III determination were absent in the genomes of Papaveraceae and Type III‐exhibiting superasterids.Our findings identify a novel position‐dependent type of HC patterning, reverse Type III, and suggest that Type III emerged independently or diversified during eudicot evolution. [ABSTRACT FROM AUTHOR]

Summary: Arsenic poses a global threat to living organisms, compromising crop security and yield. Limited understanding of the transcriptional network integrating arsenic‐tolerance mechanisms with plant developmental responses hinders the development of strategies against this toxic metalloid.Here, we conducted a high‐throughput yeast one‐hybrid assay using as baits the promoter region from the arsenic‐inducible genes ARQ1 and ASK18 from Arabidopsis thaliana, coupled with a transcriptomic analysis, to uncover novel transcriptional regulators of the arsenic response.We identified the GLABRA2 (GL2) transcription factor as a novel regulator of arsenic tolerance, revealing a wider regulatory role beyond its established function as a repressor of root hair formation. Furthermore, we found that ANTHOCYANINLESS2 (ANL2), a GL2 subfamily member, acts redundantly with this transcription factor in the regulation of arsenic signaling. Both transcription factors act as repressors of arsenic response. gl2 and anl2 mutants exhibit enhanced tolerance and reduced arsenic accumulation. Transcriptional analysis in the gl2 mutant unveils potential regulators of arsenic tolerance.These findings highlight GL2 and ANL2 as novel integrators of the arsenic response with developmental outcomes, offering insights for developing safer crops with reduced arsenic content and increased tolerance to this hazardous metalloid. [ABSTRACT FROM AUTHOR]

Pax‐6 emerges as a critical transcription factor that guides the fate of stem cells towards neural lineages. Its expression influences the differentiation of neural progenitors into diverse neuronal subtypes, glial cells, and other neural cell types. Pax‐6 operates with other regulatory factors to ensure the precise patterning and organization of the developing nervous system. The intricate interplay between Pax‐6 and other signaling pathways, transcription factors, and epigenetic modifiers underpins the complicated balance between stem cell maintenance, proliferation, and differentiation in neuroectodermal and ocular contexts. Dysfunction of Pax‐6 can lead to a spectrum of developmental anomalies, underscoring its importance in these processes. This review highlights the essential role of Pax‐6 expression in neuroectodermal and ocular stem cells, shedding light on its significance in orchestrating the intricate journey from stem cell fate determination to the emergence of diverse neural and ocular cell types. The comprehensive understanding of Pax‐6 function gained from a developmental biology perspective offers valuable insights into normal development and potential therapeutic avenues for neuroectodermal and ocular disorders. [ABSTRACT FROM AUTHOR]

Heterotopic ossification (HO), often arising in response to traumatic challenges, results from the aberrant osteochondral differentiation of mesenchymal stem cells (MSCs). Nevertheless, the impact of trauma‐induced inflammatory exposure on MSC fate determination remains ambiguous. In this study, the cellular diversity within inflammatory lesions is elucidated, comprising MSCs and several innate and adaptive immune cells. It is observed that quiescent MSCs transition into cycling MSCs, subsequently giving rise to chondrogenic (cMSC) and/or osteogenic (oMSC) lineages within the inflammatory microenvironment following muscle or tendon injuries, as revealed through single‐cell RNA sequencing (scRNA‐seq), spatial transcriptome and lineage tracing analysis. Moreover, these investigations demonstrate that neutrophils and natural killer (NK) cells enhance transition of quiescent MSCs into cycling MSCs, which is also controlled by M1 macrophages, a subpopulation of macrophages can also stimulate cMSC and oMSC production from cycling MSCs. Additionally, M2 macrophages, CD4+ and CD8+ T lymphocytes are found to promote chondrogenesis. Further analysis demonstrates that immune cells promotes the activation of signaling transducers and activators of transcription (STAT) pathway and phosphoinositide 3 (PI3K)/protein kinase B (AKT) pathway in MSC proliferation and osteochondral progenitors' production, respectively. These findings highlight the dynamics of MSC fate within the inflammatory lesion and unveil the molecular landscape of osteoimmunological interactions, which holds promise for advancing HO treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT Notch1 and Notch2, transmembrane receptors belonging to the Notch family, are pivotal mediators of intercellular communication and have profound implications including cell fate determination, embryonic development, and tissue homeostasis in various cellular processes. Despite their structural homology, Notch1 and Notch2 exhibit discrete phenotypic characteristics and functional nuances that necessitate their individualized targeting in specific medical scenarios. Aberrant Notch signaling, often driven by the dysregulated activity of one receptor over the other, is implicated under various pathological conditions. Notch1 dysregulation is frequently associated with T‐cell acute lymphoblastic leukemia, whereas Notch2 perturbations are linked to B‐cell malignancies and solid tumors, including breast cancer. Hence, tailored therapeutic interventions that selectively inhibit the relevant Notch receptor need to be devised to disrupt the signaling pathways driving the specific disease phenotype. In this review, we emphasize the importance of distinct tissue‐specific expression patterns, functional divergence, disease‐specific considerations, and the necessity to minimize off‐target effects that collectively underscore the significance of “individualized” targeting for Notch1 and Notch2. This comprehensive review sheds light on the receptor‐specific characteristics of Notch1 and Notch2, providing insights into their roles in cellular processes and offering opportunities for developing tailored therapeutic interventions in the fields of biomedical research and clinical practice. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusion DNA repair plays a major role in maintaining genomic stability, thus limiting the transformation of normal cells into cancer cells. However, in cancer patients treated with DNA‐targeting drugs, DNA repair can decrease efficacy by removing the damage generated by such molecules that is needed to induce pharmacological activity. Inhibiting DNA repair thus represents an interesting approach to potentiating the activity of chemotherapy in this setting.Here, we continue the characterization of an inhibitor of the interaction between Excision Repair Cross‐Complementing Rrodent repair deficiency complementation group 1 (ERCC1) and Xeroderma Pigmentousum group F (XPF) (B9), two key proteins of nucleotide excision repair.We used various cell lines and co‐incubation studies for the determination of cell survival and DNA repair capacities.We show that it is synergistic with other platinum derivatives than previously described, and that synergy is lacking in cells not expressing ERCC1 or XPF. Finally, a series of experiments show that potentiation is observed only in cells expressing wild‐type p53.Our results confirm the mechanism of action of our ERCC1–XPF inhibitor and give important additional data on this approach to enhance the activity of already existing cancer drugs. [ABSTRACT FROM AUTHOR]

Epigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By transcriptional sequence and ATAC analysis, this study identifies that activation of RANK signaling upregulates PRMT6 by epigenetic modification, triggering a metabolic switching from fatty acids oxidation toward glycolysis. Conversely, Prmt6 deficiency reverses this shift, markedly reducing HIF‐1α‐mediated glycolysis and enhancing fatty acid oxidation. Consequently, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss in ovariectomized (OVX) mice. At the molecular level, Prmt6 deficiency reduces asymmetric dimethylation of H3R2 at the promoters of genes including Ppard, Acox3, and Cpt1a, enhancing genomic accessibility for fatty acid oxidation. PRMT6 thus emerges as a metabolic checkpoint, mediating metabolic switch from fatty acid oxidation to glycolysis, thereby supporting osteoclastogenesis. Unveiling PRMT6's critical role in epigenetically orchestrating metabolic shifts in osteoclastogenesis offers a promising target for anti‐resorptive therapy. [ABSTRACT FROM AUTHOR]

Organogenesis, the phase of embryonic development that starts at the end of gastrulation and continues until birth is the critical process for understanding cellular differentiation and maturation during organ development. The rapid development of single‐cell transcriptomics technology has led to many novel discoveries in understanding organogenesis while also accumulating a large quantity of data. To fill this gap, OrganogenesisDB (http://organogenesisdb.com/), which is a comprehensive database dedicated to exploring cell‐type identification and gene expression dynamics during organogenesis, is developed. OrganogenesisDB contains single‐cell RNA sequencing data for more than 1.4 million cells from 49 published datasets spanning various developmental stages. Additionally, 3324 cell markers are manually curated for 1120 cell types across 9 human organs and 4 mouse organs. OrganogenesisDB leverages various analysis tools to assist users in annotating and understanding cell types at different developmental stages and helps in mining and presenting genes that exhibit specific patterns and play key regulatory roles during cell maturation and differentiation. This work provides a critical resource and useful tool for deciphering cell lineage determination and uncovering the mechanisms underlying organogenesis. [ABSTRACT FROM AUTHOR]

A recent study published in Cell by Liu et al. introduced a new dual homologous recombinase‐mediated genetic profiling tracer technique to track lung epithelial cells accurately, shedding light on the regenerative origin and regulatory mechanism of adult alveolar epithelial stem cells. The research highlights the importance of alveolar regeneration for maintaining lung homeostasis and facilitating post‐injury healing, emphasizing the role of club cells and bronchioalveolar stem cells in promoting alveolar regeneration after lung injury. By developing a novel dual homologous recombination tool, the authors were able to identify club cells as the primary source of alveolar stem cell regeneration, offering new insights for lung stem cell therapy and potential treatment approaches for lung damage healing. [Extracted from the article]

The formation of stomata presents a compelling model system for comprehending the initiation, proliferation, commitment and differentiation of de novo lineage‐specific stem cells. Precise, timely and robust cell fate and identity decisions are crucial for the proper progression and differentiation of functional stomata. Deviations from this precise specification result in developmental abnormalities and nonfunctional stomata. However, the molecular underpinnings of timely cell fate commitment have just begun to be unravelled. In this review, we explore the key regulatory strategies governing cell fate commitment, emphasizing the distinctions between embryonic and postembryonic stomatal development. Furthermore, the interplay of transcription factors and cell cycle machineries is pivotal in specifying the transition into differentiation. We aim to synthesize recent studies utilizing single‐cell as well as cell‐type‐specific transcriptomics, epigenomics and chromatin accessibility profiling to shed light on how master‐regulatory transcription factors and epigenetic machineries mutually influence each other to drive fate commitment and maintenance. Summary statement: In this review, we delve into the molecular mechanisms underlying timely and precise cell fate commitment during stomatal development. Emphasis is made on the differences between embryonic and postembryonic stomatal differentiation. We highlight recent discoveries on the transcriptional circuits that initiate and fortify stomatal fate transitions, as well as the epigenetic processes that facilitate fate commitment and maintenance. [ABSTRACT FROM AUTHOR]

Summary: The role of maternal tissue in embryogenesis remains enigmatic in many complex organisms. Here, we investigate the contribution of maternal tissue to apical–basal patterning in the kelp embryo.Focussing on Undaria pinnatifida, we studied the effects of detachment from the maternal tissue using microsurgery, staining of cell wall modifications, morphometric measurements, flow cytometry, genotyping and a modified kelp fertilisation protocol synchronising kelp embryogenesis.Detached embryos are rounder and often show aberrant morphologies. When a part of the oogonial cell wall remains attached to the zygote, the apical–basal patterning is rescued. Furthermore, the absence of contact with maternal tissue increases parthenogenesis, highlighting the critical role of maternal signals in the initial stages of development.These results show a key role for the connection to the maternal oogonial cell wall in apical–basal patterning in kelps. This observation is reminiscent of another brown alga, Fucus, where the cell wall directs the cell fate. Our findings suggest a conserved mechanism across phylogenetically distant oogamous lineages, where localised secretion of sulphated F2 fucans mediates the establishment of the apical–basal polarity. In this model, the maternal oogonial cell wall mediates basal cell fate determination by providing an extrinsic patterning cue to the future kelp embryo. [ABSTRACT FROM AUTHOR]

Summary: Inter‐subspecific indica–japonica hybrid rice (Oryza sativa) has the potential for increased yields over traditional indica intra‐subspecies hybrid rice, but limited yield of F1 hybrid seed production (FHSP) hinders the development of indica–japonica hybrid rice breeding. Diurnal flower‐opening time (DFOT) divergence between indica and japonica rice has been a major contributing factor to this issue, but few DFOT genes have been cloned. Here, we found that manipulating the expression of jasmonate (JA) pathway genes can effectively modulate DFOT to improve the yield of FHSP in rice. Treating japonica cultivar Zhonghua 11 (ZH11) with methyl jasmonate (MeJA) substantially advanced DFOT. Furthermore, overexpressing the JA biosynthesis gene OPDA REDUCTASE 7 (OsOPR7) and knocking out the JA inactivation gene CHILLING TOLERANCE 1 (OsHAN1) in ZH11 advanced DFOT by 1‐ and 2‐h respectively; and knockout of the JA signal suppressor genes JASMONATE ZIM‐DOMAIN PROTEIN 7 (OsJAZ7) and OsJAZ9 resulted in 50‐min and 1.5‐h earlier DFOT respectively. The yields of FHSP using japonica male‐sterile lines GAZS with manipulated JA pathway genes were significantly higher than that of GAZS wildtype. Transcriptome analysis, cytological observations, measurements of elastic modulus and determination of cell wall components indicated that the JA pathway could affect the loosening of the lodicule cell walls by regulating their composition through controlling sugar metabolism, which in turn influences DFOT. This research has vital implications for breeding japonica rice cultivars with early DFOT to facilitate indica–japonica hybrid rice breeding. [ABSTRACT FROM AUTHOR]

MicroRNAs play critical roles in multiple developmental processes in insects. Our previous study showed that CRISPR/Cas9‐mediated knock down of the microRNA let‐7 in silkworms increased the size of larvae and silk glands, thereby improving the silk production capacity. In this study, we elucidate the molecular mechanism underlying of let‐7 regulates growth. Identification of differentially expressed genes in response to let‐7 knock down revealed enrichment of pathways associated with cell proliferation and DNA replication. let‐7 dysregulation affected the cell cycle and proliferation of the Bombyx mori cell line BmN. Dual‐luciferase and target site mutation assays showed that BmCDK1 is a direct target gene of let‐7, with only 1 binding site on its 3′‐untranslated region. RNA interference of BmCDK1 inhibited cell proliferation, but this effect was counteracted by co‐transfection with let‐7 antagomir. Moreover, let‐7 knock down induced BmCDK1 expression and promoted cell proliferation in multiple tissues, and further induced endomitosis in the silk gland in vivo. Knock down of BmCDK1 resulted in abnormal formation of a new epidermis, and larval development was arrested at the 2nd or 3rd molt stage. Taken together, our results demonstrated that BmCDK1 is a novel target of let‐7 in cell fate determination, possessing potential for improving silk yield in silkworm. [ABSTRACT FROM AUTHOR]

Human stem cells and derivatives transplantation are widely used to treat nervous system diseases, while the fate determination of transplanted cells is not well elucidated. To explore cell fate changes of human brain organoids before and after transplantation, human brain organoids are transplanted into prefrontal cortex (PFC) and hippocampus (HIP), respectively. Single‐cell sequencing is then performed. According to time‐series sample comparison, transplanted cells mainly undergo neural development at 2 months post‐transplantation (MPT) and then glial development at 4MPT, respectively. A different brain region sample comparison shows that organoids grafted to PFC have obtained cell fate close to those of host cells in PFC, other than HIP, which may be regulated by the abundant expression of dopamine (DA) and acetylcholine (Ach) in PFC. Meanwhile, morphological complexity of human astrocyte grafts is greater in PFC than in HIP. DA and Ach both activate the calcium activity and increase morphological complexity of astrocytes in vitro. This study demonstrates that human brain organoids receive host niche factor regulation after transplantation, resulting in the alignment of grafted cell fate with implanted brain regions, which may contribute to a better understanding of cell transplantation and regenerative medicine. [ABSTRACT FROM AUTHOR]

Summary: Cell fate determination and primordium initiation on the placental surface are two key events for ovule formation in seed plants, which directly affect ovule density and seed yield. Despite ovules form in the marginal meristematic tissues of the carpels, angiosperm carpels evolved after the ovules. It is not clear how the development of the ovules and carpels is coordinated in angiosperms. In this study, we identify the S. lycopersicum CRABS CLAW (CRC) homologue SlCRCa as an essential determinant of ovule fate. We find that SlCRCa is not only expressed in the placental surface and ovule primordia but also functions as a D‐class gene to block carpel fate and promote ovule fate in the placental surface. Loss of function of SlCRCa causes homeotic transformation of the ovules to carpels. In addition, we find low levels of the S. lycopersicum AINTEGUMENTA (ANT) homologue (SlANT2) favour the ovule initiation, whereas high levels of SlANT2 promote placental carpelization. SlCRCa forms heterodimer with tomato INNER NO OUTER (INO) and AGAMOUS (AG) orthologues, SlINO and TOMATO AGAMOUS1 (TAG1), to repress SlANT2 expression during the ovule initiation. Our study confirms that angiosperm basal ovule cells indeed retain certain carpel properties and provides mechanistic insights into the ovule initiation. [ABSTRACT FROM AUTHOR]

The clinical translation of induced pluripotent stem cells (iPSCs) holds great potential for personalized therapeutics. However, one of the main obstacles is that the current workflow to generate iPSCs is expensive, time‐consuming, and requires standardization. A simplified and cost‐effective microfluidic approach is presented for reprogramming fibroblasts into iPSCs and their subsequent differentiation into neural stem cells (NSCs). This method exploits microphysiological technology, providing a 100‐fold reduction in reagents for reprogramming and a ninefold reduction in number of input cells. The iPSCs generated from microfluidic reprogramming of fibroblasts show upregulation of pluripotency markers and downregulation of fibroblast markers, on par with those reprogrammed in standard well‐conditions. The NSCs differentiated in microfluidic chips show upregulation of neuroectodermal markers (ZIC1, PAX6, SOX1), highlighting their propensity for nervous system development. Cells obtained on conventional well plates and microfluidic chips are compared for reprogramming and neural induction by bulk RNA sequencing. Pathway enrichment analysis of NSCs from chip showed neural stem cell development enrichment and boosted commitment to neural stem cell lineage in initial phases of neural induction, attributed to a confined environment in a microfluidic chip. This method provides a cost‐effective pipeline to reprogram and differentiate iPSCs for therapeutics compliant with current good manufacturing practices. [ABSTRACT FROM AUTHOR]

Vps34 is the unique member of the class III phosphoinositide 3‐kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this study, a model without Vps34 (Vps34fl/fl/CD122Cre/+) is generated, deleting Vps34 during and after NK‐cell commitment. These mice exhibit a nearly 90% decrease in NK cell count and impaired differentiation. A mechanistic study reveals that the absence of Vps34 disrupts the transport of IL‐15 receptor subunit alpha CD122 to the cell membrane, resulting in reduced responsiveness of NK cells to IL‐15. In mice lacking Vps34 at the terminal stage of NK‐cell development (Vps34fl/fl/Ncr1Cre/+), NK cells gradually diminish during aging. This phenotype is associated with autophagy deficiency and the stress induced by reactive oxygen species (ROS). Therefore, terminally differentiated NK cells lacking Vps34 display an accelerated senescence phenotype, while the application of antioxidants effectively reverses the senescence caused by Vps34 deletion by neutralizing ROS. In summary, this study unveils the dual and unique activity of Vps34 in NK cells. Vps34‐mediated vesicular transport is crucial for CD122 membrane trafficking during NK cell commitment, whereas Vps34‐mediated autophagy can delay NK cell senescence. [ABSTRACT FROM AUTHOR]

Background: Inhibitors of DNA binding (ID) proteins mainly inhibit gene expression and regulate cell fate decisions by interacting with E‐proteins. All four ID proteins (ID1–4) are present in the testis, and ID4 has a particularly important role in spermatogonial stem cell fate determination. Several lines of evidence indicate that ID proteins are involved in meiosis; however, functional experiments have not been conducted to validate this observation. Results: In this study, we report that ID2 is enriched in spermatocytes and that forced ID2 expression in germ cells causes defects in spermatogenesis. A detailed analysis demonstrated that Id2 overexpression (Id2 OE) decreased the total number of spermatogonia and changed the dynamics of meiosis progression. Specifically, spermatocytes were enriched in the zygotene stage, and the proportion of pachytene spermatocytes was significantly decreased, indicating defects in the zygotene–pachytene transition. The number of MLH1‐positive foci per cell was decreased in pachytene spermatocytes from Id2 OE testes, suggesting abnormalities in recombination. Transcriptome analysis revealed that forced Id2 expression changed the expression of a list of genes mainly associated with meiosis and spermatid development. Conclusions: ID2 protein is expressed in spermatocytes, and its genetic ablation in the germline does not affect spermatogenesis, likely due to genetic compensation of its family members. However, forced Id2 expression changes meiosis progression and causes defects in spermiogenesis. These data provide important evidence that ID proteins play pivotal roles in male meiosis and spermatid development. Key Findings: ID proteins; Spermatogenesis; Recombination; Meiosis; Pachytene. [ABSTRACT FROM AUTHOR]

The development of embryonic stem (ES) cells to extraembryonic trophectoderm and primitive endoderm lineages manifests distinct steady‐state expression patterns of two key transcription factors—Oct4 and Nanog. How dynamically such kind of steady‐state expressions are maintained remains elusive. Herein, we demonstrate that steady‐state dynamics involving two bistable switches which are interlinked via a stepwise (Oct4) and a mushroom‐like (Nanog) manner orchestrate the fate specification of ES cells. Our hypothesis qualitatively reconciles various experimental observations and elucidates how different feedback and feedforward motifs orchestrate the extraembryonic development and stemness maintenance of ES cells. Importantly, the model predicts strategies to optimize the dynamics of self‐renewal and differentiation of embryonic stem cells that may have therapeutic relevance in the future. [ABSTRACT FROM AUTHOR]

The Hippo signalling pathway, an evolutionarily conserved kinase cascade, has been shown to be crucial for cell fate determination, homeostasis and tissue regeneration. Recent experimental and clinical studies have demonstrated that the Hippo signalling pathway is involved in the pathophysiology of ocular diseases. This article provides the first systematic review of studies on the regulatory and functional roles of mammalian Hippo signalling systems in eye diseases. More comprehensive studies on this pathway are required for a better understanding of the pathophysiology of eye diseases and the development of effective therapies. [ABSTRACT FROM AUTHOR]

Cell fate determination in mammalian development is complex and precisely controlled and accumulating evidence indicates that epigenetic mechanisms are crucially involved. N4‐acetylcytidine (ac4C) is a recently identified modification of messenger RNA (mRNA); however, its functions are still elusive in mammalian. Here, we show that N‐acetyltransferase 10 (NAT10)‐mediated ac4C modification promotes ectoderm differentiation of human embryonic stem cells (hESCs) by acetylating nuclear receptor subfamily 2 group F member 1 (NR2F1) mRNA to enhance translation efficiency (TE). Acetylated RNA immunoprecipitation sequencing (acRIP‐seq) revealed that levels of ac4C modification were higher in ectodermal neuroepithelial progenitor (NEP) cells than in hESCs or mesoendoderm cells. In addition, integrated analysis of acRIP‐seq and ribosome profiling sequencing revealed that NAT10 catalysed ac4C modification to improve TE in NEP cells. RIP‐qRT‐PCR analysis identified an interaction between NAT10 and NR2F1 mRNA in NEP cells and NR2F1 accelerated the nucleus‐to‐cytoplasm translocation of yes‐associated protein 1, which contributed to ectodermal differentiation of hESCs. Collectively, these findings point out the novel regulatory role of ac4C modification in the early ectodermal differentiation of hESCs and will provide a new strategy for the treatment of neuroectodermal defects diseases. [ABSTRACT FROM AUTHOR]

Persistent infection with high‐risk human papillomavirus (HR‐HPV) is a well‐established risk factor to the development of cervical intraepithelial neoplasia (CIN), a condition that can progress to cervical cancer (CC) a major health problem worldwide. Recently, there has been growing interest in exploring alternative therapies utilizing natural products, among which is the algae species Laurencia johnstonii Setchell & Gardner, 1924 (L. johnstonii), proposed for the management of precancerous lesions. The aim of this work was to determine the effect of an organic extract from L. johnstonii (ELj) in early cervical lesions (CIN 1). These CIN 1 lesions were generated in a murine model expressing the HR‐HPV16 E7 oncoprotein (K14E7HPV transgenic mice) with a single exogenous hormonal stimulus using 17β‐estradiol. The histopathological studies, the determination of cell proliferation and of the apoptotic levels in cervical tissue, showed that, seven doses of ELj (30 mg/kg weight per day diluted in a DMSO‐saline solution [1:7]) lead to recovery the architecture of cervical epithelium. Accordingly, in the transgenic mice it was observed a statistically significant decrease of the PCNA expression levels, a marker of cell proliferation, and a statistically significant increase in the apoptosis levels using Caspase 3 as a marker. In addition, we determined the expression levels of the tumor suppressor miR‐218 and the oncomiRNA miR‐21. Interestingly, our results may suggest that ELj treatment tended to restore the normal expression of both miRNAs as compared with controls being more evident in the non‐transgenic induced mice. Differences of p < 0.05 were considered statistically significant through the whole study. Based on these results, we propose that the use of ELj could be an alternative for the treatment of cervical early lesions. [ABSTRACT FROM AUTHOR]

Temperate lakes experience variation in mixing and stratification that affects the distributions, activities, abundances, and diversity of plankton communities. We examined temporal and vertical changes in the composition of planktonic microorganisms (including Bacteria and Archaea) in oligotrophic Flathead Lake, Montana. Using a combination of approaches that included 16S rRNA gene sequencing and flow cytometric determination of cell abundances, we found that the microbial community was responsive to variations in stratification and mixing at time scales ranging from episodic (scale of days) to seasonal. However, the impact of such physical dynamics varied among taxa, likely reflecting taxa‐specific responses to environmental changes that coincide with stratification and mixing (e.g., light availability and nutrient supply). During the early spring, periods of relatively short‐term (< 7 d) intermittency in stratification and mixing influenced the vertical distributions of specific microbial taxa, notably including the cyanobacteria. These events highlight time scales of biological responses to high‐frequency variations associated with lake stratification and mixing, particularly during the transition to the growing season in the early spring. [ABSTRACT FROM AUTHOR]

A simple, sensitive and quick HPLC method was developed for the determination of ketoprofen in cell culture media (EMEM, DMEM, RPMI). Separation was performed using a gradient on the C18 column with a mobile phase of acetonitrile and miliQ water acidified by 0.1 % (v/v) formic acid. The method was validated for parameters including linearity, accuracy, precision, limit of quantitation and limit of detection, as well as robustness. The response was found linear over the range of 3–100 μg/mL as demonstrated by the acquired value of correlation coefficient R2=0.9997. The described method is applicable for determination of various pharmacokinetic aspects of ketoprofen in vitro. [ABSTRACT FROM AUTHOR]

The generation of tissue from stem cells is an alluring concept as it holds a number of potential applications in clinical therapeutics and regenerative medicine. Mesenchymal stromal/stem cells (MSCs) can be isolated from a number of different somatic sources, and have the capacity to differentiate into adipogenic, osteogenic, chondrogenic, and myogenic lineages. Although the first three have been extensively investigated, there remains a paucity of literature on the latter. This review looks at the various strategies available in vitro to enhance harvested MSC commitment and differentiation into the myogenic pathway. These include chemical inducers, myogenic‐enhancing cell culture substrates, and mechanical and dynamic culturing conditions. Drawing on information from embryonic and postnatal myogenesis from somites, satellite, and myogenic progenitor cells, the mechanisms behind the chemical and mechanical induction strategies can be studied, and the sequential gene and signaling cascades can be used to monitor the progression of myogenic differentiation in the laboratory. Increased understanding of the stimuli and signaling mechanisms in the initial stages of MSC myogenic commitment will provide tools with which we can enhance their differentiation efficacy and advance the process to clinical translation. [ABSTRACT FROM AUTHOR]

SUMMARY: Trichomes, the outward projection of plant epidermal tissue, provide an effective defense against stress and insect pests. Although numerous genes have been identified to be involved in trichome development, the molecular mechanism for trichome cell fate determination is not well enunciated. Here, we reported GoSTR functions as a master repressor for stem trichome formation, which was isolated by map‐based cloning based on a large F2 segregating population derived from a cross between TM‐1 (pubescent stem) and J220 (smooth stem). Sequence alignment revealed a critical G‐to‐T point mutation in GoSTR's coding region that converted codon 2 from GCA (Alanine) to TCA (Serine). This mutation occurred between the majority of Gossypium hirsutum with pubescent stem (GG‐haplotype) and G. barbadense with glabrous stem (TT‐haplotype). Silencing of GoSTR in J220 and Hai7124 via virus‐induced gene silencing resulted in the pubescent stems but no visible change in leaf trichomes, suggesting stem trichomes and leaf trichomes are genetically distinct. Yeast two‐hybrid assay and luciferase complementation imaging assay showed GoSTR interacts with GoHD1 and GoHOX3, two key regulators of trichome development. Comparative transcriptomic analysis further indicated that many transcription factors such as GhMYB109, GhTTG1, and GhMYC1/GhDEL65 which function as positive regulators of trichomes were significantly upregulated in the stem from the GoSTR‐silencing plant. Taken together, these results indicate that GoSTR functions as an essential negative modulator of stem trichomes and its transcripts will greatly repress trichome cell differentiation and growth. This study provided valuable insights for plant epidermal hair initiation and differentiation research. [ABSTRACT FROM AUTHOR]

Summary: Stalk rot caused by Fusarium verticillioides (Fv) is one of the most destructive diseases in maize production. The defence response of root system to Fv invasion is important for plant growth and development. Dissection of root cell type‐specific response to Fv infection and its underlying transcription regulatory networks will aid in understanding the defence mechanism of maize roots to Fv invasion. Here, we reported the transcriptomes of 29 217 single cells derived from root tips of two maize inbred lines inoculated with Fv and mock condition, and identified seven major cell types with 21 transcriptionally distinct cell clusters. Through the weighted gene co‐expression network analysis, we identified 12 Fv‐responsive regulatory modules from 4049 differentially expressed genes (DEGs) that were activated or repressed by Fv infection in these seven cell types. Using a machining‐learning approach, we constructed six cell type‐specific immune regulatory networks by integrating Fv‐induced DEGs from the cell type‐specific transcriptomes, 16 known maize disease‐resistant genes, five experimentally validated genes (ZmWOX5b, ZmPIN1a, ZmPAL6, ZmCCoAOMT2, and ZmCOMT), and 42 QTL or QTN predicted genes that are associated with Fv resistance. Taken together, this study provides not only a global view of maize cell fate determination during root development but also insights into the immune regulatory networks in major cell types of maize root tips at single‐cell resolution, thus laying the foundation for dissecting molecular mechanisms underlying disease resistance in maize. [ABSTRACT FROM AUTHOR]

The role of transcription factors and biomolecules in cell type conversion has been widely studied. Yet, it remains unclear whether and how intracellular mechanotransduction through focal adhesions (FAs) and the cytoskeleton regulates the epigenetic state and cell reprogramming. Here, it is shown that cytoskeletal structures and the mechanical properties of cells are modulated during the early phase of induced neuronal (iN) reprogramming, with an increase in actin cytoskeleton assembly induced by Ascl1 transgene. The reduction of actin cytoskeletal tension or cell adhesion at the early phase of reprogramming suppresses the expression of mesenchymal genes, promotes a more open chromatin structure, and significantly enhances the efficiency of iN conversion. Specifically, reduction of intracellular tension or cell adhesion not only modulates global epigenetic marks, but also decreases DNA methylation and heterochromatin marks and increases euchromatin marks at the promoter of neuronal genes, thus enhancing the accessibility for gene activation. Finally, micro‐ and nano‐topographic surfaces that reduce cell adhesions enhance iN reprogramming. These novel findings suggest that the actin cytoskeleton and FAs play an important role in epigenetic regulation for cell fate determination, which may lead to novel engineering approaches for cell reprogramming. [ABSTRACT FROM AUTHOR]

DNA methylation (5mC) is an essential epigenetic mark associated with transcriptional silencing. The role of 5mC in transcriptional repression is well established for a few hundred genes through methylation of their promoters. Yet, whether 5mC contributes more broadly to gene expression is an important open question. 5mC removal has recently been associated with the activation of enhancers, opening the possibility that 5mC may globally contribute to the expression of genes defining cell identities. Here, we will review the evidence and molecular mechanisms that link 5mC with the activity of enhancers. We will discuss the spread and amplitude of the potential gene expression changes controlled by 5mC at enhancers, and how these may contribute to the determination of cell identities during development. [ABSTRACT FROM AUTHOR]

Fusarium crown rot (FCR) and sharp eyespot (SE) are serious soil‐borne diseases in wheat and its relatives that have been reported to cause wheat yield losses in many areas. In this study, the expression of a cell wall invertase gene, TaCWI‐B1, was identified to be associated with FCR resistance through a combination of bulk segregant RNA sequencing and genome resequencing in a recombinant inbred line population. Two bi‐parental populations were developed to further verify TaCWI‐B1 association with FCR resistance. Overexpression lines and ethyl methanesulfonate (EMS) mutants revealed TaCWI‐B1 positively regulating FCR resistance. Determination of cell wall thickness and components showed that the TaCWI‐B1‐overexpression lines exhibited considerably increased thickness and pectin and cellulose contents. Furthermore, we found that TaCWI‐B1 directly interacted with an alpha‐galactosidase (TaGAL). EMS mutants showed that TaGAL negatively modulated FCR resistance. The expression of TaGAL is negatively correlated with TaCWI‐B1 levels, thus may reduce mannan degradation in the cell wall, consequently leading to thickening of the cell wall. Additionally, TaCWI‐B1‐overexpression lines and TaGAL mutants showed higher resistance to SE; however, TaCWI‐B1 mutants were more susceptible to SE than controls. This study provides insights into a FCR and SE resistance gene to combat soil‐borne diseases in common wheat. [ABSTRACT FROM AUTHOR]

It is essential to design a multifunctional well‐controlled platform to transfer mechanical cues to the cells in different magnitudes. This study introduces a platform, a miniaturized bioreactor, which enables to study the effect of shear stress in microsized compartmentalized structures. In this system, the well‐established cell encapsulation system of liquefied capsules (LCs) is used as microbioreactors in which the encapsulated cells are exposed to variable core viscosities to experience different mechanical forces under a 3D dynamic culture. The LC technology is joined with electrospraying to produce such microbioreactors at high rates, thus allowing the application of microcapsules for high‐throughput screening. Using this platform for osteogenic differentiation as an example, shows that microbioreactors with higher core viscosity which produce higher shear stress lead to significantly higher osteogenic characteristics. Moreover, in this system the forces experienced by cells in each LC are simulated by computational modeling. The maximum wall shear stress applied to the cells inside the bioreactor with low, and high core viscosity environment is estimated to be 297 and 1367 mPa, respectively, for the experimental setup employed. This work outlines the potential of LC microbioreactors as a reliable in vitro customizable platform with a wide range of applications. [ABSTRACT FROM AUTHOR]

The article "Editorial highlights" from Developmental Dynamics explores recent advances in developmental biology, focusing on topics such as ciliogenesis, organogenesis, teeth development, and regeneration in various organisms. The studies discussed in the article shed light on the genetic, molecular, and cellular mechanisms that regulate these biological processes, emphasizing the importance of interdisciplinary research in understanding development, evolution, disease, and regeneration. The authors highlight the significance of primary cilia, retinoic acid signaling in tooth development, and the role of Creb3l1 in zebrafish fin regeneration, providing valuable insights into these complex biological phenomena. [Extracted from the article]

To achieve successful cultivation of pluripotent stem cells using suspension (3D) culture methods, it is essential to maintain the pluripotent state while stimulating the proliferation of the cells. Currently, the methods available to rapidly assess the pluripotency during expansion are limited. Most rely on time‐consuming post hoc‐analyses, which are prone to operator‐variation, to assess this critical attribute. In this study we propose the use of Raman spectroscopy coupled with chemometric analysis as a process analytical tool to classify the pluripotency by using the spent cultivation medium as samples. Using Support Vector Machines (SVM), a classification accuracy of 94% is achieved on a validation set of various media samples. This study indicates that there may be increased possibilities for monitoring and control in large‐scale expansion of stem cells by Raman spectroscopy. [ABSTRACT FROM AUTHOR]

Current osteochondral (OC) defect repair approaches using premade scaffolds face clinical limitations due to invasiveness, weak integrity, and/or insufficient interfacial bonding. An injectable hydrophobic laminous adhesive is developed that rapidly photocross‐link subaqueously and forms robust bi‐layered structure that orchestrates biophysical‐chemical cues for stimulating OC repair. Liquid hydrophobic photo‐cross‐linkable poly (lactide‐co‐propylene glycol‐co‐lactide) dimethacrylates (PmLnDMA) are adopted as cartilage phase and PmLnDMA encapsulating methacrylated hydroxyapatite nanoparticles (PmLnDMA/MH) as the mineralized subchondral bone phase. Both phases exhibit strong interfacial bonding due to the presence of "CC". Mechanotransduction and growth factor‐mediated signaling pathways are enchanced by matching the mechanical properties of two phases to native cartilage and bone via systematical modulation of the adhesives' composition and encapsulated growth factors' release profile. This enhances mesenchymal stem cells' commitment to corresponding chondrocytes and osteoblasts to augment OC repair in vitro and in vivo, and ultimately benefits patients suffering from OC fracture, osteoarthritis, and osteoporosis. [ABSTRACT FROM AUTHOR]

T cells, which are derived from hematopoietic stem cells (HSCs), are the most important components of adaptive immune system. Based on the expression of αβ and γδ receptors, T cells are mainly divided into αβ and γδ T cells. In the thymus, they share common progenitor cells, while undergoing a series of well‐characterized and different developmental processes. N6‐Methyladenosine (m6A), one of the most abundant modifications in mRNAs, plays critical roles in cell development and maintenance of function. Recently, we have demonstrated that the depletion of m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells through the regulation of Jag1/Notch2 signaling, but not αβ T cells, indicating a checkpoint role of ALKBH5 and m6A modification in the early development of γδ T cells. Based on previous studies, many key pathway molecules, which exert dominant roles in γδ T cell fate determination, have been identified as the targets regulated by m6A modification. In this review, we mainly summarize the potential regulation between m6A modification and these key signaling molecules in the γδ T cell lineage commitment, to provide new perspectives in the checkpoint of γδ T cell development. [ABSTRACT FROM AUTHOR]

The nucleosome is the fundamental subunit of chromatin. Nucleosome structures are formed by the combination of histone octamers and genomic DNA. Through a systematic and precise process of folding and compression, these structures form a 30‐nm chromatin fibre that is further organized within the nucleus in a hierarchical manner, known as the 3D genome. Understanding the intricacies of chromatin structure and the regulatory mode governing chromatin interactions is essential for unravelling the complexities of cellular architecture and function, particularly in relation to cell fate determination, regeneration, and the development of diseases. Here, we provide a general overview of the hierarchical structure of chromatin as well as of the evolution of chromatin conformation capture techniques. We also discuss the dynamic regulatory changes in higher‐order chromatin structure that occur during stem cell lineage differentiation and somatic cell reprogramming, potential regulatory insights at the chromatin level in organ regeneration, and aberrant chromatin regulation in diseases. [ABSTRACT FROM AUTHOR]

Rejuvenation of cells by reprogramming toward the pluripotent state raises increasing attention. In fact, generation of induced pluripotent stem cells (iPSCs) completely reverses age‐associated molecular features, including elongation of telomeres, resetting of epigenetic clocks and age‐associated transcriptomic changes, and even evasion of replicative senescence. However, reprogramming into iPSCs also entails complete de‐differentiation with loss of cellular identity, as well as the risk of teratoma formation in anti‐ageing treatment paradigms. Recent studies indicate that partial reprogramming by limited exposure to reprogramming factors can reset epigenetic ageing clocks while maintaining cellular identity. So far, there is no commonly accepted definition of partial reprogramming, which is alternatively called interrupted reprogramming, and it remains to be elucidated how the process can be controlled and if it resembles a stable intermediate state. In this review, we discuss if the rejuvenation program can be uncoupled from the pluripotency program or if ageing and cell fate determination are inextricably linked. Alternative rejuvenation approaches with reprogramming into a pluripotent state, partial reprogramming, transdifferentiation, and the possibility of selective resetting of cellular clocks are also discussed. [ABSTRACT FROM AUTHOR]

Metabolites are important for cell fate determination. Fructose-1,6-bisphosphate (F1,6P) is the rate-limiting product in glycolysis and the rate-limiting substrate in gluconeogenesis. Here, it is discovered that the nuclear-accumulated F1,6P impairs cancer cell viability by directly binding to high mobility group box 1 (HMGB1), the most abundant non-histone chromosome structural protein with paradoxical roles in tumor development. F1,6P disrupts the association between the HMGB1 A-box and C-tail by targeting K43/K44 residues, inhibits HMGB1 oligomerization, and stabilizes P53 protein by increasing P53-HMGB1 interaction. Moreover, F1,6P lowers the affinity of HMGB1 for DNA and DNA adducts, which sensitizes cancer cells to chemotherapeutic drug(s)-induced DNA replication stress and DNA damage. Concordantly, F1,6P resensitizes cancer cells with chemotherapy resistance, impairs tumor growth and enhances chemosensitivity in mice, and impedes the growth of human tumor organoids. These findings reveal a novel role for nuclear-accumulated F1,6P and underscore the potential utility of F1,6P as a drug for cancer therapy. [ABSTRACT FROM AUTHOR]

Remarkable exertions are directed to reveal and understand topographic cues that induce cell mechanical sensitive responses including lineage determination. Extracellular matrix (ECM) is the sophisticated ensemble of diverse factors offering the complicated cellular microenvironment to regulate cell behaviors. However, the functions of only a few of these factors are revealed; most of them are still poorly understood. Herein, the focus is on understanding the curved structure in ECM network for regulating stem cell mechanotransduction. A curved nanofiber network mimicking the curved structure in ECM is fabricated by an improved electrospinning technology. Compared with the straight fibers, the curved fibers promote cell bridge formation because of the cytoskeleton tension. The actomyosin filaments are condensed near the curved edge of the non‐adhesive bridge in the bridging cells, which generates higher myosin‐II‐based intracellular force. This force drives cell lineage commitment toward osteogenic differentiation. This study enriches and perfects the knowledge of the effects of topographic cues on cell behaviors and guides the development of novel biomaterials. [ABSTRACT FROM AUTHOR]

Microfluidic cultivation and single‐cell analysis are inherent parts of modern microbial biotechnology and microbiology. However, implementing biochemical engineering principles based on the kinetics and stoichiometry of growth in microscopic spaces remained unattained. We here present a novel integrated framework that utilizes distinct microfluidic cultivation technologies and single‐cell analytics to make the fundamental math of process‐oriented biochemical engineering applicable at the single‐cell level. A combination of non‐invasive optical cell mass determination with sub‐pg sensitivity, microfluidic perfusion cultivations for establishing physiological steady‐states, and picoliter batch reactors, enabled the quantification of all physiological parameters relevant to approximate a material balance in microfluidic reaction environments. We determined state variables (biomass concentration based on single‐cell dry weight and mass density), biomass synthesis rates, and substrate affinities of cells grown in microfluidic environments. Based on this data, we mathematically derived the specific kinetics of substrate uptake and growth stoichiometry in glucose‐grown Escherichia coli with single‐cell resolution. This framework may initiate microscale material balancing beyond the averaged values obtained from populations as a basis for integrating heterogeneous kinetic and stoichiometric single‐cell data into generalized bioprocess models and descriptions. [ABSTRACT FROM AUTHOR]

Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post‐translational modifications and the regulation of chromatin accessibility by non‐coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental‐driven nature, piloting myeloid and lymphoid cell fate decisions with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage‐specific transcription factors and maintenance of cell type‐specific epigenetic modifications, referred to as 'epigenetic memory', dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as 'trained immunity'. Here, we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Because the dentate gyrus serves as the first site for information processing in the hippocampal trisynaptic circuit, it an important structure for the formation of associative memories. Previous findings in rabbit had recorded populations of cells within dentate gyrus that may bridge the temporal gap between stimuli to support memory formation during trace eyeblink conditioning, an associative learning task. However, this previous work was unable to identify the types of cells demonstrating this type of activity. To explore these changes further, we did in vivo single‐neuron recording in conjunction with physiological determination of cell types to investigate the functional role of granule cells, mossy cells, and interneurons in dentate gyrus during learning. Tetrode recordings were performed in young‐adult mice during training on trace eyeblink conditioning, a hippocampal‐dependent temporal associative memory task. Conditioned mice were able to successfully learn the task, with male mice learning at a faster rate than female mice. In the conditioned group, granule cells tended to show an increase in firing rate during conditioned stimulus presentation while mossy cells showed a decrease in firing rate during the trace interval and the unconditioned stimulus. Interestingly, populations of interneurons demonstrated learning‐related increases and decreases in activity that began at onset of the conditioned stimulus and persisted through the trace interval. The current study also found a significant increase in theta power during stimuli presentation in conditioned animals, and this change in theta decreased over time. Ultimately, these data suggest unique involvement of granule cells, mossy cells, and interneurons in dentate gyrus in the formation of a trace associative memory. This work expands our knowledge of dentate gyrus function, helping to discern how aging and disease might disrupt this process. [ABSTRACT FROM AUTHOR]

Background: The phalanges are the final skeletal elements to form in the vertebrate limb and their identity is regulated by signaling at the phalanx forming region (PFR) located at the tip of the developing digit ray. Here, we seek to explore the relationship between PFR activity and phalanx morphogenesis, which define the most distal limb skeletal elements, and signals associated with termination of limb outgrowth. Results: As Grem1 is extinguished in the distal chick limb mesoderm, the chondrogenesis marker Aggrecan is up‐regulated in the metatarsals and phalanges. Fate mapping confirms that subridge mesoderm cells contribute to the metatarsal and phalanges when subridge Grem1 is down‐regulated. Grem1 overexpression specifically blocks chick phalanx development by inhibiting PFR activity. PFR activity and digit development are also disrupted following overexpression of a Gli3 repressor, which results in Grem1 expression in the distal limb and downregulation of Bmpr1b. Conclusions: Based on expression and fate mapping studies, we propose that downregulation of Grem1 in the distal limb marks the transition from metatarsal to phalanx development. This suggests that downregulation of Grem1 in the distal limb mesoderm is necessary for phalanx development. Grem1 downregulation allows for full PFR activity and phalanx progenitor cell commitment to digit fate. Key Findings: When Grem1 expression is down‐regulated in the distal limb mesoderm, cells fated to become metatarsal and phalanx are present in the subridge mesoderm.Overexpression of Grem1 in the chick leg with a replication defective retrovirus specifically inhibits phalanx development by inhibiting PFR activity.Gli3 modulates phalanx development by regulating PFR formation and activity in part through Bmpr1b and Grem1 expression, respectively.Down‐regulation of Grem1 in the distal limb marks the transition from metatarsal to phalanx development.Grem1 down‐regulation in the distal limb allows for PFR activity which is necessary for phalanx progenitor cell commitment to digit fate. [ABSTRACT FROM AUTHOR]

To sum up, Bcl-3 was decreased during BMSCs senescence, and the supply of Bcl-3 could protect BMSCs from aging. Skeletal aging is characterized by progressive bone loss and increased marrow adiposity.1,2 Age-related bone loss impairs the exercise activity of patients and increases the risk of fracture. (F) Bcl-3, Ac-K49- -catenin and -catenin were analysed by immunoblot in control and Bcl-3-knockdown BMSCs after treated with Wnt 3a for 0 h or 4 h. (G) The levels of Bcl-3 in nuclear and cytoplasmic. B-cell lymphoma-3 controls mesenchymal stem cell commitment and senescence during skeletal aging. [Extracted from the article]

N6-methyladenosine (m6A) modification plays a pivotal role in cell fate determination. Previous studies show that eliminating m6A using Mb1-Cre dramatically impairs B cell development. However, whether disturbing m6A modification at later stages affects B cell development and function remains elusive. Here, we deleted m6A methyltransferase Mettl3 from the pro-B stage on using Cd19-Cre (Mettl3 cKO) and found that the frequency of total B cells in peripheral blood, peritoneal cavity, and liver is comparable between Mettl3 cKO mice and wild-type (WT) littermates, while the percentage of whole splenic B cells slightly increases in Mettl3 cKO individuals. The proportion of pre-pro-B, pro-B, pre-B, immature, and mature B cells in the bone marrow were minimally affected. Loss of Mettl3 resulted in increased apoptosis but barely affected B cells' proliferation and IgG production upon LPS, CD40L, anti-IgM, or TNF-α stimulation. Different stimuli had different effects on B cell activation. In addition, B cell-specific Mettl3 knockout had no influence on the pro-fibrogenic activity of B cells in liver fibrosis, evidenced by comparable fibrosis in carbon tetrachloride- (CCl4-) treated Mettl3 cKO mice and WT controls. In summary, our study demonstrated that deletion of Mettl3 from the pro-B stage on has minimal effects on B cell development and function, as well as profibrogenic activity of B cells in liver fibrosis, revealing a stage-specific dependence on Mettl3-mediated m6A of B cell development. [ABSTRACT FROM AUTHOR]

Rcor2, the corepressor 2 of REST, a transcriptional repressor, is predominantly expressed in embryonic stem cells (ESCs) and plays a major role in regulating ESC pluripotency and neurogenesis. The function of Rcor2 in development of other germ layers is yet unclear. We utilized a Rcor2-/- mouse embryonic stem cell (mESC) line to investigate the role of Rcor2 in mESC differentiation. Rcor2-/- mESC shows reduced proliferation and severely compromised capacity to differentiate to all three germ layers. In contrast, Rcor2 knockout promotes primordial germ cells (PGCs) specific gene expression and possibly PGC formation. Mechanistically, we revealed that Rcor2 inhibits expression of genes required for PGC development, such as Dppa3 and Dazl, by associating to their promoters and enhancing local suppressive H3K9me3 modifications. Our results suggest that Rcor2 plays an important role in somatic cell fate determination by suppressing PGC differentiation through regulating epigenetic modifications of PGC specific genes. [ABSTRACT FROM AUTHOR]

Tyrosinase is an important enzyme in the metabolism of melanin and catecholamine, as well as an important antigen in autoimmunity of vitiligo. However, it is still a challenge to develop a selective and sensitive sensing approach for monitoring of tyrosinase in cell environment. In this work, a sensing strategy based on ion current rectification induced by nanochannels was established to electrochemically detect inactive tyrosinase. Functionalized alumina nanochannels were decorated by tyramine as an electrochemical platform to selectively determine tyrosinase via chemically specific reaction between phenolic hydroxyl groups of tyramine and tyrosinase. On the other hand, Fe2+ was further bonded with dihydroxyl groups generated by tyrosinase in nanochannels to amplify charge changes, resulting in the enhancement on the detection sensitivity for tyrosinase. Based on this principle, the developed electrochemical sensor showed a good linearity towards tyrosinase from 2 to 50 U/mL with a detection limit down to 0.83 U/mL, which can fulfil the requirement for detection of tyrosinase in cells. Eventually, the present electrochemical sensor was successfully employed in the selective and sensitive determination of tyrosinase in cell lysates. The results suggested that the activity of tyrosinase in B16 cells was 1.7‐fold higher than that of Hela cells. [ABSTRACT FROM AUTHOR]