Search

Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a large, clinically annotated cohort of patients with metastatic hormone receptor-positive (HR+) breast cancer, we identify TP53 loss (27.6%) and MDM2 amplification (6.4%) to be associated with lack of long-term disease control. Human breast cancer models reveal that p53 loss does not alter CDK4/6 activity or G1 blockade but instead promotes drug-insensitive p130 phosphorylation by CDK2. The persistence of phospho-p130 prevents DREAM complex assembly, enabling cell-cycle re-entry and tumor progression. Inhibitors of CDK2 can overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically diverse HR+ breast cancers. [Display omitted] • TP53 mutation is associated with lack of long-term disease control on CDK4/6i • p53 deficiency suppresses DREAM complex in BC cells, enabling cell-cycle re-entry • Disruption of DREAM complex is sufficient to promote long-term CDK4/6i resistance • Inhibition of CDK2 overcomes p53 loss, promoting geroconversion and disease control Kudo et al. demonstrate that TP53 loss in HR+ breast cancer is clinically associated with long-term failure of CDK4/6i due to cellular escape from quiescence via impaired DREAM complex assembly. Selective CDK2 inhibition is found to reinforce p130 dephosphorylation in p53 mutant models and facilitate durable tumor growth suppression. [ABSTRACT FROM AUTHOR]

Astrocytes play many essential roles in the central nervous system (CNS) and are altered significantly in disease. These reactive astrocytes contribute to neuroinflammation and disease progression in many pathologies, including glioblastoma (GB), an aggressive form of brain cancer. Current in vitro platforms do not allow for accurate modeling of reactive astrocytes. In this study, we sought to engineer a simple bioengineered hydrogel platform that would support the growth of primary human astrocytes and allow for accurate analysis of various reactive states. After validating this platform using morphological analysis and qPCR, we then used the platform to begin investigating how astrocytes respond to GB derived extracellular vesicles (EVs) and soluble factors (SF). These studies reveal that EVs and SFs induce distinct astrocytic states. In future studies, this platform can be used to study how astrocytes transform the tumor microenvironment in GB and other diseases of the CNS. Recent work has shown that astrocytes help maintain brain homeostasis and may contribute to disease progression in diseases such as glioblastoma (GB), a deadly primary brain cancer. In vitro models allow researchers to study basic mechanisms of astrocyte biology in healthy and diseased conditions, however current in vitro systems do not accurately mimic the native brain microenvironment. In this study, we show that our hydrogel system supports primary human astrocyte culture with an accurate phenotype and allows us to study how astrocytes change in response to a variety of inflammatory signals in GB. This platform could be used further investigate astrocyte behavior and possible therapeutics that target reactive astrocytes in GB and other brain diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Many animals share a lifelong capacity to adapt their growth rates and body sizes to changing environmental food supplies. However, the cellular and molecular basis underlying this plasticity remains only poorly understood. We therefore studied how the sea anemones Nematostella vectensis and Aiptasia (Exaiptasia pallida) respond to feeding and starvation. Combining quantifications of body size and cell numbers with mathematical modelling, we observed that growth and shrinkage rates in Nematostella are exponential, stereotypic and accompanied by dramatic changes in cell numbers. Notably, shrinkage rates, but not growth rates, are independent of body size. In the facultatively symbiotic Aiptasia, we show that growth and cell proliferation rates are dependent on the symbiotic state. On a cellular level, we found that >7% of all cells in Nematostella juveniles reversibly shift between S/G2/M and G1/G0 cell cycle phases when fed or starved, respectively. Furthermore, we demonstrate that polyp growth and cell proliferation are dependent on TOR signalling during feeding. Altogether, we provide a benchmark and resource for further investigating the nutritional regulation of body plasticity on multiple scales using the genetic toolkit available for Nematostella. [ABSTRACT FROM AUTHOR]

This article discusses the concept of quiescence and dormancy in plants and their importance in plant development, acclimation, and survival. The article highlights recent research on the molecular and metabolic regulation of quiescence, as well as the ecological modeling and molecular perception of temperature in relation to dormancy. The integration of hormone and cell-to-cell signaling, as well as the role of epigenetic mechanisms in establishing and maintaining dormancy, is also explored. The article concludes by emphasizing the potential applications of this research in enhancing plant resilience in the face of climate change. [Extracted from the article]

This article, published in the Journal of Experimental Botany, reinterprets the concept of olive bud dormancy. The authors argue that olive buds do not undergo true physiological dormancy, but rather go through a process of para-dormancy and eco-dormancy. They discuss the challenges of studying bud dormancy in olive trees, which are evergreen and have different growth patterns compared to deciduous trees. The article also explores the relationship between cold temperatures and flowering in olive trees, highlighting the role of the FT gene in promoting flower induction. Overall, the authors suggest that further research is needed to better understand the reproductive biology of olive trees and improve olive production. [Extracted from the article]

Geophytic plants synchronize growth and quiescence with the external environment to survive and thrive under changing seasons. Together with seasonal growth adaptation, dormancy and sprouting are critical factors determining crop yield and market supply, as various geophytes also serve as major food, floriculture, and ornamental crops. Dormancy in such crops determines crop availability in the market, as most of them are consumed during the dormant stage. On the other hand, uniform/maximal sprouting is crucial for maximum yield. Thus, dormancy and sprouting regulation have great economic importance. Dormancy–sprouting cycles in geophytes are regulated by genetic, exogenous (environmental), and endogenous (genetic, metabolic, hormonal, etc.) factors. Comparatively, the temperature is more dominant in regulating dormancy and sprouting in geophytes, unlike above-ground tissues, where both photoperiod and temperature control are involved. Despite huge economic importance, studies concerning the regulation of dormancy and sprouting are scarce in the majority of geophytes. To date, only a few molecular factors involved in the process have been suggested. Recently, omics studies on molecular and metabolic factors involved in dormancy and growth regulation of underground vegetative tissues have provided more insight into the mechanism. Here, we discuss current knowledge of the environmental and molecular regulation and control of dormancy and sprouting in geophytes, and discuss challenges/questions that need to be addressed in the future for crop improvement. [ABSTRACT FROM AUTHOR]

Plant quiescence and seed dormancy can be triggered by reduced oxygen availability. Under water, oxygen depletion caused by flooding can culminate in a quiescent state, which is a plant strategy for energy preservation and survival. In adult plants, a quiescent state can be activated by sugar starvation, leading to metabolic depression. In seeds, secondary dormancy can be activated by reduced oxygen availability, which creates an unfavourable state for germination. The physical dormancy of some seeds and buds includes barriers to external conditions, which indirectly results in hypoxia. The molecular processes that support seed dormancy and plant survival through quiescence under hypoxia include the N-degron pathway, which enables the modulation of ethylene-responsive factors of group VII and downstream targets. This oxygen- and nitric oxide-dependent mechanism interacts with phytohormone-related pathways to control growth. [ABSTRACT FROM AUTHOR]

Persistence of quiescent leukemia stem cells (LSCs) after treatment most likely contributes to chemotherapy resistance and poor prognosis of leukemia patients. Identification of this quiescent cell population would facilitate eradicating LSCs. Here, using a cell‐tracing PKH26 (PKH) dye that can be equally distributed to daughter cells following cell division in vivo, we identify a label‐retaining slow‐cycling leukemia cell population from AML1‐ETO9a (AE9a) leukemic mice. We find that, compared with cells not maintaining PKH‐staining, a higher proportion of PKH‐retaining cells are in G0 phase, and PKH‐retaining cells exhibit increased colony formation ability and leukemia initiation potential. In addition, PKH‐retaining cells possess high chemo‐resistance and are more likely to be localized to the endosteal bone marrow region. Based on the transcriptional signature, HLA class II histocompatibility antigen gamma chain (Cd74) is highly expressed in PKH‐retaining leukemia cells. Furthermore, cell surface CD74 was identified to be highly expressed in LSCs of AE9a mice and CD34+ human leukemia cells. Compared to Lin−CD74− leukemia cells, Lin−CD74+ leukemia cells of AE9a mice exhibit higher stemness properties. Collectively, our findings reveal that the identified slow‐cycling leukemia cell population represents an LSC population, and CD74+ leukemia cells possess stemness properties, suggesting that CD74 is a candidate LSC surface marker. [ABSTRACT FROM AUTHOR]

Despite having >1200 described species and despite their nearly worldwide distribution and prevalence in many xeric ecosystems, relative to many other arachnid groups, we know little about the natural history and behaviour of animals in the order Solifugae (camel spiders, sun spiders, sun scorpions, etc.). Here, we review the current solifuge literature through the lens of conceptual research areas in ecology, evolution, and behaviour and propose ways in which solifuges can contribute to research in specific subfields, as follows: (i) ecology: community and trophic dynamics; connecting food webs; habitat specialization; and biodiversity and conservation; (ii) evolution: speciation and diversification; activity cycles and associated traits; adaptations for speed; and living in extreme environments; and (iii) behaviour and sensory systems: sleep, quiescence, and diapause; sensory systems and sensory ecology; learning and cognition; and mating systems, sexual selection, and sexual conflict. This resource can provide a starting point for identifying research programmes that will simultaneously contribute basic natural history information about this under-studied group and provide a broader understanding of fundamental concepts and theories across the life sciences. We hope that scientists will take this review as a challenge to develop creative ways of leveraging the unique features of solifuges to advance scientific knowledge and understanding. [ABSTRACT FROM AUTHOR]

Neural stem cells (NSCs) persist in the adult mammalian brain and are able to give rise to new neurons and glia throughout life. The largest stem cell niche in the adult mouse brain is the ventricular-subventricular zone (V-SVZ) lining the lateral ventricles. Adult NSCs in the V-SVZ coexist in quiescent and actively proliferating states, and they exhibit a regionalized molecular identity. The importance of such spatial diversity is just emerging, as depending on their position within the niche, adult NSCs give rise to distinct subtypes of olfactory bulb interneurons and different types of glia. However, the functional relevance of stem cell heterogeneity in the V-SVZ is still poorly understood. Here, we put into perspective findings highlighting the importance of adult NSC diversity for brain plasticity, and how the body signals to brain stem cells in different physiological states to regulate their behavior. [ABSTRACT FROM AUTHOR]

Life on Earth has been through numerous challenges over eons and, one way or another, has always triumphed. From mass extinctions to more daily plights to find food, unpredictability is everywhere. The adaptability of life-forms to ever-changing environments is the key that confers life's robustness. Adaptability has become synonymous with Darwinian evolution mediated by heritable genetic changes. The extreme gene-centric view, while being of central significance, at times has clouded our appreciation of the cell as a self-regulating entity informed of, and informing, the genetic data. An essential element that powers adaptability is the ability to regulate cell growth. In this review, we provide an extensive overview of growth regulation spanning species, tissues, and regulatory mechanisms. We aim to highlight the commonalities, as well as differences, of these phenomena and their molecular regulators. Finally, we curate open questions and areas for further exploration. [ABSTRACT FROM AUTHOR]

Stem cell therapy holds significant potential for skeletal muscle repair, with in vitro-generated human muscle reserve cells (MuRCs) emerging as a source of quiescent myogenic stem cells that can be injected to enhance muscle regeneration. However, the clinical translation of such therapies is hampered by the need for fetal bovine serum (FBS) during the in vitro generation of human MuRCs. This study aimed to determine whether fresh allogeneic human platelet-rich plasma (PRP) combined or not with hyaluronic acid (PRP-HA) could effectively replace xenogeneic FBS for the ex vivo expansion and differentiation of human primary myoblasts. Cells were cultured in media supplemented with either PRP or PRP-HA and their proliferation rate, cytotoxicity and myogenic differentiation potential were compared with those cultured in media supplemented with FBS. The results showed similar proliferation rates among human myoblasts cultured in PRP, PRP-HA or FBS supplemented media, with no cytotoxic effects. Human myoblasts cultured in PRP or PRP-HA showed reduced fusion ability upon differentiation. Nevertheless, we also observed that human MuRCs generated from PRP or PRP-HA myogenic cultures, exhibited increased Pax7 expression and delayed re-entry into the cell cycle upon reactivation, indicating a deeper quiescent state of human MuRCs. These results suggest that allogeneic human PRP effectively replaces FBS for the ex vivo expansion and differentiation of human myoblasts and favors the in vitro generation of Pax7High human MuRCs, with important implications for the advancement of stem cell-based muscle repair strategies. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to examine microvascular changes and identify predictors of short-term quiescence in active birdshot chorioretinitis (BSCR). Methods: An observational, prospective, 12-month follow-up cohort study was conducted. BSCR eyes were clinically assessed at baseline, categorized as active or inactive, and reevaluated at 12 months. Based on their clinical activity at both timepoints, eyes were divided into three subgroups: active-to-inactive (A-I), consistently active (A-A), and consistently inactive (I-I). Structural OCT, OCT-angiography (OCT-A), and ultra-widefield imaging were utilized. Exam data from fundus and nasal subfields were analyzed for microvascular changes and quiescence predictors. Results: Sixty eyes from 30 BSCR patients (47% women, 53% men, mean age 59.7 ± 12.3 years) were included. In the A-I group (16 eyes), vascular density and perfusion indices increased in all subfields post-quiescence, contrasting with the other groups. Perifoveal looping in the superficial capillary plexus predicted quiescence at 12 months compared with the A-A group. Conclusions: Vascular density rises after complete inflammation control in BSCR, and perifoveal capillary loops serve as potential predictors of short-term quiescence in active BSCR. [ABSTRACT FROM AUTHOR]

Harmful Algal Blooms (HABs) can produce phycotoxins that accumulate in shellfish and subsequently poison aquatic predators and human consumers, potentially causing significant economic impacts to the shellfish aquaculture industry. HAB events are challenging to foresee as they are driven by complex inter‐annual and seasonal changes in physical, chemical and biological factors. Accounting for these environmental drivers and their interactions in statistical models allows for the development of HAB early warning systems. Typically, these have a forecasting horizon of 1–2 weeks, allowing shellfish businesses and regulators to increase monitoring intensity and take evasive action, including harvesting suspensions to protect consumer health. However, there is critical need for longer‐term predictions of risk, to enable more proactive mitigation, business planning, harvest scheduling and supply chain management. We present a statistical framework for providing seasonal‐scale early warnings of the occurrence and impacts of Dinophysis spp. HABs on shellfish aquaculture in Scotland, UK. We use penalized smooth functions of winter‐spring daily sea surface temperature to predict the severity and impact of ensuing summer blooms, including the percentage of toxicity measurements exceeding the harvesting closure threshold, as well as the anticipated start, end, and overall duration of closures. We illustrate the application of this framework to two Scottish aquaculture regions: One with a high spatial concentration of harvesting sites (Shetland) and one with more dispersed sites (West Scotland and the Hebrides). Through a comprehensive yearly prediction experiment, we demonstrate considerable skill in predicting the impact of unseen HAB seasons at a regional level. Key Points: We present a new statistical approach for seasonal predictions of toxic Dinophysis species blooms in two regions of ScotlandResults indicate a link between low winter‐spring sea surface temperatures and high summer toxin concentrations in shellfish samplesWe demonstrate improved early warnings of harmful summer blooms using the first 120 days of sea surface temperature measurements each year [ABSTRACT FROM AUTHOR]

Persistence of quiescent leukemia stem cells (LSCs) after treatment most likely contributes to chemotherapy resistance and poor prognosis of leukemia patients. Identification of this quiescent cell population would facilitate eradicating LSCs. Here, using a cell‐tracing PKH26 (PKH) dye that can be equally distributed to daughter cells following cell division in vivo, we identify a label‐retaining slow‐cycling leukemia cell population from AML1‐ETO9a (AE9a) leukemic mice. We find that, compared with cells not maintaining PKH‐staining, a higher proportion of PKH‐retaining cells are in G0 phase, and PKH‐retaining cells exhibit increased colony formation ability and leukemia initiation potential. In addition, PKH‐retaining cells possess high chemo‐resistance and are more likely to be localized to the endosteal bone marrow region. Based on the transcriptional signature, HLA class II histocompatibility antigen gamma chain (Cd74) is highly expressed in PKH‐retaining leukemia cells. Furthermore, cell surface CD74 was identified to be highly expressed in LSCs of AE9a mice and CD34+ human leukemia cells. Compared to Lin−CD74− leukemia cells, Lin−CD74+ leukemia cells of AE9a mice exhibit higher stemness properties. Collectively, our findings reveal that the identified slow‐cycling leukemia cell population represents an LSC population, and CD74+ leukemia cells possess stemness properties, suggesting that CD74 is a candidate LSC surface marker.

Signaling interactions are important during skeletal muscle regeneration, where muscle cells in distinct states (quiescent, reactivated, proliferating and differentiated) must coordinate their response to injury. Here, we probed the role of secreted small extracellular vesicles (sEV/exosomes) using a culture model of physiologically relevant cell states seen in muscle regeneration. Unexpectedly, G0 myoblasts exhibited enhanced secretion of sEV (~150 nm) displaying exosome markers (Alix, TSG101, flotillin-1, and CD9), and increased expression of Kibra, a regulator of exosome biogenesis. Perturbation of Kibra levels confirmed a role in controlling sEV secretion rates. Purified sEVs displayed a common exosome marker-enriched proteome in all muscle cell states, as well as state-specific proteins. Exosomes derived from G0 cells showed an antioxidant signature, and were most strongly internalized by differentiated myotubes. Functionally, donor exosomes from all muscle cell states could activate an integrated Wnt reporter in target cells, but only G0-derived exosomes could induce myogenic differentiation in proliferating cells. Taken together, we provide evidence that quiescence in muscle cells is accompanied by enhanced secretion of exosomes with distinct uptake, cargo and signal activating features. Our study suggests the novel possibility that quiescent muscle stem cells in vivo may play a previously under-appreciated signaling role during muscle homeostasis. [ABSTRACT FROM AUTHOR]

Precise regulation of stem cell quiescence is essential for tissue development and homeostasis. Therefore, its aberrant regulation is intimately correlated with various human diseases. However, the detailed mechanisms of stem cell quiescence and its specific role in the pathogenesis of various diseases remain to be determined. Recent studies have revealed that the intrinsic and microenvironmental factors are the potential candidates responsible for the orderly switch between the dormant and activated states of stem cells. In addition, defects in signaling pathways related to internal and external factors of stem cells might contribute to the initiation and development of diseases by altering the dormancy of stem cells. In this review, we focus on the mechanisms underlying stem cell quiescence, especially the involvement of intrinsic and microenvironmental factors. In addition, we discuss the relationship between the anomalies of stem cell quiescence and related diseases, hopefully providing therapeutic insights for developing novel treatments. [ABSTRACT FROM AUTHOR]

Background and Aims Turions are vegetative, dormant overwintering organs formed in aquatic plants in response to unfavourable ecological conditions. Contents of cytokinin (CK), auxin metabolites and abscisic acid (ABA) as main growth and development regulators were compared in innately dormant autumnal turions of 22 aquatic plant species of different functional ecological or taxonomic groups with those in non-dormant winter apices in three aquatic species and with those in spring turions of four species after their overwintering. Methods The hormones were analysed in miniature turion samples using ultraperformance liquid chromatography coupled with triple quadrupole mass spectrometry. Key Results In innately dormant turions, the total contents of each of the four main CK types, biologically active forms and total CKs differed by two to three orders of magnitude across 22 species; the proportion of active CK forms was 0.18–67 %. Similarly, the content of four auxin forms was extremely variable and the IAA proportion as the active form was 0.014–99 %. The ABA content varied from almost zero to 54 µmol kg−1 dry weight and after overwintering it usually significantly decreased. Of all functional traits studied, hormone profiles depended most on the place of turion sprouting (surface vs bottom) and we suggest that this trait is crucial for turion ecophysiology. Conclusions The key role of ABA in regulating turion dormancy was confirmed. However, the highly variable pattern of the ABA content in innately dormant and in overwintered turions indicates that the hormonal mechanism regulating the innate dormancy and its breaking in turions is not uniform within aquatic plants. [ABSTRACT FROM AUTHOR]

Cellular senescence, traditionally viewed as a consequence of proliferating and growing cells overwhelmed by extensive stresses and damage, has long been recognized as a critical cellular aging mechanism. Recent research, however, has revealed a novel pathway termed "quiescence-origin senescence", where cells directly transition into senescence from the quiescent state, bypassing cell proliferation and growth. This opinion paper presents a framework conceptualizing a continuum between quiescence and senescence with quiescence deepening as a precursor to senescence entry. We explore the triggers and controllers of this process and discuss its biological implications. Given that the majority of cells in the human body are dormant rather than proliferative, understanding quiescence-origin senescence has significant implications for tissue homeostasis, aging, cancer, and various disease processes. The new paradigm in exploring this previously overlooked senescent cell population may reshape our intervention strategies for age-related diseases and tissue regeneration. [ABSTRACT FROM AUTHOR]

Summary: Skeletal muscle's regenerative ability is vital for maintaining muscle function, but chronic diseases like Duchenne muscular dystrophy can deplete this capacity. Muscle satellite cells, quiescent in normal situations, are activated during muscle injury, expressing myogenic regulatory factors, and producing myogenic progenitor cells. It was reported that muscle stem cells in primary culture and reserve cells in C2C12 cells express anti-apoptotic protein Bcl-2. Although the role of Bcl-2 expressed in myogenic cells has been thought to be to enhance cell viability, we hypothesized that Bcl-2 may promote the formation of reserve cells. The expression pattern analysis showed the expression of Bcl-2 in undifferentiated mononucleated cells, emphasizing its usefulness as a reserve cell marker and reminding us that cells expressing Bcl-2 have low proliferative potential. Silencing of Bcl-2 by transfection with siRNA decreased cell viability and the number of reserve cells, while overexpression of Bcl-2 not only increases cell viability but also inhibits muscle differentiation and proliferation. These results emphasize dual roles of Bcl-2 in protecting cells from apoptosis and contributing to reserve cell formation by regulating myoblast proliferation and/or differentiation. Overall, the study sheds light on the multifaceted role of Bcl-2 in the maintenance of skeletal muscle regeneration. [ABSTRACT FROM AUTHOR]

Mating experience impacts the physiology and behavior of animals. Although mating effects of female Drosophila melanogaster have been studied extensively, the behavioral changes of males following copulation have not been fully understood. In this study, we characterized the mating-dependent behavioral changes of male flies, especially focusing on fly-to-fly interaction, and their dependence on rearing conditions. Our data demonstrate that male flies quiesce their courtship toward both females and males, as well as their locomotor activity. This post-copulatory quiescence appears to be contingent upon the presence of a peer, as minimal variation is noted in locomotion when the male is measured in isolation. Interestingly, copulated males influence a paired male without successful copulation to reduce his locomotion. Our findings point to a conditional behavioral quiescence following copulation, influenced by the presence of other flies. [ABSTRACT FROM AUTHOR]

Melanocyte stem cells (McSCs) of the hair follicle are a rare cell population within the skin and are notably underrepresented in whole‐skin, single‐cell RNA sequencing (scRNA‐seq) datasets. Using a cell enrichment strategy to isolate KIT+/CD45− cells from the telogen skin of adult female C57BL/6J mice, we evaluated the transcriptional landscape of quiescent McSCs (qMcSCs) at high resolution. Through this evaluation, we confirmed existing molecular signatures for qMcCS subpopulations (e.g., Kit+, Cd34+/−, Plp1+, Cd274+/−, Thy1+, Cdh3+/−) and identified novel qMcSC subpopulations, including two that differentially regulate their immune privilege status. Within qMcSC subpopulations, we also predicted melanocyte differentiation potential, neural crest potential, and quiescence depth. Taken together, the results demonstrate that the qMcSC population is heterogeneous and future studies focused on investigating changes in qMcSCs should consider changes in subpopulation composition. [ABSTRACT FROM AUTHOR]

Unlike in most laboratory settings, microbes in natural habitats often lack essential nutrients and withstand widely fluctuating or extreme temperatures; thus, laboratory studies fail to capture the widespread phenomenon of slowed or suspended lives of microbes manifested as, for example, in dormancy and quiescence. Quantitative, single-cell-level measurements and mathematical modeling are overcoming the challenges of observing and understanding slow dynamics of individual cells at long timescales. New conceptual, quantitative frameworks have re-defined and clarified microbes' suspended states, with dormancy defined as a continuous spectrum and antibiotic-induced growth-arrest defined into distinct states. Studying slowed and suspended growth in microbes revealed fundamental constraints to remaining viable without growing and limits to slowing a cell's life. Microbes in nature often lack nutrients and face extreme or widely fluctuating temperatures, unlike microbes in growth-optimized settings in laboratories that much of the literature examines. Slowed or suspended lives are the norm for microbes. Studying them is important for understanding the consequences of climate change and for addressing fundamental questions about life: are there limits to how slowly a cell's life can progress, and how long cells can remain viable without self-replicating? Recent studies began addressing these questions with single-cell-level measurements and mathematical models. Emerging principles that govern slowed or suspended lives of cells – including lives of dormant spores and microbes at extreme temperatures – are re-defining discrete cellular states as continuums and revealing intracellular dynamics at new timescales. Nearly inactive, lifeless-appearing microbes are transforming our understanding of life. Microbes in nature often lack nutrients and face extreme or widely fluctuating temperatures, unlike microbes in growth-optimized settings in laboratories that much of the literature examines. Slowed or suspended lives are the norm for microbes. Studying them is important for understanding the consequences of climate change and for addressing fundamental questions about life: are there limits to how slowly a cell's life can progress, and how long cells can remain viable without self-replicating? Recent studies began addressing these questions with single-cell-level measurements and mathematical models. Emerging principles that govern slowed or suspended lives of cells– including lives of dormant spores and microbes at extreme temperatures – are re-defining discrete cellular states as continuums and revealing intracellular dynamics at new timescales. Nearly inactive, lifeless-appearing microbes are transforming our understanding of life. [ABSTRACT FROM AUTHOR]

Abstract Background Efficacy of parasitic wasps from the genus Trichogramma to attack the eggs of numerous important pests in various agricultural crops makes them one of the most prevalent biocontrol agents. In Trichogramma, the pre-pupal stage can survive during the cold season in a dormant state (diapause or quiescence). The optimal conditions for the induction of this pause of development during mass rearing to store the parasitoid for a long time in good quality depend on the species. In the present study, four factors [the incubation periods (24 and 48 h), diapause induction temperatures (9 and 11 °C), durations of the diapause induction (from 0 to 6 weeks), and the periods of storage (from 0 to 6 months)], were experimented to force Trichogramma evanescens Westwood, reared on Sitotroga cerealella, to enter diapause or quiescence and estimating their impacts on the efficacy of stored parasitoid. Results Results confirmed that the life parameters of T. evanescens as the percentage of adult emergence, female percentage, rates of wing deformation of emerged adults, and fecundity of emerged females were significantly affected by all experimented factors. The pre-storage treatments made it possible to store the parasitoid for at least 2 months at 3 °C, with no much changes in their fitness, the emergence rate of adults reached more than 80%, and the egg-laying efficacy of females reached more than 42 eggs per emerged female, when diapause induction treatments were applied for 5 weeks at 11 °C after 24 h of incubation. Furthermore, there is the possibility of storage for 6 months with an acceptable level of parasitoid’s quality, when diapause induction treatments were applied for 5 weeks at 9 °C after 24 h of incubation, the emergence rate reached 70%, and the number of eggs per female was 52 eggs, while no emergence of adult insects was recorded after 3 months of cold storage without diapause induction treatments. Conclusion Two storage programs were reached for T. evanescens (depending on the adult emergence rate and fecundity of emerged females). There is a long-term storage (6 months), when diapause was induced at a low temperature (9 °C) after 24 h of incubation. Short-term storage (from 2 to 4 months), when quiescence was induced under a higher temperature of 11 °C after both 24 and 48 h of incubation.

Adult muscle tissue largely comprised of differentiated myofibers also harbors quiescent muscle-resident stem cells (MuSCs) that are responsible for its maintenance, repair and regeneration. Emerging evidence suggests that quiescent MuSCs exhibit a specific metabolic state, which is regulated during physiological and pathological alterations. However, a detailed understanding of the metabolic state of quiescent MuSCs and its alteration during activation and repair is lacking. Direct profiling of MuSCs in vivo is challenging because the cells are rare and dispersed, while isolation and enrichment leads to their activation and loss of quiescence. In this study, we employed 1H-nuclear magnetic resonance (NMR) spectroscopy to profile metabolites in an established culture model of quiescent MuSC-derived myoblasts and compared with activated, proliferative and differentiated muscle cells to determine the state-specific metabolome. We report that the proliferating and differentiated cells are highly enriched in metabolites involved in energy generation, the quiescent state is enriched in metabolites related to phospholipid catabolism (glycerophosphocholine and choline) and depleted for phosphocholine which is enriched in proliferating cells. We propose that the ratio of these metabolites may be useful as a biomarker of MuSC quiescence. [ABSTRACT FROM AUTHOR]

A delicate balance between quiescence and division of the radial glia-like stem cells (RGLs) ensures continuation of adult hippocampal neurogenesis (AHN) over the lifespan. Transient or persistent perturbations of this balance due to a brain pathology, drug administration, or therapy can lead to unfavorable long-term outcomes such as premature depletion of the RGLs, decreased AHN, and cognitive deficit. Memantine, a drug used for alleviating the symptoms of Alzheimer's disease, and electroconvulsive seizure (ECS), a procedure used for treating drug-resistant major depression or bipolar disorder, are known strong AHN inducers; they were earlier demonstrated to increase numbers of dividing RGLs. Here, we demonstrated that 1-month stimulation of quiescent RGLs by either memantine or ECS leads to premature exhaustion of their pool and altered AHN at later stages of life and that aging of the brain modulates the ability of the quiescent RGLs to be recruited into the cell cycle by these AHN inducers. Our findings support the aging-related divergence of functional features of quiescent RGLs and have a number of implications for the practical assessment of drugs and treatments with respect to their action on quiescent RGLs at different stages of life in animal preclinical studies. [ABSTRACT FROM AUTHOR]

Background: Efficacy of parasitic wasps from the genus Trichogramma to attack the eggs of numerous important pests in various agricultural crops makes them one of the most prevalent biocontrol agents. In Trichogramma, the pre-pupal stage can survive during the cold season in a dormant state (diapause or quiescence). The optimal conditions for the induction of this pause of development during mass rearing to store the parasitoid for a long time in good quality depend on the species. In the present study, four factors [the incubation periods (24 and 48 h), diapause induction temperatures (9 and 11 °C), durations of the diapause induction (from 0 to 6 weeks), and the periods of storage (from 0 to 6 months)], were experimented to force Trichogramma evanescens Westwood, reared on Sitotroga cerealella, to enter diapause or quiescence and estimating their impacts on the efficacy of stored parasitoid. Results: Results confirmed that the life parameters of T. evanescens as the percentage of adult emergence, female percentage, rates of wing deformation of emerged adults, and fecundity of emerged females were significantly affected by all experimented factors. The pre-storage treatments made it possible to store the parasitoid for at least 2 months at 3 °C, with no much changes in their fitness, the emergence rate of adults reached more than 80%, and the egg-laying efficacy of females reached more than 42 eggs per emerged female, when diapause induction treatments were applied for 5 weeks at 11 °C after 24 h of incubation. Furthermore, there is the possibility of storage for 6 months with an acceptable level of parasitoid's quality, when diapause induction treatments were applied for 5 weeks at 9 °C after 24 h of incubation, the emergence rate reached 70%, and the number of eggs per female was 52 eggs, while no emergence of adult insects was recorded after 3 months of cold storage without diapause induction treatments. Conclusion: Two storage programs were reached for T. evanescens (depending on the adult emergence rate and fecundity of emerged females). There is a long-term storage (6 months), when diapause was induced at a low temperature (9 °C) after 24 h of incubation. Short-term storage (from 2 to 4 months), when quiescence was induced under a higher temperature of 11 °C after both 24 and 48 h of incubation. [ABSTRACT FROM AUTHOR]

Tissue stem cells are maintained in the adult body throughout life and are crucial for tissue homeostasis as they supply newly functional cells. Quiescence is a reversible arrest in the G0/G1 phase of the cell cycle and a strategy to maintain the quality of tissue stem cells. Quiescence maintains stem cells in a self-renewable and differentiable state for a prolonged period by suppressing energy consumption and cell damage and depletion. Most adult neural stem cells in the brain maintain the quiescent state and produce neurons and glial cells through differentiation after activating from the quiescent state to the proliferating state. In this process, proteostasis, including proteolysis, is essential to transition between the quiescent and proliferating states associated with proteome remodeling. Recent reports have demonstrated that quiescent and proliferating neural stem cells have different expression patterns and roles as proteostatic molecules and are affected by age, indicating differing processes for protein homeostasis in these two states in the brain. This review discusses the multiple regulatory stages from protein synthesis (protein birth) to proteolysis (protein death) in quiescent neural stem cells. [ABSTRACT FROM AUTHOR]

Spermatogenesis involves a complex process of cellular differentiation maintained by spermatogonial stem cells (SSCs). Being critical to male reproduction, it is generally assumed that spermatogenesis starts and ends in equivalent transcriptional states in related species. Based on single-cell gene expression profiling, it has been proposed that undifferentiated human spermatogonia can be subclassified into four heterogenous subtypes, termed states 0, 0A, 0B, and 1. To increase the resolution of the undifferentiated compartment and trace the origin of the spermatogenic trajectory, we re-analysed the single-cell (sc) RNA-sequencing libraries of 34 post-pubescent human testes to generate an integrated atlas of germ cell differentiation. We then used this atlas to perform comparative analyses of the putative SSC transcriptome both across human development (using 28 foetal and pre-pubertal scRNA-seq libraries) and across species (including data from sheep, pig, buffalo, rhesus and cynomolgus macaque, rat, and mouse). Alongside its detailed characterisation, we show that the transcriptional heterogeneity of the undifferentiated spermatogonial cell compartment varies not only between species but across development. Our findings associate 'state 0B' with a suppressive transcriptomic programme that, in adult humans, acts to functionally oppose proliferation and maintain cells in a ready-to-react state. Consistent with this conclusion, we show that human foetal germ cells—which are mitotically arrested—can be characterised solely as state 0B. While germ cells with a state 0B signature are also present in foetal mice (and are likely conserved at this stage throughout mammals), they are not maintained into adulthood. We conjecture that in rodents, the foetal-like state 0B differentiates at birth into the renewing SSC population, whereas in humans it is maintained as a reserve population, supporting testicular homeostasis over a longer reproductive lifespan while reducing mutagenic load. Together, these results suggest that SSCs adopt differing evolutionary strategies across species to ensure fertility and genome integrity over vastly differing life histories and reproductive timeframes. [ABSTRACT FROM AUTHOR]

While loss of function (LOF) of retinoblastoma 1 (RB1) tumor suppressor is known to drive initiation of small‐cell lung cancer and retinoblastoma, RB1 mutation is rarely observed in breast cancers at their initiation. In this study, we investigated the impact on untransformed mammary epithelial cells given by RB1 LOF. Depletion of RB1 in anon‐tumorigenic MCF10A cells induced reversible growth arrest (quiescence) featured by downregulation of multiple cyclins and MYC, upregulation of p27KIP1, and lack of expression of markers which indicate cellular senescence or epithelial–mesenchymal transition (EMT). We observed a similar phenomenon in human mammary epithelial cells (HMEC) as well. Additionally, we found that RB1 depletion attenuated the activity of RAS and the downstream MAPK pathway in an RBL2/p130‐dependent manner. The expression of farnesyltransferase β, which is essential for RAS maturation, was found to be downregulated following RB1 depletion also in an RBL2/p130‐dependent manner. These findings unveiled an unexpected mechanism whereby normal mammary epithelial cells resist to tumor initiation upon RB1 LOF. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are a long‐lived and self‐renewing cancer cell population that drives tumor propagation and maintains cancer heterogeneity. They are also implicated in the therapeutic resistance of various types of cancer. Recent studies of CSCs in colorectal cancer (CRC) have uncovered fundamental paradigms that have increased understanding of CSC systems in solid tumors. Colorectal CSCs share multiple biological properties with normal intestinal stem cells (ISCs), including expression of the stem cell marker Lgr5. New evidence suggests that colorectal CSCs manifest substantial heterogeneity, as exemplified by the existence of both actively cycling Lgr5+ CSCs as well as quiescent Lgr5+ CSCs that are resistant to conventional anticancer therapies. The classical view of a rigid cell hierarchy and irreversible cell differentiation trajectory in normal and neoplastic tissues is now challenged by the finding that differentiated cells have the capacity to revert to stem cells through dynamic physiological reprogramming events. Such plasticity of CSC systems likely underlies both carcinogenesis and therapeutic resistance in CRC. Further characterization of the mechanisms underpinning the heterogeneity and plasticity of CSCs should inform future development of eradicative therapeutic strategies for CRC. [ABSTRACT FROM AUTHOR]

Astrocytes and ependymal cells have been reported to be able to switch from a mature cell identity towards that of a neural stem/progenitor cell. Astrocytes are widely scattered in the brain where they exert multiple functions and are routinely targeted for in vitro and in vivo reprogramming. Ependymal cells serve more specialized functions, lining the ventricles and the central canal, and are multiciliated, epithelial-like cells that, in the spinal cord, act as bi-potent progenitors in response to injury. Here, we isolate or generate ependymal cells and post-mitotic astrocytes, respectively, from the lateral ventricles of the mouse brain and we investigate their capacity to reverse towards a progenitor-like identity in culture. Inhibition of the GSK3 and TGFβ pathways facilitates the switch of mature astrocytes to Sox2-expressing, mitotic cells that generate oligodendrocytes. Although this medium allows for the expansion of quiescent NSCs, isolated from live rats by "milking of the brain", it does not fully reverse astrocytes towards the bona fide NSC identity; this is a failure correlated with a concomitant lack of neurogenic activity. Ependymal cells could be induced to enter mitosis either via exposure to neuraminidase-dependent stress or by culturing them in the presence of FGF2 and EGF. Overall, our data confirm that astrocytes and ependymal cells retain a high capacity to reverse to a progenitor identity and set up a simple and highly controlled platform for the elucidation of the molecular mechanisms that regulate this reversal. [ABSTRACT FROM AUTHOR]

Adhesion between stem cells and their niche provides stable anchorage and signaling cues to sustain properties such as quiescence. Skeletal muscle stem cells (MuSCs) adhere to an adjacent myofiber via cadherin-catenin complexes. Previous studies on N- and M-cadherin in MuSCs revealed that although N-cadherin is required for quiescence, they are collectively dispensable for MuSC niche localization and regenerative activity. Although additional cadherins are expressed at low levels, these findings raise the possibility that cadherins are unnecessary for MuSC anchorage to the niche. To address this question, we conditionally removed from MuSCs β- and γ-catenin, and, separately, αE- and αT-catenin, factors that are essential for cadherin-dependent adhesion. Catenindeficient MuSCs break quiescence similarly to N-/M-cadherindeficient MuSCs, but exit the niche and are depleted. Combined in vivo, ex vivo and single cell RNA-sequencing approaches reveal that MuSC attrition occurs via precocious differentiation, re-entry to the niche and fusion to myofibers. These findings indicate that cadherin-catenin-dependent adhesion is required for anchorage of MuSCs to their niche and for preservation of the stem cell compartment. Furthermore, separable cadherin-regulated functions govern niche localization, quiescence and MuSC maintenance. [ABSTRACT FROM AUTHOR]

During the last years, there has been an increased effort in the discovery of selective and potent kinase inhibitors for targeted cancer therapy. Kinase inhibitors exhibit less toxicity compared to conventional chemotherapy, and several have entered the market. Mirk/Dyrk1B kinase is a promising pharmacological target in cancer since it is overexpressed in many tumors, and its overexpression is correlated with patients' poor prognosis. Mirk/Dyrk1B acts as a negative cell cycle regulator, maintaining the survival of quiescent cancer cells and conferring their resistance to chemotherapies. Many studies have demonstrated the valuable therapeutic effect of Mirk/Dyrk1B inhibitors in cancer cell lines, mouse xenografts, and patient-derived 3D-organoids, providing a perspective for entering clinical trials. Since the majority of Mirk/Dyrk1B inhibitors target the highly conserved ATP-binding site, they exhibit off-target effects with other kinases, especially with the highly similar Dyrk1A. In this review, apart from summarizing the data establishing Dyrk1B as a therapeutic target in cancer, we highlight the most potent Mirk/Dyrk1B inhibitors recently reported. We also discuss the limitations and perspectives for the structure-based design of Mirk/Dyrk1B potent and highly selective inhibitors based on the accumulated structural data of Dyrk1A and the recent crystal structure of Dyrk1B with AZ191 inhibitor. [ABSTRACT FROM AUTHOR]

Quiescence is a fundamental state of adult hematopoietic stem cells (HSCs) characterized by their residence in the G0 phase of the cell cycle. Despite being quiescent, HSCs retain their capacities for self-renewal and multipotency, enabling them to produce all blood lineages. Recent discoveries have shown that HSCs can dive into an even deeper state of quiescence with a very low division rate in steady-state conditions, known as dormancy. Dormant HSCs (dHSCs) have the most superior stem cell properties among HSCs, placing them at the top of the hematopoietic hierarchy. In this review, we argue that quiescence and dormancy are not synonyms in the context of HSCs. Specifically, dHSCs constitute a unique reserve pool of HSCs, mobilized only under stress conditions to protect the HSC compartment throughout life. While HSC quiescence is well-studied, the molecular features of HSC dormancy remain less well-defined. We will discuss the available methods for dHSC isolation and summarize the latest findings on the roles of niche factors, transcription factors, chromatin regulators, and cell cycle-related proteins in maintaining HSC dormancy. Additionally, we will explore whether insights from the quiescent HSC research can be applied to dHSCs. Lastly, we will assess the therapeutic potential of utilizing or targeting dHSCs to improve stem cell transplantation outcomes and treat hematological diseases, opening new avenues for research and clinical applications in regenerative medicine and oncology.

Signaling interactions are important during skeletal muscle regeneration, where muscle cells in distinct states (quiescent, reactivated, proliferating and differentiated) must coordinate their response to injury. Here, we probed the role of secreted small extracellular vesicles (sEV/exosomes) using a culture model of physiologically relevant cell states seen in muscle regeneration. Unexpectedly, G0 myoblasts exhibited enhanced secretion of sEV (∼150 nm) displaying exosome markers (Alix, TSG101, flotillin-1, and CD9), and increased expression of Kibra, a regulator of exosome biogenesis. Perturbation of Kibra levels confirmed a role in controlling sEV secretion rates. Purified sEVs displayed a common exosome marker-enriched proteome in all muscle cell states, as well as state-specific proteins. Exosomes derived from G0 cells showed an antioxidant signature, and were most strongly internalized by differentiated myotubes. Functionally, donor exosomes from all muscle cell states could activate an integrated Wnt reporter in target cells, but only G0-derived exosomes could induce myogenic differentiation in proliferating cells. Taken together, we provide evidence that quiescence in muscle cells is accompanied by enhanced secretion of exosomes with distinct uptake, cargo and signal activating features. Our study suggests the novel possibility that quiescent muscle stem cells in vivo may play a previously under-appreciated signaling role during muscle homeostasis.

Dormancy in cancer is a clinical state in which residual disease remains undetectable for a prolonged duration. At a cellular level, rare cancer cells cease proliferation and survive chemotherapy and disseminate disease. We created a suspension culture model of high-grade serous ovarian cancer (HGSOC) dormancy and devised a novel CRISPR screening approach to identify survival genes in this context. In combination with RNA-seq, we discovered the Netrin signaling pathway as critical to dormant HGSOC cell survival. We demonstrate that Netrin-1, –3, and its receptors are essential for low level ERK activation to promote survival, and that Netrin activation of ERK is unable to induce proliferation. Deletion of all UNC5 family receptors blocks Netrin signaling in HGSOC cells and compromises viability during the dormancy step of dissemination in xenograft assays. Furthermore, we demonstrate that Netrin-1 and –3 overexpression in HGSOC correlates with poor outcome. Specifically, our experiments reveal that Netrin overexpression elevates cell survival in dormant culture conditions and contributes to greater spread of disease in a xenograft model of abdominal dissemination. This study highlights Netrin signaling as a key mediator HGSOC cancer cell dormancy and metastasis.

Mating experience impacts the physiology and behavior of animals. Although mating effects of female Drosophila melanogaster have been studied extensively, the behavioral changes of males following copulation have not been fully understood. In this study, we characterized the mating-dependent behavioral changes of male flies, especially focusing on fly-to-fly interaction, and their dependence on rearing conditions. Our data demonstrate that male flies quiesce their courtship toward both females and males, as well as their locomotor activity. This post-copulatory quiescence appears to be contingent upon the presence of a peer, as minimal variation is noted in locomotion when the male is measured in isolation. Interestingly, copulated males influence a paired male without successful copulation to reduce his locomotion. Our findings point to a conditional behavioral quiescence following copulation, influenced by the presence of other flies.

Quiescence, or dormancy, is a response to stressful conditions in which an organism slows or halts physiological functioning. Although most species that undergo dormancy maintain complex microbiomes, there is little known about how dormancy influences and is influenced by the host's microbiome, including in the temperate coral Astrangia poculata. Northern populations of A. poculata undergo winter quiescence. Here, we characterized wild A. poculata microbiomes in a high-resolution sampling time series before, during, and after quiescence using 16S rRNA gene sequencing on active (RNA) and present (DNA) microbiomes. We observed a restructuring of the coral microbiome during quiescence that persisted after reemergence. Upon entering quiescence, corals shed copiotrophic microbes, including putative pathogens, suggesting a removal of these taxa as corals cease normal functioning. During and after quiescence, bacteria and archaea associated with nitrification were enriched, suggesting that the quiescent microbiome may replace essential functions through supplying nitrate to corals and/or microbes. Overall, this study demonstrates that key microbial groups related to quiescence in A. poculata may play a role in the onset or emergence from dormancy and long-term regulation of the microbiome composition. The predictability of dormancy in A. poculata provides an ideal natural manipulation system to further identify factors that regulate host-microbial associations. IMPORTANCE Using a high-resolution sampling time series, this study is the first to demonstrate a persistent microbial community shift with quiescence (dormancy) in a marine organism, the temperate coral Astrangia poculata. Furthermore, during this period of community turnover, there is a shedding of putative pathogens and copiotrophs and an enhancement of the ammonia-oxidizing bacteria (Nitrosococcales) and archaea ("Candidatus Nitrosopumilus"). Our results suggest that quiescence represents an important period during which the coral microbiome can reset, shedding opportunistic microbes and enriching for the reestablishment of beneficial associates, including those that may contribute nitrate while the coral animal is not actively feeding. We suggest that this work provides foundational understanding of the interplay of microbes and the host's dormancy response in marine organisms.

Abstract Stem cells are pivotal players in the intricate dance of embryonic development, tissue maintenance, and regeneration. Their behavior is delicately balanced between maintaining their pluripotency and differentiating as needed. Disruptions in this balance can lead to a spectrum of diseases, underscoring the importance of unraveling the complex molecular mechanisms that govern stem cell fate. Forkhead box O (FOXO) proteins, a family of transcription factors, are at the heart of this intricate regulation, influencing a myriad of cellular processes such as survival, metabolism, and DNA repair. Their multifaceted role in steering the destiny of stem cells is evident, as they wield influence over self-renewal, quiescence, and lineage-specific differentiation in both embryonic and adult stem cells. This review delves into the structural and regulatory intricacies of FOXO transcription factors, shedding light on their pivotal roles in shaping the fate of stem cells. By providing insights into the specific functions of FOXO in determining stem cell fate, this review aims to pave the way for targeted interventions that could modulate stem cell behavior and potentially revolutionize the treatment and prevention of diseases.

Intra-tumor heterogeneity is now arguably one of the most-studied topics in tumor biology, as it represents a major obstacle to effective cancer treatment. Since tumor cells are highly diverse at genetic, epigenetic, and phenotypic levels, intra-tumor heterogeneity can be assumed as an important contributing factor to the nullification of chemotherapeutic effects, and recurrence of the tumor. Based on the role of heterogeneous subpopulations of cancer cells with varying cell-cycle dynamics and behavior during cancer progression and treatment; herein, we aim to establish a comprehensive definition for adaptation of neoplastic cells against therapy. We discuss two parallel and yet distinct subpopulations of tumor cells that play pivotal roles in reducing the effects of chemotherapy: “resistant” and “tolerant” populations. Furthermore, this review also highlights the impact of the quiescent phase of the cell cycle as a survival mechanism for cancer cells. Beyond understanding the mechanisms underlying the quiescence, it provides an insightful perspective on cancer stem cells (CSCs) and their dual and intertwined functions based on their cell cycle state in response to treatment. Moreover, CSCs, epithelial–mesenchymal transformed cells, circulating tumor cells (CTCs), and disseminated tumor cells (DTCs), which are mostly in a quiescent state of the cell cycle are proved to have multiple biological links and can be implicated in our viewpoint of cell cycle heterogeneity in tumors. Overall, increasing our knowledge of cell cycle heterogeneity is a key to identifying new therapeutic solutions, and this emerging concept may provide us with new opportunities to prevent the dreadful cancer recurrence.

Centromeres are large structural regions in the genomic DNA, which are essential for accurately transmitting a complete set of chromosomes to daughter cells during cell division. In humans, centromeres consist of highly repetitive α-satellite DNA sequences and unique epigenetic components, forming large proteinaceous structures required for chromosome segregation. Despite their biological importance, there is a growing body of evidence for centromere breakage across the cell cycle, including periods of quiescence. In this review, we provide an up-to-date examination of the distinct centromere environments at different stages of the cell cycle, highlighting their plausible contribution to centromere breakage. Additionally, we explore the implications of these breaks on centromere function, both in terms of negative consequences and potential positive effects. [ABSTRACT FROM AUTHOR]

The BMP pathway is one of the major signaling pathways in embryonic development, ontogeny and homeostasis, identified many years ago by pioneers in developmental biology. Evidence of the deregulation of its activity has also emerged in many cancers, with complex and sometimes opposing effects. Recently, its role has been suspected in Diffuse Midline Gliomas (DMG), among which Diffuse Intrinsic Pontine Gliomas (DIPG) are one of the most complex challenges in pediatric oncology. Genomic sequencing has led to understanding part of their molecular etiology, with the identification of histone H3 mutations in a large proportion of patients. The epigenetic remodeling associated with these genetic alterations has also been precisely described, creating a permissive context for oncogenic transcriptional program activation. This review aims to describe the new findings about the involvement of BMP pathway activation in these tumors, placing their appearance in a developmental context. Targeting the oncogenic synergy resulting from this pathway activation in an H3K27M context could offer new therapeutic perspectives based on targeting treatment-resistant cell states. [ABSTRACT FROM AUTHOR]