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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]

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]

There is dynamic and bidirectional regulation of cell metabolism and cell cycle progression that is incompletely understood. Changes to cellular metabolism, including redox state, can directly affect the activity of cell cycle regulators and signaling pathways to impact cell cycle control. Mitochondrial metabolism changes dramatically during the cell cycle and most acutely during mitosis. Cells adjust cell cycle duration and growth rate to couple cell size to cell cycle progression and maintain uniform cell size across generations. Disruption of protein synthesis or DNA replication can drive cells to exit the cell cycle and become quiescent. The relationship between metabolism and cell cycle progression is complex and bidirectional. Cells must rewire metabolism to meet changing biosynthetic demands across cell cycle phases. In turn, metabolism can influence cell cycle progression through direct regulation of cell cycle proteins, through nutrient-sensing signaling pathways, and through its impact on cell growth, which is linked to cell division. Furthermore, metabolism is a key player in mediating quiescence–proliferation transitions in physiologically important cell types, such as stem cells. How metabolism impacts cell cycle progression, exit, and re-entry, as well as how these processes impact metabolism, is not fully understood. Recent advances uncovering mechanistic links between cell cycle regulators and metabolic processes demonstrate a complex relationship between metabolism and cell cycle control, with many questions remaining. [ABSTRACT FROM AUTHOR]

• Quiescence halts cell cycling while retaining potential to resume proliferation upon stimuli. • Quiescence is tissue-specific and highly regulated by extrinsic and intrinsic cues. • Quiescent NSCs are molecularly unique and entail deeper and shallower states. • NSC quiescence understanding holds promise for glioblastoma and rejuvenation therapies. Cell quiescence is an essential mechanism that allows cells to temporarily halt proliferation while preserving the potential to resume it at a later time. The molecular mechanisms underlying cell quiescence are complex and involve the regulation of various signaling pathways, transcription factors and epigenetic modifications. The importance of unveiling the mechanisms regulating the quiescent state is undeniable, as its long-term maintenance is key to sustain tissue homeostasis throughout life. Neural stem cells (NSCs) are maintained in the subependymal zone (SEZ) niche of adult mammalian brains mostly as long-lasting quiescent cells, owing to multiple intrinsic and extrinsic cues that actively regulate this state. Differently from other non-proliferative states, quiescence is a reversible and tightly regulated condition that can re-activate to support the formation of new neurons throughout adult lifespan. Decoding its regulatory mechanisms in homeostasis and unveiling how it is modulated in the context of the aged brain or during tumorigenesis, could bring us closer to the development of new potential strategies to intervene in adult neurogenesis with therapeutic purposes. Starting with a general conceptualization of the quiescent state in different stem cell niches, we here review what we have learned about NSC quiescence in the SEZ, encompassing the experimental strategies used for its study, to end up discussing the modulation of quiescence in the context of a physiology or pathological NSC dysregulation. [ABSTRACT FROM AUTHOR]

Mitochondrial dynamics and metabolism govern embryonic and adult neural stem cell (NSC) behavior. Quiescent adult NSCs have active mitochondria and rely on mitochondrial metabolism to sustain their cell state. Single-cell RNA sequencing reveals dynamic expression of mitochondrial metabolism genes in NSCs, but does not always provide an accurate picture of the metabolic state. Novel technologies exploiting metabolic parameters allow for separation of distinct NSC states in real time. Metabolism has emerged as a key regulator of stem cell behavior. Mitochondria are crucial metabolic organelles that are important for differentiated cells, yet considered less so for stem cells. However, recent studies have shown that mitochondria influence stem cell maintenance and fate decisions, inviting a revised look at this topic. In this review, we cover the current literature addressing the role of mitochondrial metabolism in mouse and human neural stem cells (NSCs) in the embryonic and adult brain. We summarize how mitochondria are implicated in fate regulation and how substrate oxidation affects NSC quiescence. We further explore single-cell RNA sequencing (scRNA-seq) data for metabolic signatures of adult NSCs, highlight emerging technologies reporting on metabolic signatures, and discuss mitochondrial metabolism in other stem cells. [ABSTRACT FROM AUTHOR]

Cellular quiescence – reversible exit from the cell cycle – is an important feature of many cell types important for organismal health. Aging and cellular dysfunction compromise the survival and reactivation of quiescent cells over time. Studies suggest that autophagic processes and lysosomal function are critical to maintaining the function of quiescent cells, especially adult stem cells, throughout life. Findings also point to both pro-senescence and anti-senescence functions for macroautophagy depending on context. In this review, we will discuss these findings, unanswered questions on the role of macroautophagy and lysosomal function in quiescent and senescent cells, and the possibility for interventions that stimulate macroautophagy and lysosomes to promote quiescent cell function and tissue regeneration. Cellular quiescence (reversible cell cycle arrest) and senescence (irreversible cell cycle arrest) are inter-related cell fates that govern many aspects of tissue homeostasis. With age, quiescent cells lose reactivation efficiency, and senescent cells accumulate, possibly contributing to tissue dysfunction with age. Lysosomes and macroautophagy are central to maintaining the function of quiescent cells, possibly by destroying damaged and toxic cellular components such as mitochondria. 'Basal' levels of macroautophagy mitigate quiescence-to-senescence transition, but high levels of macroautophagy may be detrimental. Therefore, autophagy-stimulating interventions should be evaluated for their effects on quiescent and senescent cells. [ABSTRACT FROM AUTHOR]

The existence of stem cells (SCs) at the tip of the cellular differentiation hierarchy has fascinated the scientific community ever since their discovery in the early 1950s to 1960s. Despite the remarkable success of the SC theory and the development of SC-based treatments, fundamental features of SCs remain enigmatic. Recent advances in single-cell lineage tracing, live imaging, and genomic technologies have allowed capture of life histories and transcriptional signatures of individual cells, leaving SCs much less space to 'hide'. Focusing on epithelial SCs and comparing them to other SCs, we discuss new paradigms of the SC niche, dynamics, and pathology, highlighting key open questions in SC biology that need to be resolved for harnessing SC potential in regenerative medicine. The traditional stem cell (SC) model relies on assays that reflect stress conditions. Individual cell fate mapping suggests that SCs are abundant and that their self-renewal or differentiation is unpredictable. SC competition results in clonal evolution in aging and pathology. The abundance of SCs suggests the presence of widespread supportive niches. Poor knowledge about the SC–niche interaction is hindering SC applications in disease modeling and regenerative medicine. Resident SCs possess distinct traits that are potentially tailored for local physiology. [ABSTRACT FROM AUTHOR]

• β-Hydroxybutyrate differentially impacts neuron and astrocyte mitochondria. • β-Hydroxybutyrate promotes neuron quiescence. • SH-SY5Y responses to β-hydroxybutyrate better reflect neuron responses. While ketone bodies support overall brain energy metabolism, it is increasingly clear specific brain cell types respond differently to ketone body availability. Here, we characterized how SH-SY5Y neuroblastoma cell, primary neuron, and primary astrocyte bioenergetics and nutrient sensing pathways respond to β-hydroxybutyrate (βOHB). SH-SY5Y cells and primary neurons, but not astrocytes, exposed to βOHB increased respiration and decreased PI3K-Akt-mTOR signaling. Despite increased carbon availability and respiration, SH-SY5Y cells treated with βOHB reduced their overall metabolic activity and cell cycling rate. Levels of the quiescence-regulating Yamanaka factors increased to a broader extent in SH-SY5Y cells and primary neurons. We propose a βOHB-induced increase in neuron respiration, accompanied by activation of quiescence associated pathways, could alleviate bioenergetic stress and limit cell senescence. This in turn could potentially benefit conditions, including brain aging and neurodegenerative diseases, that feature bioenergetic decline and cell senescence. [ABSTRACT FROM AUTHOR]

Quiescence is an important non-pathological state in which cells pause cell cycle progression temporarily, sometimes for decades, until they receive appropriate proliferative stimuli. Quiescent cells make up a significant proportion of the body, and maintaining genomic integrity during quiescence is crucial for tissue structure and function. While cells in quiescence are spared from DNA damage associated with DNA replication or mitosis, they are still exposed to various sources of endogenous DNA damage, including those induced by normal transcription and metabolism. As such, it is vital that cells retain their capacity to effectively repair lesions that may occur and return to the cell cycle without losing their cellular properties. Notably, while DNA repair pathways are often found to be downregulated in quiescent cells, emerging evidence suggests the presence of active or differentially regulated repair mechanisms. This review aims to provide a current understanding of DNA repair processes during quiescence in mammalian systems and sheds light on the potential pathological consequences of inefficient or inaccurate repair in quiescent cells. • Quiescent cells in a state of reversible growth arrest retain the ability to repair DNA damage. • DNA repair mechanisms are often channelled to restore specific regions of the genome. • DNA repair factors may have different functions in cycling and non-cycling cells. • DNA repair in quiescent cells has important implications for human disease. [ABSTRACT FROM AUTHOR]

Alternative histone acylations integrate gene expression with cellular metabolic states. Recent measurements of cellular acyl-coenzyme A (acyl-CoA) pools highlight the potential that histone post-translational modifications (PTMs) contribute directly to the regulation of metabolite pools. A metabolite-centric view throws new light onto roles and evolution of histone PTMs. [ABSTRACT FROM AUTHOR]

The change in the phase, from quiescence to surge, may perturb the glacier's dynamical behavior. To understand these changes through geospatial technique, the fastest moving tidewater Monacobreen Glacier, Svalbard, was studied for the year 2016–2019. It was elucidated that the surge had initiated during 2017–2018 before it the glacier was in quiescence since 2001. Initially, the glacier radar zones, namely percolation refreeze, lower percolation, and clean ice, were identified using the multi-temporal SAR data. These zones were utilized to delineate the equilibrium line altitude, and it was found that it is continuously moving down during surging, unlike the quiescence phase. The accumulation area ratio was always more than 0.67 throughout the analysis. The seasonal change in glacier surface velocity for both the phases was estimated, adapting the most appropriate Offset Tracking approach using the SAR data. The mean velocity over the main trunk was found to vary from 0.5 to 4 m/day. Thereafter, Glen's flow law equation was used to estimate the ice-thickness and found that the glacier has an average thickness range of 216–326 m in quiescence and 136–244 m during the surging. The analysis depicted that the basal shear stresses are increasing with surging, and the viscosity is decreasing. It can be said that the transition of the glacier from quiescent to surging phase has entirely changed its dynamic behavior and characteristics. Further, in the absence of field observations, the geospatial technique may provide reasonable estimates of the glacier's physical and dynamical parameters. [ABSTRACT FROM AUTHOR]

Prostate cancer can progress rapidly after diagnosis, but can also become undetectable after curative intent radiation or surgery, only to recur years or decades later. This capacity to lie dormant and recur long after a patient was thought to be cured, is relatively unique to prostate cancer, with estrogen receptor positive breast cancer being the other common and well-studied example. Most investigators agree that the bone marrow is an important site for dormant tumor cells, given the frequency of bone metastases and that multiple studies have reported disseminated tumor cells in patients with localized disease. However, while more difficult to study, lymph nodes and the prostate bed are likely to be important reservoirs as well. Dormant tumor cells may be truly quiescent and in the G0 phase of the cell cycle, which is commonly called cellular dormancy. However, tumor growth may also be held in check through a balance of proliferation and cell death (tumor mass dormancy). For induction of cellular dormancy, prostate cancer cells respond to signals from their microenvironment, including TGF-β2, BMP-7, GAS6, and Wnt-5a, which result in signals transduced in part through p38 MAPK and pluripotency associated transcription factors including SOX2 and NANOG, which likely affect the epi-genome through histone modification. Clinical use of adjuvant radiation or androgen deprivation has been modestly successful to prevent recurrence. With the rapid pace of discovery in this field, systemic adjuvant therapy is likely to continue to improve in the future. [ABSTRACT FROM AUTHOR]

Having faced increased clinical treatment failures with dihydroartemisinin-piperaquine (DHA-PPQ), Cambodia swapped the first line artemisinin-based combination therapy (ACT) from DHA-PPQ to artesunate-mefloquine given that parasites resistant to piperaquine are susceptible to mefloquine. However, triple mutants have now emerged, suggesting that drug rotations may not be adequate to keep resistance at bay. There is, therefore, an urgent need for alternative treatment strategies to tackle resistance and prevent its spread. A proper understanding of all contributors to artemisinin resistance may help us identify novel strategies to keep artemisinins effective until new drugs become available for their replacement. This review highlights the role of the key players in artemisinin resistance, the current strategies to deal with it and suggests ways of protecting future antimalarial drugs from bowing to resistance as their predecessors did. [Display omitted] • Molecular Mechanisms of Artemisinin action and Resistance. • Current Strategies for Combating ACT failures. • Profiles of the Antimalarial Drugs in Development. • Lessons learnt from ACT failures as guide for the development of future antimalarial drugs. • The ideal antimalarial Single Exposure Radical Cure and Prophylaxis (SERCaP). [ABSTRACT FROM AUTHOR]

Quiescent adult neural stem cells (NSCs) in the mammalian brain arise from proliferating NSCs during development. Beyond acquisition of quiescence, an adult NSC hallmark, little is known about the process, milestones, and mechanisms underlying the transition of developmental NSCs to an adult NSC state. Here, we performed targeted single-cell RNA-seq analysis to reveal the molecular cascade underlying NSC development in the early postnatal mouse dentate gyrus. We identified two sequential steps, first a transition to quiescence followed by further maturation, each of which involved distinct changes in metabolic gene expression. Direct metabolic analysis uncovered distinct milestones, including an autophagy burst before NSC quiescence acquisition and cellular reactive oxygen species level elevation along NSC maturation. Functionally, autophagy is important for the NSC transition to quiescence during early postnatal development. Together, our study reveals a multi-step process with defined milestones underlying establishment of the adult NSC pool in the mammalian brain. [Display omitted] • NSC development into an adult state is a multi-step process with defined milestones • Molecular cascade underlying NSC quiescence acquisition and subsequent maturation • Sequential metabolic changes in autophagy and ROS during NSC development • Autophagy promotes NSC quiescence during early postnatal development Jimenez-Cyrus et al. report the molecular cascade underlying the neural stem cell transition to the quiescent adult state in the early postnatal mouse dentate gyrus. Neural stem cells sequentially progress through multiple states accompanied by transcriptional and metabolic changes. Autophagy functionally promotes the neural stem cell transition to quiescence. [ABSTRACT FROM AUTHOR]

Neural stem cells (NSCs) are multipotent progenitors that are responsible for producing all of the neurons and macroglia in the nervous system. In adult mammals, NSCs reside predominantly in a mitotically dormant, quiescent state, but they can proliferate in response to environmental inputs such as feeding or exercise. It is hoped that quiescent NSCs could be activated therapeutically to contribute towards repair in humans. This will require an understanding of quiescent NSC heterogeneities and regulation during normal physiology and following brain injury. Non-mammalian vertebrates (zebrafish and salamanders) and invertebrates (Drosophila) offer insights into brain repair and quiescence regulation that are difficult to obtain using rodent models alone. We review conceptual progress from these various models, a first step towards harnessing quiescent NSCs for therapeutic purposes. The adult mammalian brain harbours quiescent neural stem cells (NSCs), which possess a latent capacity to generate neurons and glia. Mechanistic insights into the origins and functional properties of quiescent NSCs are starting to arise in rodents, Drosophila , and regenerative vertebrates. It is becoming apparent that NSCs undergo different types of quiescence, such as G 0 and G 2 quiescence, or resting and dormant quiescence. Environmental signals, such as exercise or feeding, might increase the activation of quiescent NSCs. Putative trajectories from quiescence to activation have been reconstructed bioinformatically from single-cell transcriptome data. In general, quiescent NSCs are restricted to producing specific neuron subtypes after activation in vivo. It is possible to modify these outputs experimentally in some instances. The ability to control the outputs of quiescent NSCs will be an essential step in harnessing them for brain repair. [ABSTRACT FROM AUTHOR]

Artemisinin is the most widely-used compound against malaria and plays a critical role in the treatment of malaria worldwide. Resistance to artemisinin emerged about a decade ago in Southeast Asia and it is paramount to prevent its spread or emergence in Africa. Artemisinin has a complex mode of action and can cause widespread injury to many components of the parasite. In this review, we outline the different metabolic pathways affected by artemisinin, including the unfolded protein response, protein polyubiquitination, proteasome, phosphatidylinositol-3-kinase, and the eukaryotic translation initiation factor 2α. Based on recently published data, we present a model of how these different pathways interplay and how mutations in K13, the main identified resistance marker, may help parasites survive under artemisinin pressure. Artemisinin is currently the most widely used and effective compound against malaria parasites and it plays a critical role in treatment and ongoing control efforts of malaria worldwide. Unfortunately, emergence of resistance to artemisinin has occurred in Southeast Asia and was shown to be associated with mutations in the K13 gene. Artemisinin kills parasites by increasing oxidative stress in the infected red blood cell, leading to an increased level of unfolded protein. The unfolded protein response of the parasite is associated with a PK4/EIf2a response that can lead to parasite latency. K13 mutations are thought to alter ubiquitination patterns and help parasites to resist the accumulation of polyubiquinated proteins. How these two pathways interplay is not fully understood. Recombinant parasite and single-cell technologies provide powerful avenues to decipher the mode of action of artemisinin and the function of K13. [ABSTRACT FROM AUTHOR]

Stem cells are required for lifelong homeostasis and regeneration of tissues and organs in mammals, but the function of stem cells declines during aging. To preserve stem cells during life, they are kept in a quiescent state with low metabolic and low proliferative activity. However, activation of quiescent stem cells – an essential process for organ homeostasis/regeneration – requires concerted and faithful regulation of multiple molecular circuits controlling biosynthetic processes, repair mechanisms, and metabolic activity. Thus, while protecting stem cell maintenance, quiescence comes at the cost of vulnerability during the process of stem cell activation. Here we discuss molecular and biochemical processes regulating stem cells' maintenance in and exit from quiescence and how age-related failures of these circuits can contribute to organism aging. The quiescence stage of stem cells has beneficial and adverse effects on stem cell aging. Stem cell quiescence delays stem cell aging by reducing DNA replication, metabolic activity, gene transcription, and mRNA translation, since all of these activities are accompanied by induction of molecular damage. Stem cell quiescence comes at the cost of impaired expression of repair factors in quiescence and increased vulnerability in response to stem cell activation requiring the concerted and faithful activation of multiple molecular circuits controlling biosynthetic processes, repair, and metabolic activity. Aging-associated increases in stem cell-intrinsic accumulation of molecular damage as well as stem cell-extrinsic alterations (e.g., chronic inflammation, niche cell defects) contribute to the deregulation of quiescence maintenance and increasing vulnerability during exit from quiescence. Epigenetic alterations occur during aging in quiescent and activated stem cells and lead to aberrant expression of developmental genes resulting in alterations of quiescence maintenance, self-renewal, and differentiation. In conclusion, quiescence protects stem cells against molecular damage but comes at the cost of aging-associated failure in the correct regulation of quiescence maintenance and exit, thus increasing the vulnerability of stem cells during aging. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Although many drugs/treatments are now available for most diseases, too often, resistance to these treatments impedes complete therapeutic success. Acquired resistance is a major problem in many pathologies but it is an acute one in cancers and infections. This is probably because these diseases often require long durations of treatment, which ascribe to the selection of resistant cells. However, the actual mechanisms implicated in the selection process are still under debate. It is becoming increasingly clear that resistance is associated with the heterogeneity of cancer cells or micro-organisms and that multiple mechanisms underlie the emergence of drug-resistant subpopulations. Recently, it has been suggested that a subpopulation of drug tolerant cells present in cancer populations and called "persisters" play a major role in this resistance. Recent studies have shown that microorganisms share similar properties. Still, how persister/tolerant cells intervene in the development of resistance is not completely elucidated but seems to be related to epigenetic changes in treated cells and the capacity of persisters to modulate and/or highjack their microenvironment. Due to the complexity of this process, the input from mathematicians, as well as new methods of bioinformatics and statistics, is necessary to fully comprehend the acquisition of resistance/tolerance deriving from and leading to the heterogeneous cell populations. The present review will give a brief overview of the most recent data available on drug tolerant cells in cancers and their similarities with microorganisms. [ABSTRACT FROM AUTHOR]

Highlights • The circadian clock regulates maintenance of neural stem cells. • Metabolism modulates both neural stem cell fates and circadian clock machinery. • Disruption of the circadian clock causes loss of quiescence resulting indepletion of the neural stem cell population. • We propose that the NAD+-dependent deacetylase SIRT1 mediates neural stem cell fates by modulating the circadian clock. Abstract Neural stem cells persist in the adult central nervous system as a continuing source of astrocytes, oligodendrocytes and neurons. Various signalling pathways and transcription factors actively maintain this population by regulating cell cycle entry and exit. Similarly, the circadian clock is interconnected with the cell cycle and actively maintains stem cell populations in various tissues. Here, we discuss emerging evidence for an important role of the circadian clock in neural stem cell maintenance. We propose that the NAD+-dependent deacetylase SIRT1 exerts control over the circadian clock in adult neural stem cell function to limit exhaustion of their population. Conversely, disruption of the circadian clock may compromise neural stem cell quiescence resulting in a premature decline of the neural stem cell population. As such, energy metabolism and the circadian clock converge in adult neural stem cell maintenance. [ABSTRACT FROM AUTHOR]

Quiescence is a common cellular state, required for stem cell maintenance and microorganismal survival under stress conditions or starvation. However, the mechanisms promoting quiescence maintenance remain poorly known. Plasma membrane components segregate into distinct microdomains, yet the role of this compartmentalization in quiescence remains unexplored. Here, we show that flavodoxin-like proteins (FLPs), ubiquinone reductases of the yeast eisosome membrane compartment, protect quiescent cells from lipid peroxidation and ferroptosis. Eisosomes and FLPs expand specifically in respiratory-active quiescent cells, and mutants lacking either show accelerated aging and defective quiescence maintenance and accumulate peroxidized phospholipids with monounsaturated or polyunsaturated fatty acids (PUFAs). FLPs are essential for the extramitochondrial regeneration of the lipophilic antioxidant ubiquinol. FLPs, alongside the Gpx1/2/3 glutathione peroxidases, prevent iron-driven, PUFA-dependent ferroptotic cell death. Our work describes ferroptosis-protective mechanisms in yeast and introduces plasma membrane compartmentalization as an important factor in the long-term survival of quiescent cells. [Display omitted] • Eisosome membrane domains expand in respiratory-active quiescent cells • Eisosomes support quiescence maintenance • Eisosomes stabilize flavodoxin-like proteins (FLPs) at the plasma membrane • Eisosomes and FLPs protect quiescent cells from lipid peroxidation and ferroptosis Quiescence is required for microorganismal survival under stress. Megarioti et al. show that eisosome membrane domains expand in quiescent cells and promote quiescence maintenance. FLPs, eisosome-resident ubiquinone reductases, generate extramitochondrial ubiquinol and protect PUFA-supplemented quiescent cells from accumulation of lipid peroxides and iron-driven ferroptotic cell death. [ABSTRACT FROM AUTHOR]

The ability of stem cells to switch between quiescent and proliferative states is crucial for maintaining tissue homeostasis and regeneration. In Drosophila , quiescent neural stem cells (qNSCs) extend a primary protrusion, a hallmark of qNSCs. Here, we have found that qNSC protrusions can be regenerated upon injury. This regeneration process relies on the Golgi apparatus that acts as the major acentrosomal microtubule-organizing center in qNSCs. A Golgi-resident GTPase Arf1 and its guanine nucleotide exchange factor Sec71 promote NSC reactivation and regeneration via the regulation of microtubule growth. Arf1 physically associates with its new effector mini spindles (Msps)/XMAP215, a microtubule polymerase. Finally, Arf1 functions upstream of Msps to target the cell adhesion molecule E-cadherin to NSC-neuropil contact sites during NSC reactivation. Our findings have established Drosophila qNSCs as a regeneration model and identified Arf1/Sec71-Msps pathway in the regulation of microtubule growth and NSC reactivation. [Display omitted] • Protrusions of Drosophila quiescent neural stem cells regenerate upon injury • Golgi functions as a microtubule-organizing center in quiescent neural stem cells • Arf1 and its GEF Sec71 promote neural stem cell reactivation and regeneration • Arf1 physically associates with its new effector mini spindles (Msps)/XMAP215 Gujar et al., establish Drosophila quiescent neural stem cell protrusions as a regeneration model. A Golgi-resident GTPase Arf1 promotes neural stem cell reactivation and regeneration via its new effector Msps/XMAP215. [ABSTRACT FROM AUTHOR]

Physical properties of modifiable hydrogels can be tuned to direct stem cell differentiation in a role akin to that played by the extracellular matrix in native stem cell niches. However, stem cells do not respond to matrix cues in isolation, but rather integrate soluble and non-soluble signals to balance quiescence, self-renewal and differentiation. Here, we encapsulated single cell suspensions of human mesenchymal stem cells (hMSC) in hyaluronic acid-based hydrogels at high and low densities to unravel the contributions of matrix- and non-matrix-mediated cues in directing stem cell response. We show that in high-density (HD) cultures, hMSC do not rely on hydrogel cues to guide their fate. Instead, they take on characteristics of quiescent cells and secrete a glycoprotein-rich pericellular matrix (PCM) in response to signaling from neighboring cells. Preventing quiescence precluded the formation of a glycoprotein-rich PCM and forced HD cultures to differentiate in response to hydrogel composition. Our observations may have important implications for tissue engineering as neighboring cells may act counter to matrix cues provided by scaffolds. Moreover, as stem cells are most regenerative if activated from a quiescent state, our results suggest that ex vivo native-like niches that incorporate signaling from neighboring cells may enable the production of clinically relevant, highly regenerative cells. [ABSTRACT FROM AUTHOR]

A variety of mild stresses have been shown to extend lifespan in diverse species through hormesis, which is a beneficial response to a stress or toxin that would cause a negative response at a higher exposure. Whether particular stresses induce hormesis can vary with genotype for a given species, and the underlying mechanisms of lifespan extension are only partly understood in most cases. We show that low doses of the DNA damaging or replication stress agents hydroxyurea, methyl methanesulfonate, 4-nitroquinoline 1-oxide, or Zeocin (a phleomycin derivative) lengthened chronological lifespan in Saccharomyces cerevisiae if cells were exposed during growth, but not if they were exposed during stationary phase. Treatment with these agents did not change mitochondrial activity, increase resistance to acetic acid, ethanol, or heat stress, and three of four treatments did not increase resistance to hydrogen peroxide. Stationary phase yeast populations consist of both quiescent and nonquiescent cells, and all four treatments increased the proportion of quiescent cells. Several mutant strains with deletions in genes that influence quiescence prevented Zeocin treatment from extending lifespan and from increasing the proportion of quiescent stationary phase cells. These data indicate that mild DNA damage stress can extend lifespan by promoting quiescence in the absence of mitohormesis or improved general stress responses that have been frequently associated with improved longevity in other cases of hormesis. Further study of the underlying mechanism may yield new insights into quiescence regulation that will be relevant to healthy aging. [ABSTRACT FROM AUTHOR]

Age-associated impairments in adult stem cell functions correlate with a decline in somatic tissue regeneration capacity. However, the mechanisms underlying the molecular regulation of adult stem cell aging remain elusive. Here, we provide a proteomic analysis of physiologically aged murine muscle stem cells (MuSCs), illustrating a pre-senescent proteomic signature. During aging, the mitochondrial proteome and activity are impaired in MuSCs. In addition, the inhibition of mitochondrial function results in cellular senescence. We identified an RNA-binding protein, CPEB4, downregulated in various aged tissues, which is required for MuSC functions. CPEB4 regulates the mitochondrial proteome and activity through mitochondrial translational control. MuSCs devoid of CPEB4 induced cellular senescence. Importantly, restoring CPEB4 expression rescued impaired mitochondrial metabolism, improved geriatric MuSC functions, and prevented cellular senescence in various human cell lines. Our findings provide the basis for the possibility that CPEB4 regulates mitochondrial metabolism to govern cellular senescence, with an implication of therapeutic intervention for age-related senescence. [Display omitted] • Geriatric MuSCs display a pre-senescence proteomic landscape • Mitochondrial defects in geriatric MuSCs cause cellular senescence • CPEB4 maintains mitochondrial proteome and metabolism • CPEB4 prevents cellular senescence in geriatric MuSCs and various human cell lines Zeng and Zhang et al. analyze a pre-senescent proteome and identify an impaired mitochondrial proteome and activity in geriatric muscle stem cells. Mitochondrial defects induce cellular senescence, and the authors show that CPEB4 governs senescence by maintaining mitochondrial functions, suggesting its diagnostic potential for senescence and therapeutic potential for treating age-associated diseases. [ABSTRACT FROM AUTHOR]

Summary Hippocampal neurogenesis is important for certain forms of cognition, and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. Here, we show that the rate of fatty acid oxidation (FAO) regulates the activity of NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity. [ABSTRACT FROM AUTHOR]

Summary There exist similarities and differences in metabolism and physiology between normal proliferative cells and tumor cells. Once a cell enters the cell cycle, metabolic machinery is engaged to facilitate various processes. The kinetics and regulation of these metabolic changes have not been properly evaluated. To correlate the orchestration of these processes with the cell cycle, we analyzed the transition from quiescence to proliferation of a non-malignant murine pro-B lymphocyte cell line in response to IL-3. Using multiplex mass-spectrometry-based proteomics, we show that the transition to proliferation shares features generally attributed to cancer cells: upregulation of glycolysis, lipid metabolism, amino-acid synthesis, and nucleotide synthesis and downregulation of oxidative phosphorylation and the urea cycle. Furthermore, metabolomic profiling of this transition reveals similarities to cancer-related metabolic pathways. In particular, we find that methionine is consumed at a higher rate than that of other essential amino acids, with a potential link to maintenance of the epigenome. [ABSTRACT FROM AUTHOR]

Summary Quiescent long-term hematopoietic stem cells (LT-HSCs) are efficiently activated by type I interferon (IFN-I). However, this effect remains poorly investigated in the context of IFN-I-inducing virus infections. Here we report that both vesicular stomatitis virus (VSV) and murine cytomegalovirus (MCMV) infection induce LT-HSC activation that substantially differs from the effects triggered upon injection of synthetic IFN-I-inducing agents. In both infections, inflammatory responses had to exceed local thresholds within the bone marrow to confer LT-HSC cell cycle entry, and IFN-I receptor triggering was not critical for this activation. After resolution of acute MCMV infection, LT-HSCs returned to phenotypic quiescence. However, non-acute MCMV infection induced a sustained inflammatory milieu within the bone marrow that was associated with long-lasting impairment of LT-HSC function. In conclusion, our results show that systemic virus infections fundamentally affect LT-HSCs and that also non-acute inflammatory stimuli in bone marrow donors can affect the reconstitution potential of bone marrow transplants. [ABSTRACT FROM AUTHOR]

Summary Nuclear actin (N-actin) is known to participate in the regulation of gene expression. We showed previously that N-actin levels mediate the growth and quiescence of mouse epithelial cells in response to laminin-111 (LN1), a component of the mammary basement membrane (BM). We know that BM is defective in malignant cells, and we show here that it is the LN1/N-actin pathway that is aberrant in human breast cancer cells, leading to continuous growth. Photobleaching assays revealed that N-actin exit in nonmalignant cells begins as early as 30 min after LN1 treatment. LN1 attenuates the PI3K pathway leading to upregulation of exportin-6 (XPO6) activity and shuttles actin out of the nucleus. Silencing XPO6 prevents quiescence. Malignant cells are impervious to LN1 signaling. These results shed light on the crucial role of LN1 in quiescence and differentiation and how defects in the LN1/PI3K/XPO6/N-actin axis explain the loss of tissue homeostasis and growth control that contributes to malignant progression. [ABSTRACT FROM AUTHOR]

Summary Cell cycle kinetics are crucial to cell fate decisions. Although live imaging has provided extensive insights into this relationship at the single-cell level, the limited number of fluorescent markers that can be used in a single experiment has hindered efforts to link the dynamics of individual proteins responsible for decision making directly to cell cycle progression. Here, we present fluorescently tagged endogenous proliferating cell nuclear antigen (PCNA) as an all-in-one cell cycle reporter that allows simultaneous analysis of cell cycle progression, including the transition into quiescence, and the dynamics of individual fate determinants. We also provide an image analysis pipeline for automated segmentation, tracking, and classification of all cell cycle phases. Combining the all-in-one reporter with labeled endogenous cyclin D1 and p21 as prime examples of cell-cycle-regulated fate determinants, we show how cell cycle and quantitative protein dynamics can be simultaneously extracted to gain insights into G1 phase regulation and responses to perturbations. [ABSTRACT FROM AUTHOR]

Summary Mammalian cells have two fundamentally different states, proliferative and quiescent, but our understanding of how and why cells switch between these states is limited. We previously showed that actively proliferating populations contain a subpopulation that enters quiescence (G0) in an apparently stochastic manner. Using single-cell time-lapse imaging of CDK2 activity and DNA damage, we now show that unresolved endogenous replication stress in the previous (mother) cell cycle prompts p21-dependent entry of daughter cells into quiescence immediately after mitosis. Furthermore, the amount of time daughter cells spend in quiescence is correlated with the extent of inherited damage. Our study thus links replication errors in one cell cycle to the fate of daughter cells in the subsequent cell cycle. More broadly, this work reveals that entry into quiescence is not purely stochastic but has a strong deterministic component arising from a memory of events that occurred in the previous generation(s). [ABSTRACT FROM AUTHOR]

This paper provides the first continuous assessment of behavioural quiescence in Eastern oysters ( Crassostrea virginica ) overwintered at their northernmost (48°N) distribution range. The paper also describes how quiescent oysters respond to sediment burial, which may occur inadvertently when cultured stocks are lowered onto soft-sediment seabeds. Long term monitoring of valve opening indicated that quiescence persisted for 164.9 ± 1.8 days (mean ± SE, n = 14 oysters) in 2014–2015. Quiescence was initiated in mid-November 2014 when the water temperature fell to 2.7 ± 0.2 °C and ended in early May 2015 when the water temperature rose to 4.4 ± 0.4 °C. The low mortality rate (3.4 ± 1.9%) of the control groups indicated that this species is well-adapted to such overwintering conditions. When buried in late October, oysters initially exhibited low-amplitude and sporadic shell movements, possibly in an attempt to clear the sediment covering their valve margins. Following a period of quiescence, behavioural morbidity ensued, with lethargic opening of valves beginning 153.3 ± 9.9 days after burial (n = 16 oysters). Death occurred 186.5 ± 3.6 days following burial (n = 16 oysters). Removing buried quiescent oysters from the sediment in late winter accelerated the depletion of energy reserves, particularly lipids and proteins, thereby advancing death. In conclusion, detrimental health effects associated with the burial of oysters in autumn cannot be mitigated through winter or spring desiltation. Thus, reducing the risk of burial by avoiding soft estuarine sediment whenever possible remains the best husbandry practice. [ABSTRACT FROM AUTHOR]

Background aims. Adipose-derived stromal cells (ASCs) are attractive sources for cell-based therapies. The hypoxic niche of ASCs in vivo implies that cells will benefit from hypoxia during in vitro expansion. Human platelet lysate (hPL) enhances ASC proliferation rates, compared with fetal bovine serum (FBS) at normoxia. However, the low proliferation rates of FBS-expanded ASCs could be signs of senescence or quiescence. We aimed to determine the effects of hypoxia and hPL on the expansion of ASCs and whether FBS-expanded ASCs are senescent or quiescent. Methods. ASCs expanded in FBS or hPL at normoxia or hypoxia until passage 7 (P7), or in FBS until P5 followed by culture in hPL until P7, were evaluated by proliferation rates, cell cycle analyses, gene expression and β-galactosidase activity. Results. hPL at normoxia and hypoxia enhanced proliferation rates and expression of cyclins, and decreased G0/G1 fractions and expression of p21 and p27, compared with FBS. The shift from FBS to hPL enhanced cyclin levels, decreased p21 and p27 levels and tended to decrease G0/G1 fractions. Conclusion. Hypoxia does not add to the effect of hPL during ASC expansion with regard to proliferation, cell cycle regulation and expression of cyclins, p21 and p27. hPL rejuvenates FBS-expanded ASCs with regard to cell cycle regulation and expression of cyclins, p21 and p27. This indicates a reversible arrest. Therefore, we conclude that ASCs expanded until P7 are not senescent regardless of culture conditions. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) stem cells (GSCs) display phenotypic and molecular features reminiscent of normal neural stem cells and exhibit a spectrum of cell cycle states (dormant, quiescent, proliferative). However, mechanisms controlling the transition from quiescence to proliferation in both neural stem cells (NSCs) and GSCs are poorly understood. Elevated expression of the forebrain transcription factor FOXG1 is often observed in GBMs. Here, using small-molecule modulators and genetic perturbations, we identify a synergistic interaction between FOXG1 and Wnt/β-catenin signaling. Increased FOXG1 enhances Wnt-driven transcriptional targets, enabling highly efficient cell cycle re-entry from quiescence; however, neither FOXG1 nor Wnt is essential in rapidly proliferating cells. We demonstrate that FOXG1 overexpression supports gliomagenesis in vivo and that additional β-catenin induction drives accelerated tumor growth. These data indicate that elevated FOXG1 cooperates with Wnt signaling to support the transition from quiescence to proliferation in GSCs. [Display omitted] • A small-molecule screen reveals synergy between FOXG1 and GSK3 inhibition on quiescence exit • Genetic and pharmacological approaches confirm the role of Wnt in the synergy • FOXG1 enhances Wnt-driven transcriptional targets and represses WIF1 • Elevated FOXG1 and β-catenin in a GBM model drive accelerated growth and reduced survival Glioblastomas contain quiescent stem cells expressing high levels of FOXG1. Robertson et al. identify a synergistic interaction between FOXG1 and Wnt/β-catenin signaling that drives exit from quiescence in vitro and accelerated tumor growth in vivo. They show that FOXG1 enhances Wnt transcriptional targets and represses the Wnt inhibitor WIF1. [ABSTRACT FROM AUTHOR]

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear. Here, we show that p53 maintains quiescence by inducing fatty-acid oxidation (FAO) and that acute p53 deletion in qNSCs results in their premature activation to a proliferative state. Mechanistically, this occurs through direct transcriptional induction of PPARGC1a, which in turn activates PPARα to upregulate FAO genes. Dietary supplementation with fish oil containing omega-3 fatty acids, natural PPARα ligands, fully restores quiescence of p53-deficient NSCs and delays tumor initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention. [Display omitted] • p53 maintains neural stem cell quiescence by inducing fatty-acid oxidation (FAO) • p53 loss prematurely activates neural stem cells during gliomagenesis • Restoration of FAO through diet reinstates quiescence to suppress tumor initiation Amodeo et al. examine the impact of a glioma-relevant mutation on murine subventricular zone neural stem cells and identify premature quiescence exit driven by metabolic rewiring as a key tumor-initiating event. They show that a fish-oil-supplemented diet is sufficient to counteract these effects, thereby silencing mutations and suppressing tumorigenesis. [ABSTRACT FROM AUTHOR]

Summary Throughout life, adult neural stem cells (NSCs) produce new neurons and glia that contribute to crucial brain functions. Quiescence is an essential protective feature of adult NSCs; however, the establishment and maintenance of this state remain poorly understood. We demonstrate that in the adult zebrafish pallium, the brain-enriched miR-9 is expressed exclusively in a subset of quiescent NSCs, highlighting a heterogeneity within these cells, and is necessary to maintain NSC quiescence. Strikingly, miR-9, along with Argonaute proteins (Agos), is localized to the nucleus of quiescent NSCs, and manipulating their nuclear/cytoplasmic ratio impacts quiescence. Mechanistically, miR-9 permits efficient Notch signaling to promote quiescence, and we identify the RISC protein TNRC6 as a mediator of miR-9/Agos nuclear localization in vivo. We propose a conserved non-canonical role for nuclear miR-9/Agos in controlling the balance between NSC quiescence and activation, a key step in maintaining adult germinal pools. [ABSTRACT FROM AUTHOR]

Summary During infection in mammals, the protozoan parasite Trypanosoma brucei transforms from a proliferative bloodstream form to a quiescent form that is pre-adapted to host transition. AMP analogs are known to induce quiescence and also inhibit TbTOR4. To examine the role of AMP-activated kinase (AMPK) in the regulation of this developmental transition, we characterized trypanosome TbAMPK complexes. Expression of a constitutively active AMPKα1 induces quiescence of the infective form, and TbAMPKα1 phosphorylation occurs during differentiation of wild-type pleomorphic trypanosomes to the quiescent stumpy form in vivo. Compound C, a well-known AMPK inhibitor, inhibits parasite differentiation in mice. We also provide evidence linking oxidative stress to TbAMPKα1 activation and quiescent differentiation, suggesting that TbAMPKα1 activation balances quiescence, proliferation, and differentiation. [ABSTRACT FROM AUTHOR]

Plants survive stressful conditions by employing three main strategies: escape, tolerance, and survival. Experiments were conducted to pinpoint the response strategy adopted by Tetradenia riparia to cadmium (Cd) stress by monitoring several physiological parameters and plants’ ability to recover once the stress receded. Cadmium (30 and 150 μM) strongly affected shoot and root growth in a dose dependent manner, with almost complete inhibition of shoot growth, stomatal opening and CO 2 assimilation in plants exposed to 150 μM CdSO 4 . Independently of the CdSO 4 concentrations, plants excluded Cd from the aboveground tissues, with concentrations in shoots remaining around 0.1 μmol g −1 dry mass. Furthermore, Cd stress was associated with a decline in methylation of Lys4 of histone H3, likely associated with the transition from an active to a quiescent state. Surprisingly, Cd also induced the initiation of root primordia in T. riparia stems, which, once placed in a Cd-free media, quickly (24 h) developed into adventitious roots, which were likely the driving factor of the rapid resumption of leaf elongation and photosynthetic activity, which increased almost 20-fold over the 3 weeks of recovery. Therefore T. riparia ability to survive Cd stress was mediated by quiescence, which associated with an excluder strategy and stem root primordia formation, enabled rapid resumption of growth under Cd-free conditions. [ABSTRACT FROM AUTHOR]

Platelet factor-4 (CXCL4/PF-4) is a member of CXC-chemokine family produced by megakaryocytic lineage and stored in platelet α-granules. Platelet stimulation by aggregating agents such as thrombin and ADP leads to CXCL4 secretion. CXCL4 plays several roles in coagulation, angiogenesis control, immune system modulation and spread of cancer. Megakaryocytes (Mks) are associated with the vascular niche in the bone marrow (BM) and are located in vicinity of BM sinusoids. Mk-derived CXCL4 is involved in several hematopoietic processes, including inhibition of megakaryopoiesis and maintenance of hematopoietic stem cell (HSC) quiescence. The major aim of this review article was to evaluate the role of CXCL4 in hematological malignancies, promotion of HSC quiescence as well as BM niche cells. [ABSTRACT FROM AUTHOR]

Four members of the Ixodes ricinus species complex, Ixodes pacificus, Ixodes persulcatus , Ixodes ricinus and Ixodes scapularis , have, between them, a worldwide distribution within the northern hemisphere. They are responsible for the transmission of several animal and human pathogens, including the causal agents of Lyme borreliosis, tick-borne encephalitis, human granulocytic anaplasmosis and human babesiosis. Despite the importance of these ticks as vectors, the knowledge and understanding of the role that diapause plays in their complex life cycles are confused and incomplete. In view of the continuing geographic spread of these tick species, as well as the effects of climate change on vector-borne diseases, it is timely to encourage research on diapause phenomena to improve understanding of their biology and of pathogen transmission dynamics. In our review we seek to clarify thinking on the topic and to address gaps in our knowledge that require the attention of researchers. [ABSTRACT FROM AUTHOR]

While it is a relatively rare disease, glioblastoma multiform (GBM) is one of the more deadly adult cancers. Following current interventions, the tumor is never eliminated whatever the treatment performed; whether it is radiotherapy, chemotherapy, or surgery. One hypothesis to explain this poor outcome is the “cancer stem cell” hypothesis. This concept proposes that a minority of cells within the tumor mass share many of the properties of adult neural stem cells and it is these that are responsible for the growth of the tumor and its resistance to existing therapies. Accumulating evidence suggests that Ca 2 + might also be an important positive regulator of tumorigenesis in GBM, in processes involving quiescence, maintenance, proliferation, or migration. Glioblastoma tumors are generally thought to develop by co-opting pathways that are involved in the formation of an organ. We propose that the cells initiating the tumor, and subsequently the cells of the tumor mass, must hijack the different checkpoints that evolution has selected in order to prevent the pathological development of an organ. In this article, two main points are discussed. (i) The first is the establishment of a so-called “cellular society,” which is required to create a favorable microenvironment. (ii) The second is that GBM can be considered to be an organism, which fights to survive and develop. Since GBM evolves in a limited space, its only chance of development is to overcome the evolutionary checkpoints. For example, the deregulation of the normal Ca 2 + signaling elements contributes to the progression of the disease. Thus, by manipulating the Ca 2 + signaling, the GBM cells might not be killed, but might be reprogrammed toward a new fate that is either easy to cure or that has no aberrant functioning. This article is part of a Special Issue entitled: Calcium and Cell Fate . Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. [ABSTRACT FROM AUTHOR]

The quiescent phase of the cell cycle is of fundamental importance for fungi, yet our understanding of this phase of the cycle is much less well understood than the mitotic cell cycle. We found that the ECM27 gene, which encodes a Na + /Ca 2+ exchanger, is responsible for influx of calcium from the extracellular space and release from intracellular stores during membrane stress. Wild type cells increase total Ca 2+ in quiescence but cells lacking ECM27 gene fail to do so and are defective in cell cycle reentry from the quiescent phase. ecm27 Δ cells are also defective in maintaining trehalose levels throughout this phase. Addition of high levels of CaCl 2 to the growth medium can increase total cellular calcium in ecm27 Δ cells during quiescence and can also restore trehalose levels as well as partially restore ability of cells to reenter the mitotic cell cycle. ecm27 Δ cells also have altered glycogen levels in exponentially growing cells. Our results show that Ecm27p and Ca 2+ play roles in maintaining a high level of trehalose in quiescent cells, which in turn is important in the ability of cells to rapidly return to proliferation. [ABSTRACT FROM AUTHOR]

An in-depth re-evaluation of hormogastrid earthworms inhabiting the Rio Ter Basin near Girona, northeastern Spain, previously assigned to the Hormogaster pretiosa Michaelsen, 1899 complex, resulted in new morpho-anatomical and genetic evidence supporting their recognition as a separate new species. Hormogaster regina sp. n., the largest-bodied species in the Hormogastridae, differs from the type material of H. pretiosa (whose precise locality in Sardinia is unknown) and from most of H. pretiosa -like forms in the authors' collection by having: clitellum and clitellar bands longer, a higher folding of the typhlosole, and different location of thickened and displaced septa. In all these traits, the new species closely resembles a population from the southernmost tip of Sardinia (Cape Teulada). A phylogenetic analysis of mitochondrial markers (COI and 16S-tRNAs) supports such close relationship, yet gives evidence for their status as distinct species. Molecular data, like fine morphology, also shows an unexpected phylogenetic divergence between H. regina sp. n. and its formerly putative relative H. pretiosa hispanica Michaelsen, 1925 from Catalonia, as the latter is recovered in a totally separate and distant cluster. This confirms once again the frequent lack of correlation between genetic and geographic distances in the Hormogastridae, and calls for accurate comparative examinations, with attention to traits of life history and forgotten anatomical details ( e.g ., the peculiar pattern of anterior septa was illustrated by Daniele Rosa in his first description of Hormogaster ), for correct species delimitation and estimations of their relationships. [ABSTRACT FROM AUTHOR]

Conventional therapy of primary bone tumors includes surgical excision with wide resection, which leads to physical and aesthetic defects. For reconstruction of bone and joints, allografts can be supplemented with mesenchymal stem cells (MSCs). Similarly, adipose tissue transfer (ATT) is supplemented with adipose-derived stem cells (ADSCs) to improve the efficient grafting in the correction of soft tissue defects. MSC-like cells may also be used in tumor-targeted cell therapy. However, MSC may have adverse effects on sarcoma development. In the present study, human ADSCs, MSCs and pre-osteoclasts were co-injected with human MNNG-HOS osteosarcoma cells in immunodeficient mice. ADSCs and MSCs, but not the osteoclast precursors, accelerated the local proliferation of MNNG-HOS osteosarcoma cells. However, the osteolysis and the metastasis process were not exacerbated by ADSCs, MSCs, or pre-osteoclasts. In vitro proliferation of MNNG-HOS and Saos-2 osteosarcoma cells was increased up to 2-fold in the presence of ADSC-conditioned medium. In contrast, ADSC-conditioned medium did not change the dormant, quiescent state of osteosarcoma cells cultured in oncospheres. Due to the enhancing effect of ADSCs/MSCs on in vivo / in vitro proliferation of osteosarcoma cells, MSCs may not be good candidates for osteosarcoma-targeted cell therapy. Although conditioned medium of ADSCs accelerated the cell cycle of proliferating osteosarcoma cells, it did not change the quiescent state of dormant osteosarcoma cells, indicating that ADSC-secreted factors may not be involved in the risk of local recurrence. [ABSTRACT FROM AUTHOR]

The nematode Caenorhabditis elegans stops feeding and moving during a larval transition stage called lethargus and following exposure to cellular stressors. These behaviors have been termed ‘sleep-like states’. We argue that these behaviors should instead be called sleep. Sleep during lethargus is similar to sleep regulated by circadian timers in insects and mammals, and sleep in response to cellular stress is similar to sleep induced by sickness in other animals. Sleep in mammals and Drosophila shows molecular and functional conservation with C. elegans sleep. The simple neuroanatomy and powerful genetic tools of C. elegans have yielded insights into sleep regulation and hold great promise for future research into sleep regulation and function. [ABSTRACT FROM AUTHOR]

Light, nutrition, and oxygen are each important cues for developmental transitions in plants. A small number of recent studies have converged to give the first indication of how these environmental cues act together and independently via auxin, cytokinin, and ethylene to regulate cell proliferation in the root and shoot meristems. [ABSTRACT FROM AUTHOR]

In healthy vessels, endothelial cells maintain a stable, differentiated, and growth-arrested phenotype for years. Upon injury, a rapid phenotypic switch facilitates proliferation to restore tissue perfusion. Here we report the identification of the endothelial cell-enriched long non-coding RNA (lncRNA) PCAT19 , which contributes to the proliferative switch and acts as a safeguard for the endothelial genome. PCAT19 is enriched in confluent, quiescent endothelial cells and binds to the full replication protein A (RPA) complex in a DNA damage- and cell-cycle-related manner. Our results suggest that PCAT19 limits the phosphorylation of RPA2, primarily on the serine 33 (S33) residue, and thereby facilitates an appropriate DNA damage response while slowing cell cycle progression. Reduction in PCAT19 levels in response to either loss of cell contacts or knockdown promotes endothelial proliferation and angiogenesis. Collectively, PCAT19 acts as a dynamic guardian of the endothelial genome and facilitates rapid switching from quiescence to proliferation. [Display omitted] • Endothelial cell-enriched lncRNA PCAT19 is upregulated with quiescence • PCAT19 depletion promotes cell proliferation, sprouting, and DNA damage • PCAT19 binds to RPA2 and blocks RPA2-S33 phosphorylation by the ATR kinase • Blocking ATR activity rescues the endothelial phenotype after PCAT19 depletion Oo et al. report an essential role for the lncRNA PCAT19 in the endothelial cell proliferation-quiescence switch. Endothelial cell-enriched PCAT19 is upregulated with quiescence and binds RPA2 to prevent aberrant phosphorylation of RPA2-S33 by ATR kinase. This ensures an appropriate DNA damage response for the endothelial cell-cycle state. [ABSTRACT FROM AUTHOR]

Long-term maintenance of the adult neurogenic niche depends on proper regulation of entry and exit from quiescence. Neural stem cell (NSC) transition from quiescence to activation is a complex process requiring precise cell-cycle control coordinated with transcriptional and morphological changes. How NSC fate transitions in coordination with the cell-cycle machinery remains poorly understood. Here we show that the Rb/E2F axis functions by linking the cell-cycle machinery to pivotal regulators of NSC fate. Deletion of Rb family proteins results in activation of NSCs, inducing a transcriptomic transition toward activation. Deletion of their target activator E2Fs1/3 results in intractable quiescence and cessation of neurogenesis. We show that the Rb/E2F axis mediates these fate transitions through regulation of factors essential for NSC function, including REST and ASCL1. Thus, the Rb/E2F axis is an important regulator of NSC fate, coordinating cell-cycle control with NSC activation and quiescence fate transitions. [Display omitted] • The Rb/E2F axis coordinates cell-cycle control with NSC activation and quiescence • The Rb/E2F axis is required for neurogenesis and NSC maintenance in the subgranular zone • The Rb/E2F axis is required for regulation of factors essential for NSC function Maintenance of adult neural stem cells (NSCs) and neurogenesis depends on proper regulation of activation and quiescence of NSCs. How these transitions are coordinated with the cell cycle is unclear. Fong et al. show that the Rb/E2F axis links the cell-cycle machinery to master regulators of NSC fate. [ABSTRACT FROM AUTHOR]