Quiescent State Research Articles

Optical monitoring in southern blazars. Analysis of variability and spectral colour behaviours

Abstract We present the results of the optical monitoring of 18 southern blazars in the V and R Johnson-Cousins bands. Our main objective is to study the variations in the optical flux and their relationship with the colour and spectral variabilities. The optical observations were acquired with the 2.15 m ‘Jorge Sahade’ telescope, CASLEO, Argentina. The whole campaign comprised from 2014 April to 2019 September. In addition, X-ray data were taken from the Chandra X-ray Observatory and the Swift/XRT databases, and γ-ray data was taken from the Fermi-LAT 3FGL catalogue. From the total of 18 blazars, we found variability in each one of the timescales considered for 6 blazars (PKS 0208-512, PKS 1116-46, PKS 1440-389, PKS 1510-089, PKS 2005-489 and PKS 2155-304). In particular, from the colour-magnitude and the multiwavelength analysis, we found that PKS 1510-089 (FSRQ) is undergoing an activity phase. For the case of PKS 2005-489 (BL Lac), this blazar is in a quiescent state, in which it has been for more than a decade, and it is compatible with its BWB (bluer-when-brighter) moderate tendency, possibly due to the presence of shocks within the jet.

Novel Populations of Mycobacterium smegmatis Under Hypoxia and Starvation: Some Insights on Cell Viability and Morphological Changes

The general features of the shift to a dormant state in mycobacterial species include several phenotypic changes, reduced metabolic activities, and increased resistance to host and environmental stress conditions. In this study, we aimed to provide novel insights into the viability state and morphological changes in dormant M. smegmatis that contribute to its long-term survival under starvation or hypoxia. To this end, we conducted assays to evaluate cell viability, morphological changes and gene expression. During starvation, M. smegmatis exhibited a reduction in cell length, the presence of viable but non-culturable (VBNC) cells and the formation of anucleated small cells, potentially due to a phenomenon known as reductive cell division. Under hypoxia, a novel population of pleomorphic mycobacteria with a rough surface before the cells reached nonreplicating persistence 1 (NRP1) was identified. This population exhibited VBNC-like behaviour, with a loss of cell wall rigidity and the presence of lipid-body-like structures. Based on dosR and hspX expression, we suggest that M. smegmatis encounters reductive stress conditions during starvation, while lipid storage may induce oxidative stress during hypoxia. These insights into the heterogeneous populations presented here could offer valuable opportunities for developing new therapeutic strategies to control dormant mycobacterial populations.

An alternative way to break the matrix barrier: an experimental study of a LIFU-mediated, visualizable targeted nanoparticle synergistic amplification for the treatment of malignant fibroblasts

Malignant fibroblasts (MFs) are widely present in various diseases and are characterized by connective tissue proliferation; these cells act as a physical barrier that severely limits drug delivery and affects disease outcomes. Based on this, we constructed the smart, integrated, theranostic, targeted lipid nanoprobe HMME-RG3@PFH to overcome the bottleneck in the early diagnosis and treatment of MF-related diseases. The protein glucose transporter protein 1 (GLUT-1) is overexpressed on MFs, and its ideal substrate, ginsenoside RG3 (RG3), significantly enhances the targeted uptake of HMME-RG3@PFH by MFs in a hypoxic environment and endows the nanomaterial with stealthiness to prolong its circulation. Perfluorohexane (PFH), a substance that can undergo phase change, was encapsulated in the lipid core and vaporized for ultrasound-enhanced imaging under low-intensity focused ultrasound (LIFU) irradiation. Moreover, hematoporphyrin monomethyl ether (HMME) was loaded into the lipid bilayer for photoacoustic molecular imaging and sonodynamic therapy (SDT) of MFs under the combined effects of LIFU. Additionally, HMME-RG3@PFH instantaneously burst during visualization to promote targeted drug delivery. In addition, the increased number of exposed RG3 fragments can regulate the MFs to enter a quiescent state. Overall, this nanoplatform ultimately achieves dual-modal imaging with targeted and precise drug release for visualization and synergistic amplification therapy, providing a new possibility for the early diagnosis and precise treatment of MF-related diseases.

Implementing Self-Healing N-Policy Queueing Models and their Impact on IoT Design Applications

We embarked on a comprehensive exploration of a single server queueing design, with a specific focus on handling soft failures. Soft failures refer to instances where customers do not need to be removed but rather need to wait for the server to be reactivated. These occurrences can happen at any time during the server's operation. When a soft failure occurs, the process automatically initiates a repair action, which we will refer to as the self-healing time. This self-healing time is relatively short, as the server possesses a remarkable restoration capability. Once the repair is complete, the server resumes its service provision and resumes normal operations. Moreover, during periods of prolonged idleness, the server can enter a dormant state, akin to a vacation mode. This dormant state is triggered when the server awaits the accumulation of N or more users. Once the threshold is reached, the server transitions into a busy state and resumes its normal operations This study represents the pioneering integration of soft failures with the N policy, marking the first of its kind in this field. Additionally, we provide explicit expressions for the transient probabilities of the model, employing generating function methodology and Laplace transform techniques. Furthermore, we include performance measures and a numerical component to underscore the significance of the model's parameters.

A major role of class III HD-ZIPs in promoting sugar beet cyst nematode parasitism in Arabidopsis.

Cyst nematodes use a stylet to secrete CLE-like peptide effector mimics into selected root cells of their host plants to hijack endogenous plant CLE signaling pathways for feeding site (syncytium) formation. Here, we identified ATHB8, encoding a HD-ZIP III family transcription factor, as a downstream component of the CLE signaling pathway in syncytium formation. ATHB8 is expressed in the early stages of syncytium initiation, and then transitions to neighboring cells of the syncytium as it expands; an expression pattern coincident with auxin response at the infection site. Conversely, MIR165a, which expresses in endodermal cells and moves into the vasculature to suppress HD-ZIP III TFs, is down-regulated near the infection site. Knocking down HD-ZIP III TFs by inducible over-expression of MIR165a in Arabidopsis dramatically reduced female development of the sugar beet cyst nematode (Heterodera schachtii). HD-ZIP III TFs are known to function downstream of auxin to promote cellular quiescence and define stem cell organizer cells in vascular patterning. Taken together, our results suggest that HD-ZIP III TFs function together with a CLE and auxin signaling network to promote syncytium formation, possibly by inducing root cells into a quiescent status and priming them for initial syncytial cell establishment and/or subsequent cellular incorporation.

Evolution of eruption rate between two caldera-forming eruptions in the Jemez Mountains volcanic field, New Mexico, USA

Rhyolites that erupted between the Otowi and Tshirege members of the Bandelier Tuff, known as the Valle Toledo Member, were investigated in the Jemez Mountains volcanic field to infer changes in eruptive rate and flux between two caldera-forming eruptions. Our analysis combines high-precision 40Ar/39Ar single-crystal laser-fusion dating of sanidine, matrix glass compositions and mineralogy of pumice, depositional textures, and volumetric estimates of erupted rhyolites to present a revised Valle Toledo Member eruptive chronology that integrates our observations with those of previous studies. With the improved temporal resolution of our high-precision eruption ages (median 2σ uncertainty of ±2.9 ka), the updated Valle Toledo Member eruption chronology consists of at least 42 temporally or mineralogically distinct eruptions that we group into four periods of time based on eruption rate. Within the first 8.1 ± 5.1 kyr (~1605–1597 ka) that followed the Otowi caldera-forming eruption at 1605.4 ± 2.3 ka, six eruptions are recognized. This suggests an average recurrence interval on the order of 1.4 ± 0.9 kyr. Twenty-seven eruptions occurred during the next 194.4 ± 5.1 kyr (from ~1597–1403 ka) and the average recurrence interval increased to 7.2 ± 0.2 kyr. Following this second period of slower eruption rate, a previously unrecognized eruption hiatus of up to 162.4 ± 3.1 kyr occurred from 1402.9 ± 2.3 ka to 1240.5 ± 2.1 ka. Resumption of volcanic activity is characterized by a series of at least nine volcanic eruptions during the next 8.6 ± 2.5 kyr, culminating in the eruption of the 400 km3 Tshirege Member of the Bandelier Tuff and formation of Valles caldera at 1231.9 ± 1.3 ka. This last phase of pre-caldera activity has the shortest observed average recurrence interval (1.0 ± 0.3 kyr) and greatest eruptive flux (≥ 0.4 ± 0.2 km3/kyr) that occurred between the two caldera-forming eruptions. We interpret the shifts in eruption rate and flux following the 162.4 ± 3.1 kyr eruption hiatus, in addition to mineralogical changes present in post-hiatus rhyolites, as indicators that the Bandelier system was trending towards another major eruption. The magmatic system may have grown gradually throughout the ca. 162 kyr period of volcanic repose; however, the heightened eruption rate in the ca. 10 kyr before caldera collapse is consistent with relatively rapid growth of the magmatic system before the Tshirege event as previously proposed by other studies. Furthermore, the new dataset is consistent with prior geochronology studies of the region that show the four largest explosive eruptions in the Jemez field were all proceeded by very slow eruptive rates or hiatuses. This demonstrates that sequences of heightened volcanic activity can initiate on rapid geological timescales from states of volcanic quiescence in the Bandelier system.

Bach2 repression of CD36 regulates lipid-metabolism-linked effector functions in follicular B cells

The transcription repressor Bach2 plays a crucial role in shaping humoral immunity, but its cell-autonomous function remains elusive. Here, we reveal the mechanism by which Bach2 regulates effector cell maturation in peripheral B cells. In response to Toll-like receptor (TLR) agonists, Bach2 deficiency promotes the differentiation of follicular, but not marginal zone, B cells into effector cells, producing interleukin (IL)-6 and antibodies. This phenomenon is associated with changes in lipid metabolism, such as increases in CD36 expression, lipid influx, and fatty acid oxidation. Consistent with this, Bach2-deficient B cells exhibit elevated levels of mitochondrial oxidative stress, lipid peroxidation, and p38 activation. Mechanistically, Bach2 acts as a repressor of Cd36, and inhibition of CD36 or fatty acid oxidation reduces the differentiation of naive B cells into IL-6- and antibody-secreting cells. These results indicate Bach2 as a key metabolic checkpoint regulator crucial for maintaining a functionally quiescent state of follicular B cells.

MAIN WAYS OF THE INITIATION OF CANCER CELL DORMANCY: TGFβ ROLE

The development of metastases even long after treatment is one of the most important problems of medicine. There are mechanisms helping cancer cells to survive at various steps of metastasis. The ability of cancer cells to turn into dormant state characterizing of reversible cell cycle blockage is one of such mechanisms. Dormancy is regulated by many factors including TGFβ. The aim of the review to summarize the information about the mechanisms of dormancy development in primary and secondary sites as well as about the role of TGFβ in cancer cell phenotype regulation and its cooperation with intra- and extracellular factors are supposed to promote dormancy development Material and methods. The materials are the results of the investigations on the theme of russian and foreign researchers and ours published data over the past 9 years, from 2015 till 2024. Results. Modern data about the roles of the factors produced by primary tumor and target organ cells in dormancy development are summarized in the article. Dormant phenotype induction can be initiated not only in primary tumor under the influence of hypoxia, pH alterations, inflammation and immune cells regulation etc., but also in the sites of metastasis as a result of the influence of factors produced by primary tumor as well as target organ cells. Modern data allow to suppose, that TGFβ influencing a number of complicated processes can prevent dormancy development and promote cancer cells to reenter cell cycle. Conclusion. Further investigation in this field allow a deeper understanding of the mechanisms of the TGFβ influence on dormant cells and will promote the creation of new strategies of anticancer therapy on the basis of TGFβ activity modulation

A kidney-specific fasting-mimicking diet induces podocyte reprogramming and restores renal function in glomerulopathy.

Cycles of a fasting-mimicking diet (FMD) promote regeneration and reduce damage in the pancreases, blood, guts, and nervous systems of mice, but their effect on kidney disease is unknown. In addition, a FMD has not been tested in rats. Here, we show that cycles of a newly developed low-salt FMD (LS-FMD) restored normal proteinuria and nephron structure and function in rats with puromycin-induced nephrosis compared with that in animals with renal damage that did not receive the dietary intervention. LS-FMD induced modulation of a nephrogenic gene program, resembling renal developmental processes in multiple kidney structures. LS-FMD also activated podocyte-lineage reprogramming pathways and promoted a quiescent state in mature podocytes in the rat kidney damage model. In a pilot clinical study in patients with chronic kidney disease, FMD cycles of 5 days each month for 3 months promoted renoprotection, including reduction of proteinuria and improved endothelial function, compared with that in patients who did not receive the FMD cycles. These results show that FMD cycles, which promote the reprogramming of multiple renal cell types and lead to glomerular damage reversal in rats, should be tested further for the treatment of progressive kidney diseases.

The Developmental Cycle of Spirodela polyrhiza Turions: A Model for Turion-Based Duckweed Overwintering?

Duckweeds are widely distributed small, simply constructed aquatic higher plants (the Lemnaceae) found on quiet freshwater surfaces. Species inhabiting temperate climates may have to cope with long periods of severe cold during the winter season. Several duckweeds form compact resting structures from the assimilatory fronds of the growing season that can bridge inhospitable conditions in a quiescent state. Of these, turions separate from the mother fronds and overwinter on the water body bottom in a dormant state. They can surface, germinate, and sprout to resume active growth upon warming in the spring. The turions of the largest duckweed, Spirodela polyrhiza, have been intensively examined as to ultrastructure, the factors governing their formation and release from dormancy, and the signals driving their germination and sprouting and the accompanying starch degradation. Comparative transcriptomics of assimilatory fronds and dormant turions are revealing the molecular features of this developmental cycle. The results illustrate an elegant sequence of reactions that ensures aquatic survival of even severe winters by frost avoidance in a vegetative mode. Since little is known about other duckweed resting fronds, the S. polyrhiza turion developmental cycle cannot be considered to be representative of duckweed resting fronds in general but can serve as a reference for corresponding investigations.

New orbital periods of high-inclination dwarf novae based on Gaia Alerts photometry

The orbital period of a cataclysmic variable stands as a crucial parameter for investigating the structure and physics of these binary systems, as well as understanding their evolution. We use photometric Gaia data for dwarf novae (DNe) in the quiescent state ---which are available for a number of years--- to determine new orbital periods and improve or modify previously suggested period values. Two approaches are implemented for selecting high-inclination targets, either eclipsing or with ellipsoidal variations. We determine new orbital periods for 75 DNe and improve ephemerides for 27 more (three of which change significantly), contributing 9.4<!PCT!> of the known DNe periods of between 0.05 and 2.0 days, and doubling the number of known periods exceeding 0.44 days. Their phase-folded light curves are presented and arranged by orbital period, illustrating the transition from short-period systems, dominated by radiation from the accretion disc and the hot spot, to longer-period DNe, where the Roche-lobe-filling secondary star is the primary visual flux source. This transition ---which occurs around the well-known period gap (between sim 2 and 3 hours)--- is expected, as DNe with larger orbital periods typically harbour more massive donors, which contribute to the visible flux. However, this transition is not abrupt. Within the same range of periods, we observe systems dominated by ellipsoidal variations, where the companion star is clearly visible, as well as others dominated by the disc and the hot spot. The presence of some DNe with ellipsoidal variations near the lower edge of the period gap is striking, as the companions in these systems are expected to be cool low-mass M-dwarfs not visible in the light curve. This could indicate that we are observing systems where the donor star was originally much more massive and underwent significant nuclear evolution before mass-transfer began, as has been suggested previously for QZ Ser.

Autophagy is required for mammary tumor recurrence by promoting dormant tumor cell survival following therapy

BackgroundMortality from breast cancer is principally due to tumor recurrence. Recurrent breast cancers arise from the pool of residual tumor cells, termed minimal residual disease, that survive treatment and may exist in a dormant state for 20 years or more following treatment of the primary tumor. As recurrent breast cancer is typically incurable, understanding the mechanisms underlying dormant tumor cell survival is a critical priority in breast cancer research. The importance of this goal is further underscored by emerging evidence suggesting that targeting dormant residual tumor cells in early-stage breast cancer patients may be a means to prevent tumor recurrence and its associated mortality. In this regard, the role of autophagy in dormant tumor cell survival and recurrence remains unresolved, with conflicting reports of both pro-survival/recurrence-promoting and pro-death/recurrence-suppressing effects of autophagy inhibition in dormant tumor cells. Resolving this question has important clinical implications.MethodsWe used genetically engineered mouse models that faithfully recapitulate key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. We used genetic and pharmacological approaches to inhibit autophagy, including treatment with chloroquine, genetic knockdown of ATG5 or ATG7, or deletion of BECN and determined their effects on dormant tumor cell survival and recurrence.ResultsWe demonstrate that the survival and recurrence of dormant mammary tumor cells following therapy is dependent upon autophagy. We find that autophagy is induced in vivo following HER2 downregulation and remains activated in dormant residual tumor cells. Using genetic and pharmacological approaches we show that inhibiting autophagy by chloroquine administration, ATG5 or ATG7 knockdown, or deletion of a single allele of the tumor suppressor Beclin 1 is sufficient to inhibit mammary tumor recurrence, and that autophagy inhibition results in the death of dormant mammary tumor cells in vivo.ConclusionsOur findings demonstrate a pro-tumorigenic role for autophagy in tumor dormancy and recurrence following therapy, reveal that dormant tumor cells are uniquely reliant upon autophagy for their survival, and indicate that targeting dormant residual tumor cells by inhibiting autophagy impairs tumor recurrence. These studies identify a pharmacological target for a cellular state that is resistant to commonly used anti-neoplastic agents and suggest autophagy inhibition as an approach to reduce dormant minimal residual disease in order to prevent lethal tumor recurrence.

On the origin of star formation quenching in massive galaxies at ≳ in the cosmological simulations IllustrisTNG

ABSTRACT Using the cosmological simulations IllustrisTNG, we perform a comprehensive analysis of quiescent, massive galaxies at $z \gtrsim 3$. The goal is to understand what suppresses their star formation so early in cosmic time, and how other similar mass galaxies remain highly star forming. As a first-order result, the simulations are able to produce massive, quiescent galaxies in this high-redshift regime. We find that active galactic nucleus (AGN) feedback is the primary cause of halting star formation in early, massive galaxies. Not only do the central, supermassive black holes (SMBHs) of the quenched galaxies have earlier seed times, but they also grow faster than in star-forming galaxies. As a result, the quenched galaxies are exposed to AGN feedback for longer, and experience the kinetic, jet mode of the AGN feedback earlier than the star-forming galaxies. The release of kinetic energy reduces inflows of gas while likely maintaining outflows, which keeps a low cold gas fraction and decreases the star formation of the galaxies down to a state of quiescence. In addition to AGN feedback, we also investigate the influence of the large-scale environment. While mergers do not play a significant role in the quenching process, the quenched galaxies tend to reside in more massive haloes and denser regions during their evolution. As this provides a greater initial amount of infalling gas to the galaxies, the large-scale environment can mildly affect the fate of the central SMBH growth and, via AGN feedback, contribute to star formation quenching.

Heterogeneity in oligodendrocyte precursor cell proliferation is dynamic and driven by passive bioelectrical properties

Oligodendrocyte precursor cells (OPCs) generate myelinating oligodendrocytes and are the main proliferative cells in the adult central nervous system. OPCs are a heterogeneous population, with proliferation and differentiation capacity varying with brain region and age. We demonstrate that during early postnatal maturation, cortical, but not callosal, OPCs begin to show altered passive bioelectrical properties, particularly increased inward potassium (K+) conductance, which correlates with G1 cell cycle stage and affects their proliferation potential. Neuronal activity-evoked transient K+ currents in OPCs with high inward K+ conductance potentially release OPCs from cell cycle arrest. Eventually, OPCs in all regions acquire high inward K+ conductance, the magnitude of which may underlie differences in OPC proliferation between regions, with cells being pushed into a dormant state as they acquire high inward K+ conductance and released from dormancy by synchronous neuronal activity. Age-related accumulation of OPCs with high inward K+ conductance might contribute to differentiation failure.

Physiological adaptations of red blood cells during aestivation in the south American lungfish Lepidosiren paradoxa

The South American lungfish Lepidosiren paradoxa inhabits areas with variable pluvial regimes. During aestivation (dormancy state observed in some species during dry seasons), the prolonged period of dryness imposes osmotic stress. We aimed to investigate the physiological and morphological adaptations of RBCs in Lepidosiren paradoxa during aestivation. Here, the lungfish were subjected to aestivation for 20 and 40 days and compared to a control group in an active period. The osmotic fragility, blood osmolality, and pH were measured. Blood smears were performed to assess morphological changes in the RBCs. Lepidosiren paradoxa presented lower hemolysis when compared with a teleost fish and tegu lizard. Hemolysis increased when the lungfish was subjected to 40 days of aestivation (from 6.04 % to 16.51 %; control vs 40-day aestivation). Hematocrit rose in both aestivation groups compared to the control (26.36 %, 41.36 % and 41 %, control, 20 and 40 days, respectively; p < 0.05) indicating changes in RBC volume and hydration status. Moreover, the results revealed increased osmolality in the 40-day aestivation group (244.4 vs 372.1 mmol/Kg; control vs 40-day aestivation). 40 days of aestivation led to a decrease in blood pH when compared to the control and 20-day aestivation groups. Both aestivation durations resulted in a reduction in the perimeter and cell diameters in at least one direction of the RBCs (24 % mean reduction in size from control to 40 days aestivation). These findings suggest that South American lungfish possess remarkable physiological and morphological adaptations in their RBCs during aestivation.

Quiescent cancer cells induced by high-density cultivation reveals cholesterol-mediated survival and lung metastatic traits.

The metastatic cascade, a multifaceted and highly aggressive process, is the primary cause of mortality. The survival of quiescent cancer cells in circulatory system during metastasis is crucial, yet our comprehension is constrained by the absence of universally accepted quiescent cancer models. We developed a quiescent cancer cell model using high-density cultivation. Based on the scRNA-seq analysis, IP-MS, metabolomics, mouse lung metastasis models, cholesterol assay, PLA and other molecular experiments, we explored the molecular mechanism. Immunofluorescence, atomic force microscope, FluidFM, and shear stress stimulation were used to analyze the cytoskeleton and membrane properties contributing to mechanical force resistance. We established a quiescent cancer cell model induced by high-density cultivation. Single-cell RNA sequencing (scRNA-seq) analysis reveals that CDC25A plays a crucial role in the transition to quiescence, with its expression significantly elevated in the quiescent state. Depletion of CDC25A leads to an increased proliferative capacity, and reduced metastasis under high-density conditions. Mechanistically, upregulated CDC25A in quiescent cells enhances cholesterol metabolism via endosome pathways, leading to cell cycle arrest. This increase in cholesterol reinforces the cytoskeleton, alters membrane properties, and improves resistance to mechanical forces in circulatory system. CDC25A significantly increased the cholesterol metabolism through endosome pathway in quiescent cancer cells, leading to the significant changes in cytoskeleton and membrane properties so as to enhance the resistance of mechanical force in circulatory system, facilitating lung metastasis. In high-density cultivation, quiescent cancer cells, up-regulate cholesterol metabolism by CDC25A through endosome pathway, enhancing the resistance to mechanical force in circulatory system, facilitating lung metastasis.

YAP Overcomes Mechanical Barriers to Induce Mitotic Rounding and Adult Cardiomyocyte Division.

Many specialized cells in adult organs acquire a state of cell cycle arrest and quiescence through unknown mechanisms. Our limited understanding of mammalian cell cycle arrest is derived primarily from cell culture models. Adult mammalian cardiomyocytes, a classic example of cell cycle arrested cells, exit the cell cycle postnatally and remain in an arrested state for the life of the organism. Cardiomyocytes can be induced to re-enter the cell cycle by YAP5SA, an active form of the Hippo signaling pathway effector YAP. We performed clonal analyses to determine the cell kinetics of YAP5SA cardiomyocytes. We also performed single-cell RNA sequencing, marker gene analysis, and functional studies to examine how YAP5SA cardiomyocytes progress through the cell cycle. We discovered that YAP5SA-expressing cardiomyocytes divided efficiently, with >20% of YAP5SA cardiomyocyte clones containing ≥2 cardiomyocytes. YAP5SA cardiomyocytes re-entered cell cycle at the G1/S transition and had an S phase lasting ≈48 hours. Sarcomere disassembly is required for cardiomyocyte progression from S to G2 phase and the induction of mitotic rounding. Although oscillatory Cdk expression was induced in YAP5SA cardiomyocytes, these cells inefficiently progressed through G2 phase. This is improved by inhibiting P21 function, implicating checkpoint activity as an additional barrier to YAP5SA-induced cardiomyocyte division. Our data reveal that YAP5SA overcomes the mechanically constrained myocardial microenvironment to induce mitotic rounding with cardiomyocyte division, thus providing new insights into the in vivo mechanisms that maintain cell cycle quiescence in adult mammals.

H2AK119ub dynamics controls hair follicle stem cell quiescence.

The transition of stem cells from a quiescent state to an active state is a finely tuned process that requires the dismantling of the quiescence program and the establishment of a cell cycle-promoting transcriptional landscape. Whether epigenetic processes control stem cell states to promote the regeneration of adult tissues remains elusive. In this study, we show that a repressive histone modification, H2AK119ub, is dynamic between quiescent and active hair follicle stem cells (HFSCs) in the adult murine skin. Ablation of H2AK119ub in HFSCs leads to impaired quiescence leading to premature activation and an eventual exhaustion of HFSC pool. Transcriptional and chromatin studies revealed that H2AK119ub directly represses a proliferation promoting transcriptional program in the HFSCs to preserve quiescence. Lastly, we identify that the inhibitory FGF signaling produced by the hair follicle niche keratinocytes maintains H2AK119ub in quiescent HFSCs. Together, these findings reveal that a repressive histone mark, H2AK119ub, is under the dynamic regulation of inhibitory niche signaling to prevent the untimely establishment of an activated state to preserve SC function and longevity.

Epigenetic Regulation in Myocardial Fibroblasts and Its Impact on Cardiovascular Diseases

Myocardial fibroblasts play a crucial role in heart structure and function. In recent years, significant progress has been made in understanding the epigenetic regulation of myocardial fibroblasts, which is essential for cardiac development, homeostasis, and disease progression. In healthy hearts, cardiac fibroblasts (CFs) play a crucial role in synthesizing the extracellular matrix (ECM) when in a dormant state. However, under pathological and environmental stress, CFs transform into activated fibroblasts known as myofibroblasts. These myofibroblasts produce an excess of ECM, which promotes cardiac fibrosis. Although multiple molecular mechanisms are associated with CF activation and myocardial dysfunction, emerging evidence highlights the significant involvement of epigenetic regulation in this process. Epigenetics refers to the heritable changes in gene expression that occur without altering the DNA sequence. These mechanisms have emerged as key regulators of myocardial fibroblast function. This review focuses on recent advancements in the understanding of the role of epigenetic regulation and emphasizes the impact of epigenetic modifications on CF activation. Furthermore, we present perspectives and prospects for future research on epigenetic modifications and their implications for myocardial fibroblasts.

Maltodextrin-derived nanoparticles resensitize intracellular dormant Staphylococcus aureus to rifampicin

Intracellular bacteria are recognized as a crucial factor in the persistence and recurrence of infections. The efficacy of current antibiotic treatments faces substantial challenges due to the dormant state formation of intracellular bacteria. In this study, we devised a strategy aimed at reverting intracellular dormant bacteria to a metabolically active state, thereby increasing their vulnerability to antibiotics. We found that oligosaccharides, especially maltodextrin (MD), can be absorbed by dormant S. aureus, leading to their revival and restoration of sensitivity to rifampicin (Rif). We then synthesized a reactive oxygen species (ROS)-responsive MD-prodrug by covalently binding MD with 4-(hydroxymethyl) phenylboronic acid pinacol ester (MD-PBAP) and prepared a ROS-responsive nanoparticles (MDNP) using a nanoprecipitation and self-assembly method. Once internalized by host cells, MDNP was degraded to MD, reactivating dormant S. aureus, and enhancing their susceptibility to Rif. More importantly, MDNP treatment restored the sensitivity of intracellular persistent S. aureus to Rif in both a reservoir transfer model and whole-body infection model. Additionally, MDNP have demonstrated excellent biocompatibility in both in vitro and in vivo settings. These results offer a promising therapeutic avenue for managing persistent intracellular bacterial infections by reviving and resensitizing intracellular dormant bacteria to conventional antibiotics.