Pan-cancer and multi-omics analyses revealed the diagnostic and prognostic value of BAZ2A in liver cancer.

BAZ2A, an epigenetic regulatory factor that affects ribosomal RNA transcription, has been shown to be highly expressed in several cancers and promotes tumor cell migration. This study explored the expression and mechanism of BAZ2A in tumorigenesis at the pan-cancer level. The Cancer Genome Atlas, Gene Expression Omnibus databases and TIMER2.0, cBioPortal and other tools were used to analyze the level of expression of BAZ2A in various tumor tissues and to examine the relationship between BAZ2A and survival, prognosis, mutation and immune invasion. In vitro experiments were performed to assess the function of BAZ2A in cancer cells. Using combined transcriptome and proteome analysis, we examined the possible mechanism of BAZ2A in tumors. BAZ2A exhibited high expression levels in multiple tumor tissues and displayed a significant association with cancer patient prognosis. The main type of BAZ2A genetic variation in cancer is gene mutation. Downregulation of BAZ2A inhibited proliferation, migration, and invasion and promoted apoptosis in LM6 liver cancer cell. The mechanism of BAZ2A in cancer development may involve lipid metabolism. These results help expand our understanding of BAZ2A in tumorigenesis and development and suggest BAZ2A may serve as a prognostic and diagnostic factor in several cancers.

A multifunctional composite nanoparticle with antibacterial activities, anti-inflammatory, and angiogenesis for diabetic wound healing.

The treatment of chronic diabetic wounds remains challenging due to the rapid bacterial infection, severe inflammation, and insufficient angiogenesis. To address these challenges, a novel multifunctional composite nanoparticle is developed by co-assembling antisolvent-induced co-assembling silk-fibroin ε-poly-l-Lysine nanoparticles (nSF-EPL) and further assembling nSF-EPL with polydeoxyribonucleotide (PDRN) and exosome derived from human umbilical mesenchymal stem cells (Exo). Owing to the modification of EPL, PDRN and Exo, composite nanoparticles exhibited synergistic antibacterial action, anti-inflammatory and angiogenesis, which can significantly benefit for promoting wound healing. Release results show that the composite nanoparticles exhibit long-term sustained PDRN and Exo release profiles as well as outstanding release efficiency. Furthermore, in vitro studies show that the composite nanoparticles exhibit effective antibacterial activity, thus inducing an anti-inflammatory M2 macrophages phenotype and promoting angiogenesis. In vivo research results of investigations pertaining to diabetic wound healing show that the composite nanoparticles have good anti-inflammatory and angiogenesis capabilities, which can promote granulation tissue formation, collagen deposition, wound tissue epithelialization, and significantly accelerate skin healing. This study presents a promising strategy for the clinical treatment of chronic diabetic wounds.

Platelet-Derived Growth Factor Nanocapsules with Tunable Controlled Release for Chronic Wound Healing.

Chronic wounds have emerged as an increasingly critical clinical challenge over the past few decades, due to their increasing incidence and socioeconomic burdens. Platelet-derived growth factor (PDGF) plays a pivotal role in regulating processes such as fibroblast migration, proliferation, and vascular formation during the wound healing process. The delivery of PDGF offers great potential for expediting the healing of chronic wounds. However, the clinical effectiveness of PDGF in chronic wound healing is significantly hampered by its inability to maintain a stable concentration at the wound site over an extended period. In this study, a controlled PDGF delivery system based on nanocapsules is proposed. In this system, PDGF is encapsulated within a degradable polymer shell. The release rate of PDGF from these nanocapsules can be precisely adjusted by controlling the ratios of two crosslinkers with different degradation rates within the shells. As demonstrated in a diabetic wound model, improved therapeutic outcomes with PDGF nanocapsules (nPDGF) treatment are observed. This research introduces a novel PDGF delivery platform that holds promise for enhancing the effectiveness of chronic wound healing.

Omega-3 polyunsaturated fatty acids supplementation improves memory in first-diagnosed, drug-naïve patients with depression: Secondary analysis of data from a randomized controlled trial.

INTRODUCTION: Cognitive impairments are found in most patients with major depressive disorder (MDD). It is believed that low Omega-3 polyunsaturated fatty acids (n-3 PUFAs) level raise the risk of anxiety, depressive symptoms and cognition dysfunction. Since our previous research has found n-3 PUFAs supplementation improves anxiety in MDD, this study was to further explore the effectiveness on cognitive impairment among depressed patients. METHODS: A total of 72 venlafaxine treated outpatients with first-diagnosed, drug-naïve depression were enrolled. Daily n-3 PUFAs supplementation (2.4 g/d of fish oil, including 1440 mg eicosapentaenoic acid and 960 mg of docosahexaenoic acid) or placebo was used for 12 weeks. Cognitive function, measure by repeatable battery for the assessment of neuropsychological status ([RBANS]) scores, was compared over time. RESULTS: Immediate memory, delayed memory and RBANS total scores were significant higher in both groups at week 4 and week 12 compared with baseline. Both groups exhibited improvement on attention scores at week 12. No significant differences were observed comparing n-3 PUFAs with placebo groups in the improvement of total RBANS scores and other subscales except in the change of immediate memory at both week 4 and week 12 (p < 0.05). LIMITATIONS: Sample size was relatively low. Moreover, multiple ethnic populations and the income of patients should be considered. Lastly, we used raw scores instead of the standardized scores of RBANS. CONCLUSION: N-3 PUFAs supplementation yielded a small but statistically significant improvement on immediate memory in first-diagnosed, drug-naïve depressed patients. While, antidepressant treatment resulted in significant improvement of cognitive function.

Synthetic Biohybrids of Red Blood Cells and Cascaded-Enzymes@ Metal-Organic Frameworks for Hyperuricemia Treatment.

Hyperuricemia, caused by an imbalance between the rates of production and excretion of uric acid (UA), may greatly increase the mortality rates in patients with cardiovascular and cerebrovascular diseases. Herein, for fast-acting and long-lasting hyperuricemia treatment, armored red blood cell (RBC) biohybrids, integrated RBCs with proximal, cascaded-enzymes of urate oxidase (UOX) and catalase (CAT) encapsulated within ZIF-8 framework-based nanoparticles, have been fabricated based on a super-assembly approach. Each component is crucial for hyperuricemia treatment: 1) RBCs significantly increase the circulation time of nanoparticles; 2) ZIF-8 nanoparticles-based superstructure greatly enhances RBCs resistance against external stressors while preserving native RBC properties (such as oxygen carrying capability); 3) the ZIF-8 scaffold protects the encapsulated enzymes from enzymatic degradation; 4) no physical barrier exists for urate diffusion, and thus allow fast degradation of UA in blood and neutralizes the toxic by-product H2 O2 . In vivo results demonstrate that the biohybrids can effectively normalize the UA level of an acute hyperuricemia mouse model within 2 h and possess a longer elimination half-life (49.7 ± 4.9 h). They anticipate that their simple and general method that combines functional nanomaterials with living cell carriers will be a starting point for the development of innovative drug delivery systems.

Automated centrifugal microfluidic system for the preparation of adaptor-ligated sequencing libraries.

The intensive workload associated with the preparation of high-quality DNA libraries remains a key obstacle toward widespread deployment of sequencing technologies in remote and resource-limited areas. We describe the development of single-use microfluidic devices driven by an advanced pneumatic centrifugal microfluidic platform, the PowerBlade, to automate the preparation of Illumina-compatible libraries based on adaptor ligation methodology. The developed on-chip workflow includes enzymatic DNA fragmentation coupled to end-repair, adaptor ligation, first DNA cleanup, PCR amplification, and second DNA cleanup. This complex workflow was successfully integrated into simple thermoplastic microfluidic devices that are amenable to mass production with injection molding. The system was validated by preparing, on chip, libraries from a mixture of genomic DNA extracted from three common foodborne pathogens (Listeria monocytogenes, Escherichia coli and Salmonella enterica serovar Typhimurium) and comparing them with libraries made via a manual procedure. The two types of libraries were found to exhibit similar quality control metrics (including genome coverage, assembly, and relative abundances) and led to nearly uniform coverage independent of GC content. This microfluidic technology offers a time-saving and cost-effective alternative to manual procedures and robotic-based automation, making it suitable for deployment in remote environments where technical expertise and resources might be scarce. Specifically, it facilitates field practices that involve mid- to low-throughput sequencing, such as tasks related to foodborne pathogen detection, characterization, and microbial profiling.

Lactate oxidase nanocapsules boost T cell immunity and efficacy of cancer immunotherapy.

Cancer immunotherapy has reshaped the landscape of cancer treatment. However, its efficacy is still limited by tumor immunosuppression associated with the excessive production of lactate by cancer cells. Although extensive efforts have been made to reduce lactate concentrations through inhibition of lactate dehydrogenase, such inhibitors disrupt the metabolism of healthy cells, causing severe nonspecific toxicity. We report herein a nanocapsule enzyme therapeutic based on lactate oxidase, which reduces lactate concentrations and releases immunostimulatory hydrogen peroxide, averting tumor immunosuppression and improving the efficacy of immune checkpoint blockade treatment. As demonstrated in a murine melanoma model and a humanized mouse model of triple-negative breast cancer, this enzyme therapeutic affords an effective tool toward more effective cancer immunotherapy.

Future of Mesoporous Silica Nanoparticles in Nanomedicine: Protocol for Reproducible Synthesis, Characterization, Lipid Coating, and Loading of Therapeutics (Chemotherapeutic, Proteins, siRNA and mRNA).

Owing to their uniform and tunable particle size, pore size, and shape, along with their modular surface chemistry and biocompatibility, mesoporous silica nanoparticles (MSNs) have found extensive applications as nanocarriers to deliver therapeutic, diagnostic and combined "theranostic" cargos to cells and tissues. Although thoroughly investigated, MSN have garnered FDA approval for only one MSN system via oral administration. One possible reason is that there is no recognized, reproducible, and widely adopted MSN synthetic protocol, meaning not all MSNs are created equal in the laboratory nor in the eyes of the FDA. This manuscript provides the sol-gel and MSN research communities a reproducible, fully characterized synthetic protocol to synthesize MSNs and corresponding lipid-coated MSN delivery vehicles with predetermined particle size, pore size, and drug loading and release characteristics. By carefully articulating the step-by-step synthetic procedures and highlighting critical points and troubleshooting, augmented with videos and schematics, this Article will help researchers entering this rapidly expanding field to yield reliable results.

Erythrocyte Membrane Fatty Acid Composition as a Potential Biomarker for Depression.

BACKGROUND: Major depressive disorders is a chronic and severe psychiatric disorder with poor prognosis and quality of life. Abnormal erythrocyte fatty acid (FA) composition in depressed patients were found in our previous study, but the relationship between erythrocyte membrane FA levels and different severity of depressive and anxiety symptoms remains to be explored. METHODS: This cross-sectional study included 139 patients with first-diagnosed, drug-naïve depression and 55 healthy controls whose erythrocyte FA composition was analyzed. Patients with depression were divided into severe depression and mild to moderate depression or depression with severe anxiety and mild to moderate anxiety. Then the differences of FA levels among different groups were analyzed. Finally, the receiver operating characteristic curve analysis was applied to identify potential biomarkers in distinguishing the severity of depressive symptoms. RESULTS: Levels of erythrocyte membrane FAs were elevated among patients with severe depression compared with healthy controls or patients with mild to moderate depression of almost all kinds. While C18:1n9t (elaidic acid), C20:3n6 (eicosatrienoic acid), C20:4n6 (arachidonic acid), C22:5n3 (docosapentaenoic acid), total fatty acids (FAs), and total monounsaturated FAs were elevated in patients with severe anxiety compared with patients with mild to moderate anxiety. Furthermore, the level of arachidonic acid, C22:4n6 (docosatetraenoic acid), elaidic acid, and the combination of all 3 were associated with the severity of depressive symptoms. CONCLUSIONS: The results suggested that erythrocyte membrane FA levels have the potential to be the biological indicator of clinical characteristics for depression, such as depressive symptoms and anxiety. In the future, more research is needed to explore the causal association between FA metabolism and depression.

Dimensional Reduction of Metal-Organic Frameworks for Enhanced Cryopreservation of Red Blood Cells.

To increase the red blood cell (RBC) cryopreservation efficiency by metal-organic frameworks (MOFs), a dimensional reduction approach has been proposed. Namely, 3D MOF nanoparticles are progressively reduced to 2D ultra-thin metal-organic layers (MOLs). We found that 2D MOLs are beneficial for enhanced interactions of the interfacial hydrogen-bonded water network and increased utilization of inner ordered structures, due to the higher surface-to-volume ratio. Specifically, a series of hafnium (Hf)-based 2D MOLs with different thicknesses (monolayer to stacked multilayers) and densities of hydrogen bonding sites have been synthesized. Both ice recrystallization inhibition activity (IRI) and RBCs cryopreservation assay confirm the pronounced better IRI activity and excellent cell recovery efficiency (up to ≈63 % at a very low concentration of 0.7 mg mL-1 ) of thin-layered Hf-MOLs compared to their 3D counterparts, thereby verifying the dimensional reduction strategy to improved cryoprotectant behaviors.

Sex differences in erythrocyte fatty acid composition of first-diagnosed, drug-naïve patients with major depressive disorders.

Background: Since depression, sex hormones, and fatty acid status are interrelated, it is important to understand their relationships. In this study, we aimed to investigate sex differences in erythrocyte membrane fatty acid composition among first-diagnosed, drug-naïve patients with major depressive disorders. Methods: The study included 139 individuals with first-diagnosed, drug-naïve depression (male/female = 48/91) and 55 healthy controls (male/female = 24/31). The levels of erythrocyte membrane fatty acids were analyzed to compare the difference between males and females in both patients with depression and healthy controls, as well as to study their correlation with depressive symptoms. Results: In first-diagnosed, drug-naïve patients with major depressive disorders, sex disparities were observed in the levels of erythrocyte saturated fatty acids (SFAs) and n-6 PUFAs (such as C18:0, C20:4n6 and C22:4n6), where higher levels evident in females compared to in males. We found a noteworthy correlation between fatty acid levels and depressive symptoms, in which there is a significant association between female patients and depression but a weaker association between male patients and depression. Conclusion: Our findings demonstrate higher levels of n-6 PUFAs and SFAs in female patients with depression. The relationship between fatty acid composition and depressive symptoms was more prominent in females than males. These findings highlight the significance of considering sex as a crucial and interconnected factor in future investigations and potential adjunctive treatment for mood disorders by targeting fatty acid metabolism.

Long-term whole blood DNA preservation by cost-efficient cryosilicification.

Deoxyribonucleic acid (DNA) is the blueprint of life, and cost-effective methods for its long-term storage could have many potential benefits to society. Here we present the method of in situ cryosilicification of whole blood cells, which allows long-term preservation of DNA. Importantly, our straightforward approach is inexpensive, reliable, and yields cryosilicified samples that fulfill the essential criteria for safe, long-term DNA preservation, namely robustness against external stressors, such as radical oxygen species or ultraviolet radiation, and long-term stability in humid conditions at elevated temperatures. Our approach could enable the room temperature storage of genomic information in book-size format for more than one thousand years (thermally equivalent), costing only 0.5 $/person. Additionally, our demonstration of 3D-printed DNA banking artefacts, could potentially allow 'artificial fossilization'.

Dual-Stage Irradiation of Size-Switchable Albumin Nanocluster for Cascaded Tumor Enhanced Penetration and Photothermal Therapy.

The triple-negative breast cancer (TNBC) microenvironment makes a feature of aberrant vasculature, high interstitial pressure, and compact extracellular matrix, which combine to reduce the delivery and penetration of therapeutic agents, bringing about incomplete elimination of cancer cells. Herein, employing the tumor penetration strategy of size-shrinkage combined with ligand modification, we constructed a photothermal nanocluster for cascaded deep penetration in tumor parenchyma and efficient eradication of TNBC cells. In our approach, the photothermal agent indocyanine green (ICG) is laded in human serum albumin (HSA), which is cross-linked by a thermally labile azo linker (VA057) and then further modified with a tumor homing/penetrating tLyP-1 peptide (HP), resulting in a TNBC-targeting photothermal-responsive size-switchable albumin nanocluster (ICG@HSA-Azo-HP). Aided by the enhanced permeability and retention effect and guidance of HP, the ca. 149 nm nanoclusters selectively accumulate in the tumor site and then, upon mild irradiation with the 808 nm laser, disintegrate into 11 nm albumin fractions that possess enhanced intratumoral diffusion ability. Meanwhile, HP initiates the CendR pathway among the nutrient-deficient tumor cells and facilitates the transcellular delivery of the nanocluster and its disintegrated fractions for subsequent therapy. By employing this size-shrinkage and peptide-initiated transcytosis strategy, ICG@HSA-Azo-HP possesses excellent penetration capabilities and shows extensive penetration depth in three-dimensional multicellular tumor spheroids after irradiation. Moreover, with a superior photothermal conversion effect, the tumor-penetrating nanocluster can implement effective photothermal therapy throughout the tumor tissue under a second robust irradiation. Both in vivo orthotopic and ectopic TNBC therapy confirmed the efficient tumor inhibition of ICG@HSA-Azo-HP after dual-stage irradiation. The synergistic penetration strategy of on-demanded size-shrinkage and ligand guidance accompanied by clinically feasible NIR irradiation provides a promising approach for deep-penetrating TNBC therapy.

Abnormal erythrocyte fatty acid composition in first-diagnosed, drug-naïve patients with depression.

BACKGROUND & AIMS: The correlation between fatty acids (FAs) and depression is not yet conclusive. This study examined the relationship of FAs composition with the presence and clinical characteristics of first-diagnosed, drug-naïve patients with depression. METHODS: A total of 139 first-diagnosed, drug-naïve patients with depression and 55 healthy controls (HCs) were included in the cross-sectional study. The levels of erythrocyte membrane FAs were compared and then the correlation between clinical symptoms and fatty acid levels in depression was investigated. RESULTS: Compared to HCs, patients with depression had higher C18:1n9t (z = -2.033, p = 0.042), C20:4n6 (z = -2.104, p = 0.035), C20:3n6 (z = -2.104, p = 0.035) and n-6 polyunsaturated fatty acids (PUFAs) (z = -2.127, p = 0.033), whereas the levels of C18:1n9c (z = -3.348, p = 0.001) were significantly lower. Higher C20:3n6, C20:4n6, C18:1n9t and n-6 PUFAs levels were associated with higher severity of depressive and anxiety symptoms in patients with depression, and the correlation remained after adjusting for the related confounding factors (p < 0.05). CONCLUSIONS: Patients with first-diagnosed, drug-naïve depression show abnormal erythrocyte fatty acid composition. Trans fatty acids (TFAs) and n-6 PUFAs levels are closely related to clinical characteristics of depression. This study indicated that increased n-6 PUFAs and TFAs are characteristic changes of first-diagnosed, drug-naïve depression.

Reactive oxygen species associated immunoregulation post influenza virus infection.

An appropriate level of reactive oxygen species (ROS) is necessary for cell proliferation, signaling transduction, and apoptosis due to their highly reactive character. ROS are generated through multiple metabolic pathways under a fine-tuned control between oxidant and antioxidant signaling. A growing number of evidence has proved their highly relevant role in modulating inflammation during influenza virus infection. As a network of biological process for protecting organism from invasion of pathogens, immune system can react and fight back through either innate immune system or adaptive immune system, or both. Herein, we provide a review about the mechanisms of ROS generation when encounter influenza virus infection, and how the imbalanced level of ROS influences the replication of virus. We also summarize the pathways used by both the innate and adaptive immune system to sense and attack the invaded virus and abnormal levels of ROS. We further review the limitation of current strategies and discuss the direction of future work.

Omega-3 Polyunsaturated Fatty Acids Supplementation Alleviate Anxiety Rather Than Depressive Symptoms Among First-Diagnosed, Drug-Naïve Major Depressive Disorder Patients: A Randomized Clinical Trial.

Background: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) augmentation of antidepressants has shown great potential in the prevention and treatment of major depressive disorders (MDD). Objective: To investigate the effect of n-3 PUFAs plus venlafaxine in patients with first-diagnosed, drug-naïve depression. Method: A total of 72 outpatients with first-diagnosed depression were recruited. The daily dose of 2.4 g/day n-3 PUFAs or placebo plus venlafaxine was used for over 12 weeks. The outcomes were assessed by the Hamilton depression scale (HAMD), Hamilton anxiety scale (HAMA), Beck depression inventory (BDI), and Self-rating anxiety scale (SAS). Results: Both groups exhibited improvement on clinical characteristics at week 4 and week 12 compared with baseline. The rate of responders for anxiety in n-3 PUFAs group (44.44%) was significantly higher than that in placebo group (21.21%) at week 4 (χ2 = 4.182, p = 0.041), while week 12 did not show a difference (χ2 = 0.900, p = 0.343). The rate of responders for depression at both week 4 (χ2 = 0.261, p = 0.609) and week 12 (χ2 = 1.443, p = 0.230) showed no significant difference between two groups. Further analysis found that Childhood Trauma Questionnaire (CTQ) had positive correlation with HAMA (r = 0.301, p = 0.012), SAS (r = 0.246, p = 0.015), HAMD (r = 0.252, p = 0.038) and BDI (r = 0.233, p = 0.022) with Pearson correlation analysis. Social Support Rating Scale (SSRS) had negative correlation with SAS (r = -0.244, p = 0.015) and BDI (r = -0.365, p = 0.000). Conclusion: This trial found that n-3 PUFAs supplementation in favor of venlafaxine alleviated the anxiety symptoms rather than depressive symptoms at the early stage of treatment (4 weeks) for first-diagnosed, drug-naïve depressed patients. However, the advantage disappeared in long-term treatment. Furthermore, childhood abuse and social support are closely related to the clinical and biological characteristics of depression. Both childhood trauma and lack of social support might be predictors of poor prognosis in depression. Clinical Trial Registration: [clinicaltrials.gov], identifier [NCT03295708].

Robust and Long-Term Cellular Protein and Enzymatic Activity Preservation in Biomineralized Mammalian Cells.

Preservation of evolved biological structure and function in robust engineering materials is of interest for storage of biological samples before diagnosis and development of vaccines, sensors, and enzymatic reactors and has the potential to avoid cryopreservation and its associated cold-chain issues. Here, we demonstrate that "freezing cells in amorphous silica" is a powerful technique for long-term preservation of whole mammalian cell proteomic structure and function at room temperature. Biomimetic silicification employs the crowded protein microenvironment of mammalian cells as a catalytic framework to proximally transform monomeric silicic acid into silicates forming a nanoscopic silica shell over all biomolecular interfaces. Silicification followed by dehydration preserves and passivates proteomic information within a nanoscale thin silica coating that exhibits size selective permeability (<3.6 nm), preventing protein leaching and protease degradation of cellular contents, while providing access of small molecular constituents for cellular enzymatic reaction. Exposure of dehydrated silicified cells to mild etchant or prolonged hydrolysis removes the silica, completely rerevealing biomolecular components and restoring their accessibility and functionality.

Cancer vaccines from cryogenically silicified tumour cells functionalized with pathogen-associated molecular patterns.

The production of personalized cancer vaccines made from autologous tumour cells could benefit from mechanisms that enhance immunogenicity. Here we show that cancer vaccines can be made via the cryogenic silicification of tumour cells, which preserves tumour antigens within nanoscopic layers of silica, followed by the decoration of the silicified surface with pathogen-associated molecular patterns. These pathogen-mimicking cells activate dendritic cells and enhance the internalization, processing and presentation of tumour antigens to T cells. In syngeneic mice with high-grade ovarian cancer, a cell-line-based silicified cancer vaccine supported the polarization of CD4+ T cells towards the T-helper-1 phenotype in the tumour microenvironment, and induced tumour-antigen-specific T-cell immunity, resulting in complete tumour eradication and in long-term animal survival. In the setting of established disease and a suppressive tumour microenvironment, the vaccine synergized with cisplatin. Silicified and surface-modified cells from tumour samples are amenable to dehydration and room-temperature storage without loss of efficacy and may be conducive to making individualized cancer vaccines across tumour types.

External signals regulate continuous transcriptional states in hematopoietic stem cells.

Hematopoietic stem cells (HSCs) must ensure adequate blood cell production following distinct external stressors. A comprehensive understanding of in vivo heterogeneity and specificity of HSC responses to external stimuli is currently lacking. We performed single-cell RNA sequencing (scRNA-Seq) on functionally validated mouse HSCs and LSK (Lin-, c-Kit+, Sca1+) progenitors after in vivo pharmacological perturbation of niche signals interferon, granulocyte colony-stimulating factor (G-CSF), and prostaglandin. We identified six HSC states that are characterized by enrichment but not exclusive expression of marker genes. External signals induced rapid transitions between HSC states but transcriptional response varied both between external stimulants and within the HSC population for a given perturbation. In contrast to LSK progenitors, HSCs were characterized by a greater link between molecular signatures at baseline and in response to external stressors. Chromatin analysis of unperturbed HSCs and LSKs by scATAC-Seq suggested some HSC-specific, cell intrinsic predispositions to niche signals. We compiled a comprehensive resource of HSC- and LSK progenitor-specific chromatin and transcriptional features that represent determinants of signal receptiveness and regenerative potential during stress hematopoiesis.

Most organs in the human body are maintained by a type of immature cells known as adult stem cells, which ensure a constant supply of new, mature cells. Adult stem cells monitor their environment through external signalling molecules and replace damaged cells as needed. Stem cell therapy takes advantage of the regenerative ability of immature stem cells and can be helpful for conditions such as blood diseases, autoimmune diseases, neurodegeneration and cancer. For example, hematopoietic stem-cell transplantation is a treatment for some types of cancer and blood disorders, in which stem cells are harvested from the blood or bone marrow and reintroduced into the body, where they can develop into all types of blood cells, including white blood cells, red blood cells and platelets. Hematopoietic stem-cell transplants have been in use for over 30 years, but they remain a highly risky procedure. One of the challenges is that outcomes can vary between patients and many of the factors that can influence the 'regenerative' potential of hematopoietic stem cells, such as external signalling molecules, are not well understood. To fill this gap, Fast et al. analysed which genes are turned on and off in hematopoietic stem cells in response to several external signalling molecules. To do so, three signalling pathways in mice were altered by injecting them with different chemicals. After two hours, the hematopoietic stem cells were purified and the gene expression for each cell was analysed. This revealed that the types of genes and the strength at which they were affected by each chemical was unique. Moreover, hematopoietic stem cells responded rapidly to external signals, with substantial differences in gene expression between individual groups of cells. Contrary to more specialised cells, the external signalling genes in some hematopoietic stem cells were already activated without being injected with external signalling molecules. This suggest that low levels of external signalling molecules released from their microenvironment may prepare stem cells to better respond to future stress or injuries. These results help to better understand stem cells and to evaluate how the signalling state of hematopoietic stem cells affects regeneration, and ultimately improve hematopoietic stem cell transplantation for patients.

Uptake and Toxicity of Respirable Carbon-Rich Uranium-Bearing Particles: Insights into the Role of Particulates in Uranium Toxicity.

Particulate matter (PM) presents an environmental health risk for communities residing close to uranium (U) mine sites. However, the role of the particulate form of U on its cellular toxicity is still poorly understood. Here, we investigated the cellular uptake and toxicity of C-rich U-bearing particles as a model organic particulate containing uranyl citrate over a range of environmentally relevant concentrations of U (0-445 µM). The cytotoxicity of C-rich U-bearing particles in human epithelial cells (A549) was U-dose-dependent. No cytotoxic effects were detected with soluble U doses. Carbon-rich U-bearing particles with a wide size distribution (<10 µm) presented 2.7 times higher U uptake into cells than the particles with a narrow size distribution (<1 µm) at 100 µM U concentration. TEM-EDS analysis identified the intracellular translocation of clusters of C-rich U-bearing particles. The accumulation of C-rich U-bearing particles induced DNA damage and cytotoxicity as indicated by the increased phosphorylation of the histone H2AX and cell death, respectively. These findings reveal the toxicity of the particulate form of U under environmentally relevant heterogeneous size distributions. Our study opens new avenues for future investigations on the health impacts resulting from environmental exposures to the particulate form of U near mine sites.