How transplanted haematopoietic stem cells (HSCs) behave soon after they reside in a preconditioned host has not been studied due to technical limitations. Here, using single-cell RNA sequencing, we ...first obtained the transcriptome-based classifications of 28 haematopoietic cell types. We then applied them in conjunction with functional assays to track the dynamic changes of immunophenotypically purified HSCs in irradiated recipients within the first week after transplantation. Based on our transcriptional classifications, most homed HSCs in bone marrow and spleen became multipotent progenitors and, occasionally, some HSCs gave rise to megakaryocytic-erythroid or myeloid precursors. Parallel in vitro and in vivo functional experiments supported the paradigm of robust differentiation without substantial HSC expansion during the first week. Therefore, this study uncovers the previously inaccessible kinetics and fate choices of transplanted HSCs in myeloablated recipients at early stage, with implications for clinical applications of HSCs and other stem cells.
Polyunsaturated fatty acids (PUFAs), specifically Omega-3 (FAω3) and docosahexaenoic acid (DHA), have been studied for their potential role in modulating pancreatic cancer (PC) risk. Although ...observational studies suggest a beneficial effect in reducing this risk, their findings are often limited by confounding variables and issues of reverse causation. This study used a two-way two-sample Mendelian randomization (MR) method to test the hypothesized genetic causal relationship between PUFAs and PC risk. Data from an extensive genome-wide association study (GWAS) were analyzed, focusing on FAω3 and FAω6 levels, their ratios, and DHA as variables and PC incidence as outcomes. This relationship was comprehensively evaluated using related MR methods, such as inverse variance weighting (IVW), MR Egger, and weighted median (WM). This study finds a significant negative correlation between FAω3 and DHA levels and PC risk, while FAω6 levels show no significant correlation. Interestingly, the ratio of FAω6 to FAω3 was positively associated with increased risk of PC. Neither the MR Egger nor the MR-PRESSO tests detected significant pleiotropy, nor did the Cochrane’s Q test show significant heterogeneity. Leave-one-out analyzes further confirmed the robustness of these results. Using MR analysis of two samples, this study provides genetic causal evidence that FAω3 and DHA levels reduce the risk of PC, whereas the ratio of FAω6 to FAω3 increases the risk of PC. These insights highlight the potential utility of supplementing FAω3 and DHA or altering PUFAs in developing PC prevention strategies.
Fully reduced polyoxometalates are predicted to give rise to a broad and strong absorption spectrum, suitable energy levels, and unparalleled electronic and optical properties. However, they are not ...available to date. Here, an unprecedented fully reduced polyoxomolybdate cluster, namely Na
Mo
O
(OH)
·19H
O {Mo
}, was successfully designed and obtained under hydrothermal conditions, which is rare and is the largest fully reduced polyoxometalate reported so far. The Mo
molecule describes one Keggin {ε-Mo
} encapsulated in an unprecedented {Mo
} cage, giving rise to a double truncated tetrahedron quasi-nesting architecture, which is further face-capped by another four {Mo
} tripods. Its crystalline stability in air, solvent tolerance, and photosensitivity were all shown. As a cheap and robust molecular light-absorber model possessing wide light absorption, Mo
was applied to build a co-sensitized solar cell photoelectronic device along with N719 dyes and the optimal power conversion efficiency was 28% higher than that of single-dye sensitization. These results show that Mo
polyoxometalate could serve as an ideal model for the design and synthesis of all-inorganic molecular light-absorbers for other light-driven processes in the future.
Ventilation is an effective solution for improving indoor air quality and reducing airborne transmission. Buildings need sufficient ventilation to maintain a low infection risk but also need to avoid ...an excessive ventilation rate, which may lead to high energy consumption. The Wells-Riley (WR) model is widely used to predict infection risk and control the ventilation rate. However, few studies compared the non-steady-state (NSS) and steady-state (SS) WR models that are used for ventilation control. To fill in this research gap, this study investigates the effects of the mechanical ventilation control strategies based on NSS/SS WR models on the required ventilation rates to prevent airborne transmission and related energy consumption. The modified NSS/SS WR models were proposed by considering many parameters that were ignored before, such as the initial quantum concentration. Based on the NSS/SS WR models, two new ventilation control strategies were proposed. A real building in Canada is used as the case study. The results indicate that under a high initial quantum concentration (e.g., 0.3 q/m
3
) and no protective measures, SS WR control underestimates the required ventilation rate. The ventilation energy consumption of NSS control is up to 2.5 times as high as that of the SS control.
Because fibrotic kidneys exhibit aberrant activation of β-catenin signaling, this pathway may be a potential target for antifibrotic therapy. In this study, we examined the effects of β-catenin ...activation on tubular epithelial-mesenchymal transition (EMT) in vitro and evaluated the therapeutic efficacy of the peptidomimetic small molecule ICG-001, which specifically disrupts β-catenin-mediated gene transcription, in obstructive nephropathy. In vitro, ectopic expression of stabilized β-catenin in tubular epithelial (HKC-8) cells suppressed E-cadherin and induced Snail1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) expression. ICG-001 suppressed β-catenin-driven gene transcription in a dose-dependent manner and abolished TGF-β1-induced expression of Snail1, PAI-1, collagen I, fibronectin, and α-smooth muscle actin (α-SMA). This antifibrotic effect of ICG-001 did not involve disruption of Smad signaling. In the unilateral ureteral obstruction model, ICG-001 ameliorated renal interstitial fibrosis and suppressed renal expression of fibronectin, collagen I, collagen III, α-SMA, PAI-1, fibroblast-specific protein-1, Snail1, and Snail2. Late administration of ICG-001 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, inhibiting β-catenin signaling may be an effective approach to the treatment of fibrotic kidney diseases.
Sonic hedgehog (Shh) signaling is a developmental signal cascade that plays an essential role in regulating embryogenesis and tissue homeostasis. Here, we investigated the potential role of Shh ...signaling in renal interstitial fibrogenesis. Ureteral obstruction induced Shh, predominantly in the renal tubular epithelium of the fibrotic kidneys. Using Gli1(lacZ) knock-in mice, we identified renal interstitial fibroblasts as Shh-responding cells. In cultured renal fibroblasts, recombinant Shh protein activated Gli1 and induced α-smooth muscle actin (α-SMA), desmin, fibronectin, and collagen I expression, suggesting that Shh signaling promotes myofibroblast activation and matrix production. Blockade of Shh signaling with cyclopamine abolished the Shh-mediated induction of Gli1, Snail1, α-SMA, fibronectin, and collagen I. In vivo, the kidneys of Gli1-deficient mice were protected against the development of interstitial fibrosis after obstructive injury. In wild-type mice, cyclopamine did not affect renal Shh expression but did inhibit induction of Gli1, Snail1, and α-SMA. In addition, cyclopamine reduced matrix expression and mitigated fibrotic lesions. These results suggest that tubule-derived Shh mediates epithelial-mesenchymal communication by targeting interstitial fibroblasts after kidney injury. We conclude that Shh/Gli1 signaling plays a critical role in promoting fibroblast activation, production of extracellular matrix, and development of renal interstitial fibrosis.
A large number of natural and anthropogenic wastes were landfilled, and dissolved organic matter (DOM) were formed during landfill. However, the composition, transformation, and coexistence ...characteristics of natural and anthropogenic DOM in leachate remain unclear. Fourier transform ion cyclotron resonance mass spectrometry, size exclusion chromatography, gas chromatography coupled with mass spectrometry, and three-dimensional excitation-emission matrix spectrum were employed to clarify comprehensively the abovementioned question. The results showed that natural DOM in young leachate constituted mainly straight-chain organic acids, protein substances, and building blocks of humic substances (BB). Straight-chain organic acids vanished in old leachates, and the concentration of protein substances and BB decreased from 44% to 26% and from 47% to 12%, respectively, while CHON and CHONS were degraded to CHO and CHOS during the process. As to anthropogenic DOM, its types and relative content in leachate increased during landfill, and aromatic acids, terpenes, halogenated organics, indoles, and phenols became the main organic components in old leachate. Compared to natural DOM, anthropogenic DOM was degraded slowly and accumulated in leachate, and some of the natural DOM facilitated the dechlorination of dichlorinated organic compounds. This study demonstrates that landfill led to an increase in humic substances and halogenated organic compounds in old leachate, which was intensified with concentrated leachate recirculation.
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•The young leachate comprised a large number of organic nitrogen.•The types and content of halogenated organic matter increased in leachate over time.•Lignin, tannin and monochlorinated organics were accumulated in the old leachate.•Low molecular natural dissolved organic matter aids the dechlorination of dichloride.
The highly regulated process of blood production is achieved through the hierarchical organization of hematopoietic stem cell (HSC) subsets and their progenies, which differ in self-renewal and ...differentiation potential. Genetic studies in mice have demonstrated that cell cycle is tightly controlled by the complex interplay between extrinsic cues and intrinsic regulatory pathways involved in HSC self-renewal and differentiation. Deregulation of these cellular programs may transform HSCs or hematopoietic progenitor cells (HPCs) into disease-initiating stem cells, and can result in hematopoietic malignancies such as leukemia. While previous studies have shown roles for some cell cycle regulators and related signaling pathways in HSCs and HPCs, a more complete picture regarding the molecular mechanisms underlying cell cycle regulation in HSCs or HPCs is lacking. Based on accumulated studies in this field, the present review introduces the basic components of the cell cycle machinery and discusses their major cellular networks that regulate the dormancy and cell cycle progression of HSCs. Knowledge on this topic would help researchers and clinicians to better understand the pathogenesis of relevant blood disorders and to develop new strategies for therapeutic manipulation of HSCs.
The bone marrow (BM) niche regulates multiple hematopoietic stem cell (HSC) processes. Clinical treatment for hematological malignancies by HSC transplantation often requires preconditioning via ...total body irradiation, which severely and irreversibly impairs the BM niche and HSC regeneration. Novel strategies are needed to enhance HSC regeneration in irradiated BM. We compared the effects of EGF, FGF2, and PDGFB on HSC regeneration using human mesenchymal stem cells (MSCs) that were transduced with these factors via lentiviral vectors. Among the above niche factors tested, MSCs transduced with PDGFB (PDGFB-MSCs) most significantly improved human HSC engraftment in immunodeficient mice. PDGFB-MSC-treated BM enhanced transplanted human HSC self-renewal in secondary transplantations more efficiently than GFP-transduced MSCs (GFP-MSCs). Gene set enrichment analysis showed increased antiapoptotic signaling in PDGFB-MSCs compared with GFP-MSCs. PDGFB-MSCs exhibited enhanced survival and expansion after transplantation, resulting in an enlarged humanized niche cell pool that provide a better humanized microenvironment to facilitate superior engraftment and proliferation of human hematopoietic cells. Our studies demonstrate the efficacy of PDGFB-MSCs in supporting human HSC engraftment.
Bone marrow (BM) mesenchymal stem cells (MSCs) are critical components of the BM microenvironment and play an essential role in supporting hematopoiesis. Dysfunction of MSCs is associated with the ...impaired BM microenvironment that promotes leukemia development. However, whether and how restoration of the impaired BM microenvironment can inhibit leukemia development remain unknown. Using an established leukemia model and the RNA-Seq analysis, we discovered functional degeneration of MSCs during leukemia progression. Importantly, intra-BM instead of systemic transfusion of donor healthy MSCs restored the BM microenvironment, demonstrated by functional recovery of host MSCs, improvement of thrombopoiesis, and rebalance of myelopoiesis. Consequently, intra-BM MSC treatment reduced tumor burden and prolonged survival of the leukemia-bearing mice. Mechanistically, donor MSC treatment restored the function of host MSCs and reprogrammed host macrophages into arginase 1 positive phenotype with tissue-repair features. Transfusion of MSC-reprogrammed macrophages largely recapitulated the therapeutic effects of MSCs. Taken together, our study reveals that donor MSCs reprogram host macrophages to restore the BM microenvironment and inhibit leukemia development.
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