Platelet Concentrates Preconditioning of Mesenchymal Stem Cells and Combined Therapies: Integrating Regenerative Strategies for Enhanced Clinical Applications.

This article presents a comprehensive review of the factors influencing the efficacy of mesenchymal stem cells (MSCs) transplantation and its association with platelet concentrates (PCs). It focuses on investigating the impact of PCs' composition, the age and health status of platelet donors, application methods, and environmental factors on the outcomes of relevant treatments. In addition, it delves into the strategies and mechanisms for optimizing MSCs transplantation with PCs, encompassing preconditioning and combined therapies. Furthermore, it provides an in-depth exploration of the signaling pathways and proteomic characteristics associated with preconditioning and emphasizes the efficacy and specific effects of combined therapy. The article also introduces the latest advancements in the application of biomaterials for optimizing regenerative medical strategies, stimulating scholarly discourse on this subject. Through this comprehensive review, the primary goal is to facilitate a more profound comprehension of the factors influencing treatment outcomes, as well as the strategies and mechanisms for optimizing MSCs transplantation and the application of biomaterials in regenerative medicine, offering theoretical guidance and practical references for related research and clinical practice.

SLIDE: Significant Latent Factor Interaction Discovery and Exploration across biological domains.

Modern multiomic technologies can generate deep multiscale profiles. However, differences in data modalities, multicollinearity of the data, and large numbers of irrelevant features make analyses and integration of high-dimensional omic datasets challenging. Here we present Significant Latent Factor Interaction Discovery and Exploration (SLIDE), a first-in-class interpretable machine learning technique for identifying significant interacting latent factors underlying outcomes of interest from high-dimensional omic datasets. SLIDE makes no assumptions regarding data-generating mechanisms, comes with theoretical guarantees regarding identifiability of the latent factors/corresponding inference, and has rigorous false discovery rate control. Using SLIDE on single-cell and spatial omic datasets, we uncovered significant interacting latent factors underlying a range of molecular, cellular and organismal phenotypes. SLIDE outperforms/performs at least as well as a wide range of state-of-the-art approaches, including other latent factor approaches. More importantly, it provides biological inference beyond prediction that other methods do not afford. Thus, SLIDE is a versatile engine for biological discovery from modern multiomic datasets.

CircPHKB decreases the sensitivity of liver cancer cells to sorafenib via miR-1234-3p/CYP2W1 axis.

Sorafenib is currently the first-line treatment for patients with advanced liver cancer, but its therapeutic efficacy declines significantly after a few months of treatment. Therefore, it is of great importance to investigate the regulatory mechanisms of sorafenib sensitivity in liver cancer cells. In this study, we provided initial evidence demonstrating that circPHKB, a novel circRNA markedly overexpressed in sorafenib-treated liver cancer cells, attenuated the sensitivity of liver cancer cells to sorafenib. Mechanically, circPHKB sequestered miR-1234-3p, resulting in the up-regulation of cytochrome P450 family 2 subfamily W member 1 (CYP2W1), thereby reducing the killing effect of sorafenib on liver cancer cells. Moreover, knockdown of circPHKB sensitized liver cancer cells to sorafenib in vivo. The findings reveal a novel circPHKB/miR-1234-3p/CYP2W1 pathway that decreases the sensitivity of liver cancer cells to sorafenib, suggesting that circPHKB and the axis may serve as promising targets to improve the therapeutic efficacy of sorafenib against liver cancer.

Washing antimony and arsenic from agricultural soil with eco-friendly organic acids and the relevant bioavailability assessment.

Antimony (Sb) and arsenic (As) contamination in agricultural soil poses human health risks through agricultural products. Soil washing with degradable low molecular weight organic acids (LMWOAs) is an eco-friendly strategy to remediate agricultural soils. In this study, three eco-friendly LMWOAs, oxalic acid (OA), tartaric acid (TA), and citric acid (CA), were used to treat Sb and As co-contaminated agricultural soil from Xikuangshan mine area. The OA, TA, and CA washed out 18.4, 16.8, and 26.6% of Sb and 15.3, 19.9, and 23.8% of As from the agricultural soil, with CA being the most efficient reagent for the soil washing. These organic acids also led to pH decline and macronutrients losses. Fraction analysis using a sequential extraction procedure showed that the three organic acids targeted and decreased the specifically sorbed (F2) (by 19.3-37.6% and 2.41-23.5%), amorphous iron oxide associated (F3) (by 49.1-61.2% and 51.2-70.2%), and crystallized iron oxide associated (F4) (by 12.3-26.0% and 26.1-29.1%) Sb and As. The leachability of Sb and As, as well as their concentrations and bioconcentration factor (BCF) in vegetables reduced due to the soil washing. It demonstrated that the bioavailability of both the elements was decreased by the organic acids washing. The concentrations of Sb and As in typical vegetable species cultivated in CA washed soil were less than the threshold value for consumption safety, while those in OA and TA washed soils were still higher than the value, suggesting that only CA is a potential washing reagent in soil washing for Sb- and As-contaminated agricultural soil.

From bench to bedside via bytes: Multi-omic immunoprofiling and integration using machine learning and network approaches.

A significant surge in research endeavors leverages the vast potential of high-throughput omic technology platforms for broad profiling of biological responses to vaccines and cutting-edge immunotherapies and stem-cell therapies under development. These profiles capture different aspects of core regulatory and functional processes at different scales of resolution from molecular and cellular to organismal. Systems approaches capture the complex and intricate interplay between these layers and scales. Here, we summarize experimental data modalities, for characterizing the genome, epigenome, transcriptome, proteome, metabolome, and antibody-ome, that enable us to generate large-scale immune profiles. We also discuss machine learning and network approaches that are commonly used to analyze and integrate these modalities, to gain insights into correlates and mechanisms of natural and vaccine-mediated immunity as well as therapy-induced immunomodulation.

Cell Type-Specific Biomarkers of Systemic Sclerosis Disease Severity Capture Cell-Intrinsic and Cell-Extrinsic Circuits.

OBJECTIVE: Systemic sclerosis (SSc) is a multifactorial autoimmune fibrotic disorder involving complex rewiring of cell-intrinsic and cell-extrinsic signaling coexpression networks involving a range of cell types. However, the rewired circuits as well as corresponding cell-cell interactions remain poorly understood. To address this, we used a predictive machine learning framework to analyze single-cell RNA-sequencing data from 24 SSc patients across the severity spectrum as quantified by the modified Rodnan skin score (MRSS). METHODS: We used a least absolute shrinkage and selection operator (LASSO)-based predictive machine learning approach on the single-cell RNA-sequencing data set to identify predictive biomarkers of SSc severity, both across and within cell types. The use of L1 regularization helps prevent overfitting on high-dimensional data. Correlation network analyses were coupled to the LASSO model to identify cell-intrinsic and cell-extrinsic co-correlates of the identified biomarkers of SSc severity. RESULTS: We found that the uncovered cell type-specific predictive biomarkers of MRSS included previously implicated genes in fibroblast and myeloid cell subsets (e.g., SFPR2+ fibroblasts and monocytes), as well as novel gene biomarkers of MRSS, especially in keratinocytes. Correlation network analyses revealed novel cross-talk between immune pathways and implicated keratinocytes in addition to fibroblast and myeloid cells as key cell types involved in SSc pathogenesis. We then validated the uncovered association of key gene expression and protein markers in keratinocytes, KRT6A and S100A8, with SSc skin disease severity. CONCLUSION: Our global systems analyses reveal previously uncharacterized cell-intrinsic and cell-extrinsic signaling coexpression networks underlying SSc severity that involve keratinocytes, myeloid cells, and fibroblasts.

Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3.

Impaired chronic viral and tumor clearance has been attributed to CD8+ T cell exhaustion, a differentiation state in which T cells have reduced and altered effector function that can be partially reversed upon blockade of inhibitory receptors. The role of the exhaustion program and transcriptional networks that control CD8+ T cell function and fate in autoimmunity is not clear. Here we show that intra-islet CD8+ T cells phenotypically, transcriptionally, epigenetically and metabolically possess features of canonically exhausted T cells, yet maintain important differences. This 'restrained' phenotype can be perturbed and disease accelerated by CD8+ T cell-restricted deletion of the inhibitory receptor lymphocyte activating gene 3 (LAG3). Mechanistically, LAG3-deficient CD8+ T cells have enhanced effector-like functions, trafficking to the islets, and have a diminished exhausted phenotype, highlighting a physiological role for an exhaustion program in limiting autoimmunity and implicating LAG3 as a target for autoimmune therapy.

Autocrine and paracrine IL-2 signals collaborate to regulate distinct phases of CD8 T cell memory.

Differential interleukin-2 (IL-2) signaling and production are associated with disparate effector and memory fates. Whether the IL-2 signals perceived by CD8 T cells come from autocrine or paracrine sources, the timing of IL-2 signaling and their differential impact on CD8 T cell responses remain unclear. Using distinct models of germline and conditional IL-2 ablation in post-thymic CD8 T cells, this study shows that paracrine IL-2 is sufficient to drive optimal primary expansion, effector and memory differentiation, and metabolic function. In contrast, autocrine IL-2 is uniquely required during primary expansion to program robust secondary expansion potential in memory-fated cells. This study further shows that IL-2 production by antigen-specific CD8 T cells is largely independent of CD4 licensing of dendritic cells (DCs) in inflammatory infections with robust DC activation. These findings bear implications for immunizations and adoptive T cell immunotherapies, where effector and memory functions may be commandeered through IL-2 programming.

Functional reprogramming of monocytes in patients with acute and convalescent severe COVID-19.

Severe COVID-19 disease is associated with dysregulation of the myeloid compartment during acute infection. Survivors frequently experience long-lasting sequelae, but little is known about the eventual persistence of this immune alteration. Herein, we evaluated TLR-induced cytokine responses in a cohort of mild to critical patients during acute or convalescent phases (n = 97). In the acute phase, we observed impaired cytokine production by monocytes in the patients with the most severe COVID-19. This capacity was globally restored in convalescent patients. However, we observed increased responsiveness to TLR1/2 ligation in patients who recovered from severe disease, indicating that these cells display distinct functional properties at the different stages of the disease. In patients with acute severe COVID-19, we identified a specific transcriptomic and epigenomic state in monocytes that can account for their functional refractoriness. The molecular profile of monocytes from recovering patients was distinct and characterized by increased chromatin accessibility at activating protein 1 (AP1) and MAF loci. These results demonstrate that severe COVID-19 infection has a profound impact on the differentiation status and function of circulating monocytes, during both the acute and the convalescent phases, in a completely distinct manner. This could have important implications for our understanding of short- and long-term COVID-19-related morbidity.

Mass flow, enrichment and potential environmental impacts of mercury in a preheater-precalciner cement plant using multiple mining and industrial wastes.

Cement plants (CPs) are one of the most important anthropogenic sources of mercury (Hg) emissions in China. Over 1000 cement production lines operate in China and use various raw materials; however, little data on Hg emissions is recorded on site. This study investigated a CP in Guizhou Province that uses multiple mining and industrial wastes as part of the circular economy policy. Among the various raw materials, carbide slag had the highest Hg content (2.6 mg/kg) and contributed half of the Hg input. High Hg concentration (27 mg/kg) in the kiln tail dust and a strong Hg enrichment factor (39) was found, which was determined as the ratio of total Hg accumulated within the clinker production process to the daily Hg input from raw materials and fuel. The clinker had negligible Hg (0.001 mg/kg), while the Hg in cement products (0.04 mg/kg) mostly came from additives and retarders. The estimated atmospheric emission factor of Hg from this CP was 161.5 mg Hg/t clinker, which was much higher than those of other CPs in Guizhou that employ low-Hg raw materials. A five-step sequential extraction experiment with kiln tail dust indicates that Hg mainly existed in fraction of F4 (73-96% of the total Hg, possibly as Hg2Cl2) and that some samples had high proportions of water-soluble Hg (up to 21% of the total), which may be easily released into surrounding water bodies and pose high environmental risks. Using low-Hg raw (or alternative raw) materials and conducting proper disposal of kiln tail dust will reduce the environmental risk of Hg from CPs.

Metabolic regulation by PD-1 signaling promotes long-lived quiescent CD8 T cell memory in mice.

Inhibitory signaling in dysfunctional CD8 T cells through the programmed cell death 1 (PD-1) axis is well established in chronic viral infections and cancers. PD-1 is also transiently induced to high concentrations during priming of acute infections and immunizations, yet its impact on the development of long-lived antigen-independent T cell memory remains unclear. In addition to its expected role in restraining clonal effector expansion, here, we show that PD-1 expression on antigen-specific CD8 T cells is required for the development of a durable CD8 T cell memory pool after antigen clearance. Loss of T cell­specific PD-1 signaling led to increased contraction and a defect in antigen-independent renewal of memory CD8 T cells in response to homeostatic cytokine signals, thus resulting in attrition of the memory pool over time. Whereas exhausted CD8 T cells regain function after PD-1 checkpoint blockade during chronic viral infection, the preexisting pool of resting functional bystander memory CD8 T cells established in response to a previously administered immunogen decreased. Metabolically, PD-1 signals were necessary for regulating the critical balance of mTOR-dependent anabolic glycolysis and fatty acid oxidation programs to meet the bioenergetic needs of quiescent CD8 T cell memory. These results define PD-1 as a key metabolic regulator of protective T cell immunity. Furthermore, these results have potential clinical implications for preexisting CD8 T cell memory during PD-1 checkpoint blockade therapy.

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We analyzed soil quality based on soil microbial characteristics of three different vegetation types in the wetlands of East Dongting Lake, including Carex tristachya wetland (CTW), Phragmites australis wetland (PAW), and Salix babylonica wetland (SBW). The soil microbial biomass carbon (MBC), nitrogen (MBN) and enzyme activities were measured and the key influen-cing factors were analyzed during the normal, flood, and dry periods. The results showed that: 1) The amounts of MBC, MBN, and the activities of invertase and cellulase (except cellulase of dry season) in 0-10 cm were higher than those in 10-20 cm for all wetlands, while the catalase activity showed an opposite pattern. 2) The amounts of MBC and MBN and the values of MBC/TOC and MBN/TN for the 0-20 cm soil layer of each vegetation type wetland were the lowest in flood period. 3) Soil invertase activity for each vegetation type wetland in the 0-20 cm soil layer peaked in the dry period, while soil cellulase activity peaked in the normal period. The seasonal fluctuation of soil catalase activities in all wetlands were small, with activities being slightly higher in flood period than the other two periods. 4) Among different vegetation types, soil invertase activity of PAW was significantly higher than that of other vegetation types, and cellulase activity of which was the lowest in both normal and flood periods. There was no difference in these two enzymes activities among wetlands during the dry period. The highest soil catalase activity was found in CTW during normal period and in SBW during dry period, respectively, while its lowest value was in PAW during flood period. 5) Soil MBC, MBN and invertase activity were correlated positively with soil TOC, TN and TP, and negatively correlated with soil pH. The activities of soil cellulase and catalase were significantly negatively correlated with TOC, TN, TP and positively correlated with pH. It suggested that the seasonal fluctuation of water level affected soil C, N, P contents and pH values, with consequences on soil MBC, MBN and enzyme activities.

Dichloroacetate enhances the anti-tumor effect of sorafenib via modulating the ROS-JNK-Mcl-1 pathway in liver cancer cells.

Liver cancer is one of the most common and high recurrence malignancies. Besides radiotherapy and surgery, chemotherapy also plays an essential role in the treatment of liver cancer. Sorafenib and sorafenib-based combination therapies have been proven efficacy against tumors. However, previous clinical studies have indicated that some patients with liver cancer are resistant to sorafenib treatment and the existing strategies are not satisfactory in the clinic. Therefore, it is urgent to investigate strategies to improve the effectiveness of sorafenib for liver cancer and to explore effective drug combinations. In the present study, we found that dichloroacetate (DCA) could significantly enhance the anti-tumor effect of sorafenib on liver cancer cells, including reduced viability and dramatically promoted apoptosis in liver cancer cells. Moreover, compared to sorafenib alone, the combination of DCA and sorafenib markedly increased the degradation of anti-apoptotic protein Mcl-1 by enhancing its phosphorylation. Overexpression of Mcl-1 could significantly attenuate the synergetic effect of DCA and sorafenib on apoptosis induction in liver cancer cells. Furthermore, we found that the ROS-JNK pathway was obviously activated in the DCA combined sorafenib group. The levels of ROS and p-JNK were dramatically up-regulated in the two drug combination groups. Antioxidant NAC could alleviate the synergetic effects of DCA and sorafenib on ROS generation, JNK activation, Mcl-1 degradation, and cell apoptosis. Moreover, DCA and sorafenib's effects on Mcl-1 degradation and apoptosis could also be inhibited by JNK inhibitor 'SP'600125. Finally, the synergetic effects of DCA and sorafenib on tumor growth suppression, Mcl-1 degradation and induction of apoptosis were also validated in liver cancer xenograft in vivo. These findings indicate that DCA enhances the anti-tumor effect of sorafenib via the ROS-JNK-Mcl-1 pathway in liver cancer cells. This study may provide new insights to improve the chemotherapeutic effect of sorafenib, which may be beneficial for further clinical application of sorafenib in liver cancer treatment.

LncRNA CRNDE Promotes ATG4B-Mediated Autophagy and Alleviates the Sensitivity of Sorafenib in Hepatocellular Carcinoma Cells.

Autophagy is closely related to the growth and drug resistance of cancer cells, and autophagy related 4B (ATG4B) performs a crucial role in the process of autophagy. The long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) promotes the progression of hepatocellular carcinoma (HCC), but it is unclear whether the tumor-promoting effect of CRNDE is associated with the regulation of ATG4B and autophagy. Herein, we for the first time demonstrated that CRNDE triggered autophagy via upregulating ATG4B in HCC cells. Mechanistically, CRNDE enhanced the stability of ATG4B mRNA by sequestrating miR-543, leading to the elevation of ATG4B and autophagy in HCC cells. Moreover, sorafenib induced CRNDE and ATG4B as well as autophagy in HCC cells. Knockdown of CRNDE sensitized HCC cells to sorafenib in vitro and in vivo. Collectively, these results reveal that CRNDE drives ATG4B-mediated autophagy, which attenuates the sensitivity of sorafenib in HCC cells, suggesting that the pathway CRNDE/ATG4B/autophagy may be a novel target to develop sensitizing measures of sorafenib in HCC treatment.

Programming of CD8 T Cell Quantity and Polyfunctionality by Direct IL-1 Signals.

IL-1, generally considered an amplifier of adaptive immune responses, has been proposed for use as adjuvant during immunization with weak immunogens. However, its effects on memory T cell function remain largely undefined. Using the murine model of acute viral infection, in this paper, we show that in addition to augmenting the size of the Ag-specific pool, IL-1 signals act directly on CD8 T cells to promote the quality of effector and memory responses. Ablation of IL-1R1 or MyD88 signaling in T cells led to functional impairment; both the ability to produce multiple cytokines on a per cell basis (polyfunctionality) and the potential for recall proliferation in response to antigenic restimulation were compromised. IL-1 supplementation during priming augmented the expansion of Ag-specific CD8 T cells through the MyD88-IRAK1/4 axis, resulting in a larger memory pool capable of robust secondary expansion in response to rechallange. Together, these findings demonstrate a critical role of the IL-1-MyD88 axis in programming the quantity and quality of memory CD8 T cell responses and support the notion that IL-1 supplementation may be exploited to enhance adoptive T cell therapies against cancers and chronic infections.

Combustion and inorganic bromine emission of waste printed circuit boards in a high temperature furnace.

High temperature combustion experiments of waste printed circuit boards (PCBs) were conducted using a lab-scale system featuring a continuously-fed drop tube furnace. Combustion efficiency and the occurrence of inorganic bromine (HBr and Br(2)) were systematically studied by monitoring the main combustion products continuously. The influence of furnace temperature (T) was studied from 800 to 1400°C, the excess air factor (EAF) was varied from 1.2 to 1.9 and the residence time in the high temperature zone (RT(HT)) was set at 0.25, 0.5, or 0.75 s. Combustion efficiency depends on temperature, EAF and RT(HT); temperature has the most significant effect. Conversion of organic bromine from flame retardants into HBr and Br(2) depends on temperature and EAF. Temperature has crucial influence over the ratio of HBr to Br(2), whereas oxygen partial pressure plays a minor role. The two forms of inorganic bromine seem substantially to reach thermodynamic equilibrium within 0.25s. High temperature is required to improve the combustion performance: at 1200°C or higher, an EAF of 1.3 or more, and a RT(HT) exceeding 0.75 s, combustion is quite complete, the CO concentration in flue gas and remained carbon in ash are sufficiently low, and organobrominated compounds are successfully decomposed (more than 99.9%). According to these results, incineration of waste PCBs without preliminary separation and without additives would perform very well under certain conditions; the potential precursors for brominated dioxins formation could be destroyed efficiently. Increasing temperature could decrease the volume percentage ratio of Br(2)/HBr in flue gas greatly.