Against all odds: The road to success in the development of human immune reconstitution mice.

The mouse genome has a high degree of homology with the human genome, and its physiological, biochemical, and developmental regulation mechanisms are similar to those of humans; therefore, mice are widely used as experimental animals. However, it is undeniable that interspecies differences between humans and mice can lead to experimental errors. The differences in the immune system have become an important factor limiting current immunological research. The application of immunodeficient mice provides a possible solution to these problems. By transplanting human immune cells or tissues, such as peripheral blood mononuclear cells or hematopoietic stem cells, into immunodeficient mice, a human immune system can be reconstituted in the mouse body, and the engrafted immune cells can elicit human-specific immune responses. Researchers have been actively exploring the development and differentiation conditions of host recipient animals and grafts in order to achieve better immune reconstitution. Through genetic engineering methods, immunodeficient mice can be further modified to provide a favorable developmental and differentiation microenvironment for the grafts. From initially only being able to reconstruct single T lymphocyte lineages, it is now possible to reconstruct lymphoid and myeloid cells, providing important research tools for immunology-related studies. In this review, we compare the differences in immune systems of humans and mice, describe the development history of human immune reconstitution from the perspectives of immunodeficient mice and grafts, and discuss the latest advances in enhancing the efficiency of human immune cell reconstitution, aiming to provide important references for immunological related researches.

Dclre1c-Mutation-Induced Immunocompromised Mice Are a Novel Model for Human Xenograft Research.

Severe combined immunodeficient (SCID) mice serve as a critical model for human xenotransplantation studies, yet they often suffer from low engraftment rates and susceptibility to graft-versus-host disease (GVHD). Moreover, certain SCID strains demonstrate 'immune leakage', underscoring the need for novel model development. Here, we introduce an SCID mouse model with a targeted disruption of the dclre1c gene, encoding Artemis, which is essential for V(D)J recombination and DNA repair during T cell receptor (TCR) and B cell receptor (BCR) assembly. Artemis deficiency precipitates a profound immunodeficiency syndrome, marked by radiosensitivity and compromised T and B lymphocyte functionality. Utilizing CRISPR/Cas9-mediated gene editing, we generated dclre1c-deficient mice with an NOD genetic background. These mice exhibited a radiosensitive SCID phenotype, with pronounced DNA damage and defective thymic, splenic and lymph node development, culminating in reduced T and B lymphocyte populations. Notably, both cell lines and patient-derived tumor xenografts were successfully engrafted into these mice. Furthermore, the human immune system was effectively rebuilt following peripheral blood mononuclear cells (PBMCs) transplantation. The dclre1c-knockout NOD mice described herein represent a promising addition to the armamentarium of models for xenotransplantation, offering a valuable platform for advancing human immunobiological research.

Bacterial and Microeukaryotic Community Compositions and Their Assembly Processes in Lakes on the Eastern Qinghai-Tibet Plateau.

Bacterial and microeukaryotic community compositions and their assembly processes have remained challenging and remained unclear in lake ecosystems on the Qinghai-Tibet Plateau (QTP). We revealed the diversity and community compositions, driving factors, ecological assembly processes, and co-occurrence networks of bacterial and microeukaryotic communities in water bodies of the eight lake ecosystems across the Eastern QTP. The results demonstrated that the predominant bacteria in most samples were Proteobacteria, with an average relative abundance of 41.78%, whereas the most abundant of microeukaryotes differed among the sample sites. The redundancy analysis revealed that latitude and pH were the most important driving factors in shaping the bacterial and microeukaryotic community compositions. Homogeneous selection (56.40%) was the dominant process in assembling the bacterial communities, whereas dispersal limitation (67.24%) was the major process in governing the microeukaryotic communities. Furthermore, dissolved organic carbon and salinity were the major factors mediating the balance of deterministic and stochastic assembly processes in the bacterial and microeukaryotic communities. Both the bacterial and microeukaryotic community co-occurrence networks exhibited topological features of modularity and non-random topological features. The results offer insights into the mechanisms underpinning bacterial and microeukaryotic diversities and communities in the lake ecosystems on the QTP.

CD147-specific chimeric antigen receptor T cells effectively inhibit T cell acute lymphoblastic leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is invasive and heterogeneous, and existing therapies are sometimes unsuccessful. Chimeric antigen receptor (CAR) T cell therapy is a breakthrough tumor treatment method, particularly for B cell acute lymphoblastic leukemia. We found that CD147 was highly expressed in tumor T cells of T-ALL patients and T cell lymphoma. Therefore, CD147-CAR T cells that contain a humanized single-chain variable fragment targeting human CD147 and a second-generation CAR frame were constructed for treating T-ALL. CD147-CAR T cells were able to maintain a healthy proliferation rate, preserving a subset of CD62L+/CCR7+ memory T cells. CD147-CAR T cells showed a potent anti-tumor activity against human T-ALL cell line and T-ALL blasts, releasing high level of cytokines in the process. However, CD147-CAR T cells exhibited potential safety toward human normal cells and CD147-deficent cells. NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt mice were used to establish a T-ALL xenograft model and CD147-CAR T cells conferred robust protection against T-ALL progression and significantly improved survival in mice. Overall, we found that CD147 is a potential antigen target of CAR T cell therapy for T-ALL.

Observer-Based Fixed-Time Secure Tracking Consensus for Networked High-Order Multiagent Systems Against DoS Attacks.

This article studies the secure tracking consensus problem of nonlinear multiagent systems (MASs) against denial-of-service (DoS) attacks. Two types of DoS attacks, i.e., connectivity-maintained attacks and connectivity-broken attacks, are considered. The resulting topologies caused by DoS attacks may destabilize the consensus performance of MASs. Especially under connectivity-broken attacks, the connectivity between agents is destroyed. To deal with these difficulties, a novel defense strategy consisting of distributed observation and decentralized control is proposed. First, a distributed fixed-time observer (DFTO) is prepared for the case of connectivity-maintained attacks, which can quickly and accurately estimate the leader's information for each follower. Besides, the adverse impact of DoS attacks is completely eliminated. Furthermore, to cope with the problem arising from connectivity-broken attacks, by using an online algorithm of updating label information, an improved resilient DFTO (RDFTO) is further developed, which can preserve those followers having directed paths from the leader to quickly and accurately estimate the leader's information, without being affected by DoS attacks. The developed DFTO and RDFTO have successfully eliminated or weakened the adverse effects caused by DoS attacks. Subsequently, based on the proposed DFTO/RDFTO with the power integrator technique, a fixed-time controller is finally constructed, which realizes the desired transient performance of consensus tracking in the finite-time interval. The effectiveness of the proposed defense strategy is verified by stability analysis and simulation examples.

Endothelial genetic deletion of CD147 induces changes in the dual function of the blood-brain barrier and is implicated in Alzheimer's disease.

AIMS: The blood-brain barrier (BBB) is a specialized and indispensable structure in brain blood vessels that is damaged during Alzheimer's disease (AD). CD147 is expressed on the BBB and deeply engaged in the AD pathological process. In this study, we aimed to provide a better understanding of the roles of CD147 in BBB function in health and neurodegenerative disease. METHODS AND RESULTS: We measured CD147 expression in mouse brains and demonstrated that CD147 is exclusively expressed in brain endothelial cells (BECs), and its expression decreases with age. After constructing endothelial-specific CD147 knockout mice, we performed RNA-sequencing on BECs isolated from mice of different ages as well as a range of database analyses. We found that endothelial CD147 is essential for the dual functions of the BBB, including barrier maintenance and transporter regulation. This study also shows that CD147 plays a pivotal role in neurodegenerative diseases, particularly in AD. CONCLUSIONS: Our findings suggested that targeting CD147 in BECs may represent a novel therapeutic strategy, which promoted the design of future experimental investigations and the mechanistic understanding of neurodegenerative diseases.

CD147 promotes DNA damage response and gemcitabine resistance via targeting ATM/ATR/p53 and affects prognosis in pancreatic cancer.

The acquisition of chemoresistance is a major clinical challenge for pancreatic cancer (PC) treatment. Chemoresistance is largely attributed to aberrant DNA damage repair. However, the underlying mechanisms of chemoresistance in pancreatic cancer remain unclear. Here, we showed that CD147 was strongly correlated to DNA damage response (DDR) indices and poor prognosis in pancreatic ductal adenocarcinoma (PDAC) patients. CD147 knockdown or monoclonal antibodies improved the killing effects of gemcitabine in gemcitabine resistant cells, exhibiting reduced activation of ATM/p53. Moreover, we found the interaction of CD147 with ATM, ATR and p53, which was augmented in gemcitabine resistant cells. High CD147/p-ATM/p-ATR/p-p53 cytoplasmic expression associated with poor survival of PC patients. Our studies thus identify CD147 as a critical player in DDR programing that affects gemcitabine therapeutic outcomes of pancreatic cancer patients.

Distributed Fixed-Time Consensus Tracking Control of Uncertain Nonlinear Multiagent Systems: A Prioritized Strategy.

This paper focuses on the fixed-time consensus tracking problem for uncertain high-order nonlinear multiagent systems (MASs) under switching topologies. Unlike the traditional methods using the given original topology directly, a prioritized strategy is first proposed to assign a priority to the topological network such that the information from the leader is delivered to each agent in a least transit route (LTR). For each agent, only parts of its received information are used to design controller, which reduces the computing burden and complexity in the design process. According to the proposed prioritized strategy, the consensus tracking problem is transformed into general tracking problem. By utilizing the power integration technique, the uncertainties of nonlinear functions in MASs are dealt with. Finally, the distributed fixed-time control protocols are developed to ensure all the followers achieve the consensus with the leader under different topological cases. Rigorous stability analysis has been given and simulation results verify the effectiveness of the proposed method.

Programmed Death Ligand 1 Indicates Pre-Existing Adaptive Immune Response by Tumor-Infiltrating CD8+ T Cells in Non-Small Cell Lung Cancer.

Aberrant expression of programmed death ligand 1 (PD-L1) on tumor cells impedes antitumor immunity and instigates immune evasion. The remarkable efficacy of immune checkpoint blockade has been confirmed in various solid tumors. However, the correlation between PD-L1 expression and host immunological landscape remains of considerable controversy in non-small cell lung cancer (NSCLC). In the present study, PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) infiltration levels were determined by immunohistochemistry (IHC) in tumor sections of 138 NSCLC patients. The expression level of PD-L1 was positively correlated with the abundance of CD8 + TILs (p < 0.0001). Furthermore, no constitutive expression of PD-L1 was observed in the majority of six NSCLC cell lines detected by Western blot; but exposure to interferon-γ (IFN-γ), a primary cytokine secreted by activated CD8+ T cells, prominently increased PD-L1 expression. Notably, a significantly positive association was determined within PD-L1, CD8 and IFN-γ gene expression by qRT-PCR, which was corroborated by RNA-sequencing from TCGA lung cancer dataset. These findings demonstrate that PD-L1 expression indicates an adaptive immune resistance mechanism adopted by tumor cells in the aversion of immunogenic destruction by CD8+ TILs. Both higher expression of PD-L1 and infiltration of CD8+ TILs were correlated with superior prognosis (p = 0.044 for PD-L1; p = 0.002 for CD8). Moreover, Cox multivariate regression analysis showed that the combination of PD-L1 and CD8 were independent prognostic factors, which was more accurate in prediction of prognosis in NSCLC than individually. Finally, we found that IFN-γ induced the upregulation of PD-L1 in NSCLC cells, mainly through the JAK/STAT1 signaling pathway. In conclusion, PD-L1 expression is mainly induced by activated CD8+ TILs via IFN-γ in the immune milieu and indicates pre-existing adaptive immune response in NSCLC.

RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression.

Rationale: Necroptosis is a programmed form of non-apoptotic cell death that requires receptor-interacting protein 3 (RIP3). RIP3 has been shown to be relevant in multiple tumor types and has differential impact on tumor progression. We investigated whether RIP3 is involved in the progression of colitis-associated cancer (CAC) in mice. Methods: Tissues from colorectal cancer patients were examined for RIP3 expression. CAC was induced using azoxymethane (AOM) injection followed by dextran sodium sulfate (DSS) treatment in RIP3-deficient or wild-type mice. Colon tissues were collected and analyzed by Western blotting and gene expression profile analyses. Immune cell infiltration and CXCL1 expression were examined by flow cytometry and Real-time PCR, respectively. Results: RIP3 expression was upregulated in mouse CAC and human colon cancer. RIP3-deficient mice showed significantly attenuated colitis-associated tumorigenesis. Bone marrow transplantation experiments suggested that RIP3's function in hematopoietic cells primarily contributes to the phenotype. RIP3 supported epithelial proliferation and tumor growth via JNK signaling but had no effect on apoptosis. RIP3 deletion increased T cell accumulation and reduced infiltration by immunosuppressive subsets of myeloid cells during acute colitis and CAC. The immune-suppressive tumor microenvironment was dependent on RIP3-induced expression of the chemokine attractant CXCL1, and administration of recombinant CXCL1 during CAC restored tumorigenesis in Rip3-/- mice. Conclusion: Our results reveal an unexpected function of RIP3 in enhancing the proliferation of premalignant intestinal epithelial cells (IECs) and promoting myeloid cell-induced adaptive immune suppression. These two distinct mechanisms of RIP3-induced JNK and CXCL1 signalling contribute to CAC progression.

Receptor-Interacting Protein Kinase 3 Deficiency Recruits Myeloid-Derived Suppressor Cells to Hepatocellular Carcinoma Through the Chemokine (C-X-C Motif) Ligand 1-Chemokine (C-X-C Motif) Receptor 2 Axis.

Receptor-interacting protein kinase 3 (RIP3) is the core regulator that switches cell death from apoptosis to necrosis. However, its role in tumor immunity is unknown. In this study, decreased RIP3 expression was observed in patients with hepatocellular carcinoma (HCC), which correlates with myeloid-derived suppressor cell (MDSC) accumulation. Moreover, RIP3 is a prognosis factor for patients with HCC. We further found that RIP3 knockdown results in an increase of MDSCs and a decrease of interferon gamma-positive (IFN-γ+ ) cluster of differentiation 8-positive (CD8+ ) tumor-infiltrating lymphocytes (IFN-γ+ CD8+ T cells) in hepatoma tissues, thus promoting immune escape and HCC growth in immunocompetent mice. By phosphorylating P65Ser536 and promoting phosphorylated P65Ser536 nuclear translocation, RIP3 knockdown increases the expression of chemokine (C-X-C motif) ligand 1 (CXCL1) in HCC cells. RIP3 knockdown induces MDSC recruitment through the CXCL1-chemokine (C-X-C motif) receptor 2 (CXCR2) axis. Furthermore, a CXCR2 antagonist substantially suppresses MDSC chemotaxis and HCC growth in RIP3 knockout mice. Conclusion: RIP3 deficiency is an essential factor directing MDSC homing to HCC and promoting CXCL1/CXCR2-induced MDSC chemotaxis to facilitate HCC immune escape and HCC progression; blocking the CXCL1-CXCR2 chemokine axis may provide an immunological therapeutic approach to suppress progression of RIP3 deficiency HCC.

Alterations of the Immunologic Co-Stimulator B7 and TNFR Families Correlate with Hepatocellular Carcinoma Prognosis and Metastasis by Inactivating STAT3.

Blockade of the immunosuppressive checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed death 1 (PD-1) and its cognate ligand, programmed death 1 ligand (PD-L1), has altered the landscape of anti-tumor immunotherapy. B7 family and tumor necrosis factor receptor (TNFR) superfamily play a crucial role in T cell activation, tolerance, and anergy through co-stimulatory and inhibitory signal transduction. Investigating the immune molecular landscapes of the B7 and TNFR families is critical in defining the promising responsive candidates. Herein, we performed comprehensive alteration analysis of the B7 and TNFR family genes across six hepatocellular carcinoma (HCC) datasets with over 1000 patients using cBioPortal TCGA data. About 16% of patients had both B7 and TNFR gene alterations. TNFR gene amplifications were relatively more common (1.73⁻8.82%) than B7 gene amplifications (1.61⁻2.94%). Analysis of 371 sequenced samples revealed that all genes were upregulated: B7 and TNFR mRNA were upregulated in 23% of cases (86/371) and 28% of cases (105/371), respectively. Promoter methylation analysis indicated an epigenetic basis for B7 and TNFR gene regulation. The mRNA levels of B7 and TNFR genes were inversely correlated with promoter methylation status. B7-H6 expression was significantly associated with worse overall survival, and B7-H6 mRNA was increased gradually in cases with gene copy number alterations. B7-H6 overexpression was associated with aggressive clinicopathologic features and poor prognosis in HCC. Downregulation of B7-H6 in HCC cells significantly inhibited cell adhesion, proliferation, migration, and invasion. Knockdown of B7-H6 in HCC cells inhibited tumor growth and metastasis in vivo. B7-H6 promoted HCC metastasis via induction of MMP-9 expression and STAT3 activation. B7-H6 and STAT3 performed functional overlapping roles on enhancing the MMP-9 promoter activity in HCC cells. These results suggest that alterations of the immunologic co-stimulator B7 and TNFR families correlate with HCC metastasis and prognosis, and especially B7-H6 plays a critical role in promoting metastasis of HCC.

Distributed Adaptive Event-Triggered Fault-Tolerant Consensus of Multiagent Systems With General Linear Dynamics.

In this paper, the distributed adaptive event-triggered fault-tolerant consensus of general linear multiagent systems (MASs) is considered. First, in order to deal with multiplicative fault, a distributed event-triggered consensus protocol is designed. Using distributed adaptive online updating strategies, the computation of the minimum eigenvalue of Laplacian matrix is avoided. Second, some adaptive parameters are introduced in trigger function to improve the self-regulation ability of event-triggered mechanism. The new trigger threshold is both state-dependent and time-dependent, which is independent of the number of agents. Then sufficient conditions are derived to guarantee the leaderless and leader-following consensus. On the basis of this, the results are extended to the case of actuator saturation. It is proved the Zeno-behavior of considered event-triggered mechanism is avoided. At last, the effectiveness of the proposed methods are demonstrated by three simulation examples.

Genetic variation in transcription factors and photosynthesis light-reaction genes regulates photosynthetic traits.

Transcription factors (TFs) play crucial roles in regulating the production of the components required for photosynthesis; elucidating the mechanisms by which underlying genetic variation in TFs affects complex photosynthesis-related traits may improve our understanding of photosynthesis and identify ways to improve photosynthetic efficiency. Promoter analysis of 96 nuclear-encoded Populus tomentosa Carr. genes within this pathway revealed 47 motifs responsive to light, stress, hormones and organ-specific regulation, as well as 86 TFs that might bind these motifs. Using phenotype-genotype associations, we identified 244 single-nucleotide polymorphisms (SNPs) within 105 genes associated with 12 photosynthesis-related traits. Most (30.33%) of these SNPs were located in intronic regions and these SNPs explained 18.66% of the mean phenotypic variation in the photosynthesis-related traits. Additionally, expression quantitative trait loci (eQTL) mapping identified 216 eQTLs associated with 110 eGenes (genes regulated by eQTLs), explaining 14.12% of the variability of gene expression. The lead SNPs of 12.04% of the eQTLs also contributed to phenotypic variation. Among these, a SNP in zf-Dof 5.6 (G120_9287) affected photosynthesis by modulating the expression of a sub-regulatory network of eight other TFs, which in turn regulate 55 photosynthesis-related genes. Furthermore, epistasis analysis identified a large interacting network representing 732 SNP-SNP pairs, of which 354 were photosynthesis gene-TF pairs, emphasizing the important roles of TFs in affecting photosynthesis-related traits. We combined eQTL and epistasis analysis and found 32 TFs harboring eQTLs being epistatic to their targets (identified by eQTL analysis), of which 15 TFs were also associated with photosynthesis traits. We therefore constructed a schematic model of TFs involved in regulating the photosynthetic light reaction pathway. Taken together, our results provide insight into the genetic regulation of photosynthesis, and may drive progress in the marker-assisted selection of desirable P. tomentosa genotypes with more efficient photosynthesis.

Various response of Pinus tabulaeformis Carr. regeneration in artifical gaps.

Understanding the influence of gaps in promoting canopy recruitment will help to maintain structural stability and achieve continuous forest cover. We established three control plots and experimental plots with three replications each (gap sizes L-I, L-II, L-III, and L-IV) in a Chinese pine (Pinus tabulaeformis Carr.) plantation to test the short-term effects of gap size on the age distribution, density and growth, and annual height and ground diameter growth for regeneration established before (REBG) and after (REAG) gap creation. Age distribution exhibited an approximately normal distribution, with the numbers of REBG and REAG decreasing and increasing, respectively, as the age increased. Although there was no difference in density among gap size classes, regeneration growth positively responded to gap size, with maximum values observed in class L-III. Annual average height growth after (AAH-A) gap creation was significantly greater than that before (AAH-B) gap creation for REBG among gap sizes, suggesting that gaps promote the rapid growth of regeneration. However, the responses of height and ground diameter growth in REBG to gap size were not immediate and exhibited a response delay of 2-4 years. Similarly, for the height and ground diameter growth of REAG, significant differences were first observed within years 2-4 after germination in the same growing season for all gap size classes.

Genetic architecture of growth traits in Populus revealed by integrated quantitative trait locus (QTL) analysis and association studies.

Deciphering the genetic architecture underlying polygenic traits in perennial species can inform molecular marker-assisted breeding. Recent advances in high-throughput sequencing have enabled strategies that integrate linkage-linkage disequilibrium (LD) mapping in Populus. We used an integrated method of quantitative trait locus (QTL) dissection with a high-resolution linkage map and multi-gene association mapping to decipher the nature of genetic architecture (additive, dominant, and epistatic effects) of potential QTLs for growth traits in a Populus linkage population (1200 progeny) and a natural population (435 individuals). Seventeen QTLs for tree height, diameter at breast height, and stem volume mapped to 11 linkage groups (logarithm of odds (LOD) ≥ 2.5), and explained 2.7-18.5% of the phenotypic variance. After comparative mapping and transcriptome analysis, 187 expressed genes (10 046 common single nucleotide polymorphisms (SNPs)) were selected from the segmental homology regions (SHRs) of 13 QTLs. Using multi-gene association models, we observed 202 significant SNPs in 63 promising genes from 10 QTLs (P ≤ 0.0001; FDR ≤ 0.10) that exhibited reproducible associations with additive/dominant effects, and further determined 11 top-ranked genes tightly linked to the QTLs. Epistasis analysis uncovered a uniquely interconnected gene-gene network for each trait. This study opens up opportunities to uncover the causal networks of interacting genes in plants using an integrated linkage-LD mapping approach.

Adaptive Neural Control of MIMO Nonstrict-Feedback Nonlinear Systems With Time Delay.

In this paper, an adaptive neural output-feedback tracking controller is designed for a class of multiple-input and multiple-output nonstrict-feedback nonlinear systems with time delay. The system coefficient and uncertain functions of our considered systems are both unknown. By employing neural networks to approximate the unknown function entries, and constructing a new input-driven filter, a backstepping design method of tracking controller is developed for the systems under consideration. The proposed controller can guarantee that all the signals in the closed-loop systems are ultimately bounded, and the time-varying target signal can be tracked within a small error as well. The main contributions of this paper lie in that the systems under consideration are more general, and an effective design procedure of output-feedback controller is developed for the considered systems, which is more applicable in practice. Simulation results demonstrate the efficiency of the proposed algorithm.

CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma.

Oscillations in intracellular Ca2+ concentrations ([Ca2+]i) mediate various cellular function. Although it is known that [Ca2+]i oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca2+]i oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca2+]i oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca2+]i oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca2+ release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca2+]i oscillations. Furthermore, CD147 accelerates ER Ca2+refilling and enhances the frequency of [Ca2+]i oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147-promoted ER Ca2+ release and refilling are tightly regulated by changing [Ca2+]i. CD147 may activate IP3R1 channel under low [Ca2+]i conditions and CD147 may activate SERCA pump under high [Ca2+]i conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca2+]i oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca2+]i oscillations to promote oncogenic progression in HCC.

Detoxification strategies and regulation of oxygen production and flowering of Platanus acerifolia under lead (Pb) stress by transcriptome analysis.

Toxic metal pollution is a major environmental problem that has received wide attention. Platanus acerifolia (London plane tree) is an important greening tree species that can adapt to environmental pollution. The genetic basis and molecular mechanisms associated with the ability of P. acerifolia to respond lead (Pb) stress have not been reported so far. In this study, 16,246 unigenes differentially expressed unigenes that were obtained from P. acerifolia under Pb stress using next-generation sequencing. Essential pathways such as photosynthesis, and gibberellins and glutathione metabolism were enriched among the differentially expressed unigenes. Furthermore, many important unigenes, including antioxidant enzymes, plants chelate compounds, and metal transporters involved in defense and detoxification mechanisms, were differentially expressed in response to Pb stress. The unigenes encoding the oxygen-evolving enhancer Psb and OEE protein families were downregulated in Pb-stressed plants, implying that oxygen production might decrease in plants under Pb stress. The relationship between gibberellin and P. acerifolia flowering is also discussed. The information and new insights obtained in this study will contribute to further investigations into the molecular regulation mechanisms of Pb accumulation and tolerance in greening tree species.

Allelic variation within the S-adenosyl-L-homocysteine hydrolase gene family is associated with wood properties in Chinese white poplar (Populus tomentosa).

BACKGROUND: S-adenosyl-l-homocysteine hydrolase (SAHH) is the only eukaryotic enzyme capable of S-adenosyl-l-homocysteine (SAH) catabolism for the maintenance of cellular transmethylation potential. Recently, biochemical and genetic studies in herbaceous species have obtained important discoveries in the function of SAHH, and an extensive characterization of SAHH family in even one tree species is essential, but currently lacking. RESULTS: Here, we first identified the SAHH family from Populus tomentosa using molecular cloning method. Phylogenetic analyses of 28 SAHH proteins from dicotyledons, monocotyledons, and lower plants revealed that the sequences formed two monophyletic groups: the PtrSAHHA with PtoSAHHA and PtrSAHHB with PtoSAHHB. Examination of tissue-specific expression profiles of the PtoSAHH family revealed similar expression patterns; high levels of expression in xylem were found. Nucleotide diversity and linkage disequilibrium (LD) in the PtoSAHH family, sampled from P. tomentosa natural distribution, revealed that PtoSAHH harbors high single-nucleotide polymorphism (SNP) diversity (π = 0.01059 ± 0.00122 and 0.00930 ± 0.00079,respectively) and low LD (r2 > 0.1, within 800 bp and 2,200 bp, respectively). Using an LD-linkage analysis approach, two noncoding SNPs (PtoSAHHB_1065 and PtoSAHHA_2203) and the corresponding haplotypes were found to significantly associate with α-cellulose content, and a nonsynonymous SNP (PtoSAHHB_410) within the SAHH signature motifs showed significant association with fiber length, with an average of 3.14% of the phenotypic variance explained. CONCLUSIONS: The present study demonstrates that PtoSAHHs were split off prior to the divergence of interspecies in Populus, and SAHHs may play a key role promoting transmethylation reactions in the secondary cell walls biosynthesis in trees. Hence, our findings provide insights into SAHH function and evolution in woody species and also offer a theoretical basis for marker-aided selection breeding to improve the wood quality of Populus.