Comparative analysis of climate-induced changes in distribution of representative fish species in the Yellow Sea.

Climate changes are posing remarkable impacts on marine fish and fisheries. Although many studies have addressed the distributional effects of climate change on single fish species or taxa in recent years, comparative studies focusing on different types of fish are still lacking. In this study, we applied dynamic bioclimate envelop models (DBEM), based on three earth system models, to predict sea surface and bottom temperature, as well as the spatial and temporal distribution of nine representative fishes in the Yellow Sea, contain two habitats, i.e., continental shelf benthopelagic (CBD) and continental shelf pelagic-neritic (CPN) fishes, and two thermophilies, i.e., warm temperate (WT) and warm water (WW) fishes. Under a low emissions scenario (RCP 2.6) and a high emissions scenario (RCP 8.5) between 1970 and 2060, results reveal that: a) CPN fishes show a distinct tendency to move to higher latitudes than CBD fishes, and WW fishes show a significant tendency to migrate more widely to the north than WT fishes; b) The relative abundance of CPN fishes is expected to be higher than that of CBD fishes, while there is no apparent difference in relative abundance between WW fishes and WT fishes. The main reasons for this difference are presumed to be: variance of temperature rise between the sea surface and bottom layers, divergent adaptations of the species, and disparate degrees of anthropogenic influence.

IL-27p28 specifically regulates MHC II expression in macrophages through CIITA.

Antigen-presenting cells (APCs) constantly express major histocompatibility complex II (MHC II), including macrophages and dendritic cells (DCs) which deliver antigens to CD4+ T cells and play an important role in adaptive immunity. The expression of MHC II is controlled by the transcriptional coactivator CIITA. Interleukin-27 (IL-27), a newly discovered IL-12 family cytokine, is composed of p28 and EBI3 subunits. In this study, we used IL-27p28 conditional knock-out mice to investigate the regulatory effects of IL-27p28 on macrophage polarization and the expression of MHC II in macrophages. We found that MHC II expression was upregulated in the bone marrow-derived and peritoneal exudate macrophages (BMDMs; PEMs) from IL-27p28-deficient mice, with their inflammation regulating function unaffected. We also demonstrated that in the APCs, IL-27p28 selectively regulated MHC II expression in macrophages but not in dendritic cells. During Pseudomonas aeruginosa (P. aeruginosa) reinfection, higher survival rate, bacterial clearance, and ratio of CD4+/CD8+ T cells in the spleen during the specific immune phase were observed in IL-27p28 defect mice, as well as an increased MHC II expression in alveolar macrophages (AMs). But these did not occur in the first infection. For the first time we discovered that IL-27p28 specifically regulates the expression of MHC II in macrophages by regulating CIITA, while its absence enhances antigen presentation and adaptive immunity against P. aeruginosa.

Identification of UBFD1 as a prognostic biomarker and molecular target among estrogen receptor-positive breast cancer.

Estrogen receptor (ER)-positive breast cancer (BRCA) is the most commonly diagnosed molecular subtype of BRCA. It is routinely treated with endocrine therapy; however, some patients relapse after therapy and develop drug resistance, resulting in treatment failure. In the present study, we identified markers of ER-positive BRCA and evaluated their putative function in immune infiltration as well as their clinicopathological significance. The ubiquitin family domain containing 1 (UBFD1) protein was associated with the prognosis of ER-positive BRCA patients. Its expression was higher in ER-positive BRCA tissues compared with adjacent nontumor tissues. Patients with higher UBFD1 expression had a poorer prognosis. UBFD1 is an independent risk factor for ER-positive BRCA patients and its function was primarily associated with hormone activity and inflammation. Taken together, UBFD1 is a potential prognostic biomarker and candidate target of ER-positive BRCA.

NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates.

Cellular senescence, characterized by stable cell cycle arrest, plays an important role in aging and age-associated pathologies. Eliminating senescent cells rejuvenates aged tissues and ameliorates age-associated diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells in vitro, regardless of stimuli that induced cellular senescence, and in various tissues of aged mice and nonhuman primates in vivo. Accordingly, we developed and demonstrated that chimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression in vitro. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects. Our findings establish that NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence.

The transcription factor VaNAC72-regulated expression of the VaCP17 gene from Chinese wild Vitis amurensis enhances cold tolerance in transgenic grape (V. vinifera).

Papain-like cysteine proteases (PLCP) play diverse roles in plant biology. In our previous studies, a VaCP17 gene from the cold-tolerant Vitis amurensis accession 'Shuangyou' was isolated and its role in cold tolerance was preliminarily verified in Arabidopsis. Here, we confirmed the function of VaCP17 in cold tolerance by stably overexpressing VaCP17 in the cold-sensitive Vitis vinifera cultivar 'Thompson Seedless' and transiently silencing VaCP17 in 'Shuangyou' leaves. The results showed that overexpression of VaCP17 improved the cold tolerance in 'Thompson Seedless' as manifested by reduced electrolyte leakage and malondialdehyde accumulation, chlorophyll homeostasis, increased antioxidant enzymes (superoxide dismutase, peroxidase, and catalase) activitiy, and rapid up-regulation of stress-related genes (VvKIN2, VvRD29B, and VvNCED1) compared with wild-type line. Conversely, RNA interfere-mediated knockdown of VaCP17 in 'Shuangyou' leaves resulted in opposite physiological and biochemical responses and exacerbated leaves wilting compared with control. Subsequently, by yeast one-hybrid, dual-luciferase assays, and transient overexpression of VaNAC72 in 'Shuangyou' leaves, a VaCP17-interacting protein VaNAC72 was confirmed to promote the expression of VaCP17 under cold stress, which depends on abscisic acid, methyl jasmonate, and salicylic acid signaling. By yeast two-hybrids, bimolecular fluorescence complementation and luciferase complementation assays, it was found that VaNAC72 could form homodimers or heterodimers with VaCBF2. Furthermore, co-expression analysis confirmed that VaNAC72 works synergistically with VaCBF2 or VaCP17 to up-regulate the expression of VaCP17. In conclusion, the study revealed that the VaNAC72-VaCP17 module positively regulated cold tolerance in grapevine, and this knowledge is useful for further revealing the cold-tolerance mechanism of V. amurensis and grape molecular breeding.

Exogenous hydrogen sulfide (H2S) exerts therapeutic potential in triple-negative breast cancer by affecting cell cycle and DNA replication pathway.

Triple negative breast cancer (TNBC) is a highly aggressive subtype with a poor prognosis due to its high rates of proliferation and metastasis. Recently, hydrogen sulfide (H2S) has been recognized as a novel gasotransmitter that plays a significant role in various pathological processes, including cancer. Here, we show that exogenous H2S inhibited TNBC cancer cell proliferation, migration and invasion in vitro, and also decreased cancer malignances in the mouse model of TNBC. To investigate the underlying mechanisms of H2S's anti-cancer effects in TNBC, we performed transcriptome sequencing and bioinformatic analyses. 2121 differentially expressed genes (DEGs) were revealed, and mainly enriched in cell cycle and DNA replication pathways. Further analysis revealed changes in alternative splicing after exogenous H2S treatment. Protein-protein interaction (PPI) network analysis was performed, which identified 458 interactions among 276 DEGs enriched in cell cycle and DNA replication pathways.We identified seven hub genes (MCM3, MCM4, MCM5, MCM6, CDC6, CDC45, and GINS2) through PPI network analysis, which were up-regulated in clinical human breast cancer but down-regulated after H2S treatment. Based on the hub genes selected, we developed a model predicting that exogenous H2S mainly exerts its anti-TNBC role by delaying DNA replication. Our findings suggest that exogenous H2S has potential as a therapeutic agent in TNBC and may exert its therapeutic potential through DNA replication and the cell cycle pathway.

VyUSPA3, a universal stress protein from the Chinese wild grape Vitis yeshanensis, confers drought tolerance to transgenic V. vinifera.

KEY MESSAGE: VyUSPA3 from the Chinese wild grape Vitis yeshanensis interacts with ERF105, PUB24 and NF-YB3, and overexpression of the VyUSPA3 gene in V. vinifera cv. 'Thompson Seedless' confers drought tolerance. Drought is a major abiotic stress factor that seriously affects the growth and yield of grapevine. Although many drought-related genes have been identified in Arabidopsis and other plants, the functions of only a few of their counterparts have been revealed in grape. Here, a universal stress protein (USP) A from the Chinese wild grape Vitis yeshanensis, VyUSPA3, was identified and its function was subsequently characterized by overexpressing or silencing the VyUSPA3 gene in V. vinifera cv. 'Thompson Seedless' via Agrobacterium-mediated genetic transformation. After 21 d of the drought treatment, most leaves of the untransformed (UT) 'Thompson Seedless' lines wilted, yet UT lines were less damaged compared to the RNAi-VyUSPA3 lines, nonetheless, the OE-VyUSPA3 lines were mostly unaffected. Meanwhile, OE-VyUSPA3 lines showed smaller stomatal aperture, more developed roots, higher leaf relative water content, proline content, and antioxidant enzyme activities, as well as lower malondialdehyde, H2O2 and O2•- accumulation than UT lines, but this response pattern was reversed in the RNAi-VyUSPA3 lines. Besides, the transcript levels of four drought-related genes (RD22, RD29B, DREB2A, and NCED1) in OE-VyUSPA3 lines were greater than those in the RNAi-VyUSPA3 and UT lines. In addition, a yeast two-hybrid assay and a bimolecular fluorescence complementation assay confirmed that VyUSPA3 interacted with ERF105, PUB24, and NF-YB3, respectively. This study revealed that VyUSPA3 improved drought tolerance in transgenic grapevines possibly through interaction with the hormone signaling, ubiquitination system, ethylene-responsive element binding factor and nuclear factors.

Simulating domain architecture evolution.

MOTIVATION: Simulation is an essential technique for generating biomolecular data with a 'known' history for use in validating phylogenetic inference and other evolutionary methods. On longer time scales, simulation supports investigations of equilibrium behavior and provides a formal framework for testing competing evolutionary hypotheses. Twenty years of molecular evolution research have produced a rich repertoire of simulation methods. However, current models do not capture the stringent constraints acting on the domain insertions, duplications, and deletions by which multidomain architectures evolve. Although these processes have the potential to generate any combination of domains, only a tiny fraction of possible domain combinations are observed in nature. Modeling these stringent constraints on domain order and co-occurrence is a fundamental challenge in domain architecture simulation that does not arise with sequence and gene family simulation. RESULTS: Here, we introduce a stochastic model of domain architecture evolution to simulate evolutionary trajectories that reflect the constraints on domain order and co-occurrence observed in nature. This framework is implemented in a novel domain architecture simulator, DomArchov, using the Metropolis-Hastings algorithm with data-driven transition probabilities. The use of a data-driven event module enables quick and easy redeployment of the simulator for use in different taxonomic and protein function contexts. Using empirical evaluation with metazoan datasets, we demonstrate that domain architectures simulated by DomArchov recapitulate properties of genuine domain architectures that reflect the constraints on domain order and adjacency seen in nature. This work expands the realm of evolutionary processes that are amenable to simulation. AVAILABILITY AND IMPLEMENTATION: DomArchov is written in Python 3 and is available at http://www.cs.cmu.edu/~durand/DomArchov. The data underlying this article are available via the same link. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

VaMYB44 transcription factor from Chinese wild Vitis amurensis negatively regulates cold tolerance in transgenic Arabidopsis thaliana and V. vinifera.

KEY MESSAGE: Heterologous expression of VaMYB44 gene in Arabidopsis and V. vinifera cv. 'Thompson Seedless' increases cold sensitivity, which is mediated by the interaction of VaMYC2 and VaTIFY5A with VaMYB44 MYB transcription factors play critical roles in plant stress response. However, the function of MYB44 under low temperature stress is largely unknown in grapes. Here, we isolated a VaMYB44 gene from Chinese wild Vitis amurensis acc. 'Shuangyou' (cold-resistant). The VaMYB44 is expressed in various organs and has lower expression levels in stems and young leaves. Exposure of the cold-sensitive V. vinifera cv. 'Thompson Seedless' and cold-resistant 'Shuangyou' grapevines to cold stress (-1 °C) resulted in differential expression of MYB44 in leaves with the former reaching 14 folds of the latter after 3 h of cold stress. Moreover, the expression of VaMYB44 was induced by exogenous ethylene, abscisic acid, and methyl jasmonate in the leaves of 'Shuangyou'. Notably, the subcellular localization assay identified VaMYB44 in the nucleus. Interestingly, heterologous expression of VaMYB44 in Arabidopsis and 'Thompson Seedless' grape increased freezing-induced damage compared to their wild-type counterparts. Accordingly, the transgenic lines had higher malondialdehyde content and electrolyte permeability, and lower activities of superoxide dismutase, peroxidase, and catalase. Moreover, the expression levels of some cold resistance-related genes decreased in transgenic lines. Protein interaction assays identified VaMYC2 and VaTIFY5A as VaMYB44 interacting proteins, and VaMYC2 could bind to the VaMYB44 promoter and promote its transcription. In conclusion, the study reveals VaMYB44 as the negative regulator of cold tolerance in transgenic Arabidopsis and transgenic grapes, and VaMYC2 and VaTIFY5A are involved in the cold sensitivity of plants by interacting with VaMYB44.

Bacteroides acidifaciens in the gut plays a protective role against CD95-mediated liver injury.

The intestinal flora plays an important role in the development of many human and animal diseases. Microbiome association studies revealed the potential regulatory function of intestinal bacteria in many liver diseases, such as autoimmune hepatitis, viral hepatitis and alcoholic hepatitis. However, the key intestinal bacterial strains that affect pathological liver injury and the underlying functional mechanisms remain unclear. We found that the gut microbiota from gentamycin (Gen)-treated mice significantly alleviated concanavalin A (ConA)-induced liver injury compared to vancomycin (Van)-treated mice by inhibiting CD95 expression on the surface of hepatocytes and reducing CD95/CD95L-mediated hepatocyte apoptosis. Through the combination of microbiota sequencing and correlation analysis, we isolated 5 strains with the highest relative abundance, Bacteroides acidifaciens (BA), Parabacteroides distasonis (PD), Bacteroides thetaiotaomicron (BT), Bacteroides dorei (BD) and Bacteroides uniformis (BU), from the feces of Gen-treated mice. Only BA played a protective role against ConA-induced liver injury. Further studies demonstrated that BA-reconstituted mice had reduced CD95/CD95L signaling, which was required for the decrease in the L-glutathione/glutathione (GSSG/GSH) ratio observed in the liver. BA-reconstituted mice were also more resistant to alcoholic liver injury. Our work showed that a specific murine intestinal bacterial strain, BA, ameliorated liver injury by reducing hepatocyte apoptosis in a CD95-dependent manner. Determination of the function of BA may provide an opportunity for its future use as a treatment for liver disease.

Evidence for exon shuffling is sensitive to model choice.

The exon shuffling theory posits that intronic recombination creates new domain combinations, facilitating the evolution of novel protein function. This theory predicts that introns will be preferentially situated near domain boundaries. Many studies have sought evidence for exon shuffling by testing the correspondence between introns and domain boundaries against chance intron positioning. Here, we present an empirical investigation of how the choice of null model influences significance. Although genome-wide studies have used a uniform null model, exclusively, more realistic null models have been proposed for single gene studies. We extended these models for genome-wide analyses and applied them to 21 metazoan and fungal genomes. Our results show that compared with the other two models, the uniform model does not recapitulate genuine exon lengths, dramatically underestimates the probability of chance agreement, and overestimates the significance of intron-domain correspondence by as much as 100 orders of magnitude. Model choice had much greater impact on the assessment of exon shuffling in fungal genomes than in metazoa, leading to different evolutionary conclusions in seven of the 16 fungal genomes tested. Genome-wide studies that use this overly permissive null model may exaggerate the importance of exon shuffling as a general mechanism of multidomain evolution.

Expression of the pyrroline-5-carboxylate reductase (P5CR) gene from the wild grapevine Vitis yeshanensis promotes drought resistance in transgenic Arabidopsis.

Proline accumulation is one of the most common reactions in plants under drought stress. Pyrroline-5-carboxylate reductase (P5CR) is the final enzyme and plays an important role in proline biosynthesis. The Chinese wild grapevine Vitis yeshanensis J.X. Chen accession 'Yanshan-1' is highly resistant to drought, but the genetic and molecular mechanisms associated with this resistance have not been elucidated. Here, we cloned a VyP5CR gene (Genbank ID: MZ226960) from 'Yanshan-1', and evaluated its transcriptional response to drought, NaCl, cold, as well as exogenous ABA, MeJA and SA. Tissue specific analysis showed that VyP5CR could be expressed in various organs and was highly expressed in roots. To gain insight into the roles of VyP5CR, we overexpressed VyP5CR in Arabidopsis thaliana (Arabidopsis). Transgenic Arabidopsis plants expressing VyP5CR showed enhanced survival rate, smaller stomata in response to severe drought, as well as stronger root growth on a medium containing mannitol. Under drought stress, VyP5CR-OE plants showed reduced levels of MDA, H2O2 and O2-, and higher proline content, SOD and POD activity. In addition, VyP5CR-OE plants showed increased induction of the drought-related genes COR15A, COR47, DREB2A, KIN1, NCED3 and RD29A. Taken together, these experiments reveal that VyP5CR can promote the drought tolerance of transgenic Arabidopsis. Besides, an interacting protein with VyP5CR, VyCSN5B (COP9 signalosome complex subunit 5b), was screened out by yeast two-hybrid and verified by bimolecular fluorescence complementation assay.

CAR-T therapy: Prospects in targeting cancer stem cells.

Cancer stem cells (CSCs), a group of tumour cells with stem cell characteristics, have the ability of self-renewal, multi-lineage differentiation and tumour formation. Since CSCs are resistant to conventional radiotherapy and chemotherapy, their existence may be one of the root causes of cancer treatment failure and tumour progression. The elimination of CSCs may be effective for eventual tumour eradication. Because of the good therapeutic effects without major histocompatibility complex (MHC) restriction and the unique characteristics of CSCs, chimeric antigen receptor T-cell (CAR-T) therapy is expected to be an important method to eliminate CSCs. In this review, we have discussed the feasibility of CSCs-targeted CAR-T therapy for cancer treatment, summarized current research and clinical trials of targeting CSCs with CAR-T cells and forecasted the challenges and future direction from the perspectives of toxicity, persistence and potency, trafficking, infiltration, immunosuppressive tumour microenvironment, and tumour heterogeneity.

Genome-wide analysis of the Universal stress protein A gene family in Vitis and expression in response to abiotic stress.

Universal Stress Protein A (USPA) plays critical roles in the regulation of growth, development and response to abiotic stress in plants. To date, most research related to the role of USPA in plants has been carried out in herbaceous models such as Arabidopsis, rice and soybean. Here, we used bioinformatics approaches to identify 21 USPA genes in the genome of Vitis vinifera L. Phylogenetic analysis revealed that VvUSPAs could be divided into eight clades. Based on predicted chromosomal locations, we identified 16 pairs of syntenic, orthologous genes between A. thaliana and V. vinifera. Further promoter cis-elements analysis, together with identification of potential microRNA (miRNA) binding sites, suggested that at least some of the VvUSPAs participate in response to phytohormones and abiotic stress. To add support for this, we analyzed the developmental and stress-responsive expression patterns of the homologous USPA genes in the drought-resistant wild Vitis yeshanensis accession 'Yanshan-1' and the drought-sensitive Vitis riparia accession 'He'an'. Most of the USPA genes were upregulated in different degrees in the two genotypes after drought stress and exposure to ethephon (ETH), abscisic acid (ABA) and methyl jasmonate (MeJA). Individual USPA genes showed various tissue-specific expression patterns. Heterologous expression of five selected genes (VvUSPA2, VvUSPA3, VvUSPA11, VvUSPA13 and VvUSPA16) in Escherichia coli (E. coli) enhanced resistance to drought stress. Our study provides a model for mapping gene function in response to abiotic stress and identified three candidate genes, VvUSPA3, VvUSPA11 and VvUSPA16, as regulators of drought response in V. vinifera.

Assessing the contribution of tumor mutational phenotypes to cancer progression risk.

Cancer occurs via an accumulation of somatic genomic alterations in a process of clonal evolution. There has been intensive study of potential causal mutations driving cancer development and progression. However, much recent evidence suggests that tumor evolution is normally driven by a variety of mechanisms of somatic hypermutability, which act in different combinations or degrees in different cancers. These variations in mutability phenotypes are predictive of progression outcomes independent of the specific mutations they have produced to date. Here we explore the question of how and to what degree these differences in mutational phenotypes act in a cancer to predict its future progression. We develop a computational paradigm using evolutionary tree inference (tumor phylogeny) algorithms to derive features quantifying single-tumor mutational phenotypes, followed by a machine learning framework to identify key features predictive of progression. Analyses of breast invasive carcinoma and lung carcinoma demonstrate that a large fraction of the risk of future clinical outcomes of cancer progression-overall survival and disease-free survival-can be explained solely from mutational phenotype features derived from the phylogenetic analysis. We further show that mutational phenotypes have additional predictive power even after accounting for traditional clinical and driver gene-centric genomic predictors of progression. These results confirm the importance of mutational phenotypes in contributing to cancer progression risk and suggest strategies for enhancing the predictive power of conventional clinical data or driver-centric biomarkers.

Ultrafast Microwave Synthesis of Carbon-Coated Lithium Vanadium Phosphate Cathode Material for Lithium Ion Batteries.

Carbon-coated lithium vanadium phosphate cathode materials were successfully prepared via an ultra-fast microwave irradiation route in 5 min with using activated carbon as the microwave adsorbent. We aimed to utilize this ultra-fast and facile route to shorten the synthesis procedure for obtaining Li3V2(PO4)3/C cathode material with superior rate capability. To characterize the intrinsic crystal structure and exterior architecture morphology of targeted material, X-ray diffraction pattern (XRD), scanning electron microscopy (SEM) in combined with transmission electron microscopy (TEM) were applied in experiment. The role of microwave irradiation treatment time in affecting the crystalline structure and related lithium-storage electrochemical performance is also investigated in detail. For the optimal Li3V2(PO4)3/C material, it delivered a specific discharge capacity of 110.1 mAh g-1 at a 0.2 C charging/discharging rate while hold a superior cycling stability over 50 cycles when tested at a 1 C rate. The ultra-fast synthesis route should pave a new way to save the energy in the preparation of phosphate-based electroactive cathode material.

Biogenic silver/silver chloride nanoparticles inhibit human glioblastoma stem cells growth in vitro and Ehrlich ascites carcinoma cell growth in vivo.

The importance of biogenic silver/silver chloride nanoparticles has become increasing day by day. In the present study, silver/silver chloride nanoparticles (Ag/AgCl-NPs) were synthesized from Kaempferia rotunda tuberous rhizome extract to evaluate the antiproliferative activity against human glioblastoma stem cells (GSCs) in vitro and Ehrlich ascites carcinoma (EAC) cells in vivo in mice. Synthesis of nanoparticles was confirmed by colour change and UV-visible spectrum and characterized by TEM, XRD, TGA, AFM and FTIR. K rotunda and recently synthesized Zizyphus mauritiana fruit extract-mediated Ag/AgCl-NPs inhibited 77.2% and 71% of GSCs growth at 32 µg/mL concentration with the IC50 values of 6.8 and 10.4 µg/mL, respectively. Cell morphological studies and caspase-3 immunofluorescence assay revealed that both biogenic nanoparticles induced apoptosis in GSCs. Expression levels of several genes were checked by real-time PCR after treatment with K rotunda tuberous rhizome-mediated Ag/AgCl-NPs. PARP, EGFR, NOTCH2 and STAT3 gene expression were decreased with the increase of NFκB, TLR9, IL1, TNFα, IKK and p21 gene that would be the cause of induction of apoptosis in GSCs. The cell cycle arrest at G2 /M phase was confirmed by flow cytometric assay. Both nanoparticles were injected intraperitoneally to rapidly growing EAC cells for 5 consecutive days. Approximately, 32.3% and 55% EAC cells growth were inhibited by K rotunda tuberous rhizome-mediated Ag/AgCl-NPs at 6 and 12 mg/kg/day doses, respectively while only 20% cell growth inhibition was monitored at 12 mg/kg/day dose of Z mauritiana-mediated Ag/AgCl-NPs. From the above results, it can be concluded that presently synthesized nanoparticles would be a potent anticancer agent.

A natural compound obtained from Valeriana jatamansi selectively inhibits glioma stem cells.

Glioblastoma is one of the most malignant tumors with very poor prognosis. Glioma stem cells (GSCs) occupy a small proportion in glioma, but they are closely associated with radiotherapy and chemotherapy resistance, promoting tumor angiogenesis, hypoxia response, invasion and recurrence. Therefore, GSCs have become a new target for tumor treatment and are used in drug screening. Rupesin E is a natural compound obtained from Valeriana jatamansi, and its antitumor activity has not been reported. In the present study, the antitumor activity of rupesin E was investigated, and the results demonstrated that it inhibited the proliferation of GSCs (GSC-3#, GSC-12#, GSC-18#) with the IC50 values of 7.13±1.41, 13.51±1.46 and 4.44±0.22 µg/ml, respectively. In addition, immunofluorescence cell staining and flow cytometry techniques demonstrated that rupesin E inhibited GSC proliferation and induced apoptosis. Furthermore, rupesin E inhibited the ability of GSC colony formation, indicating its antitumor activity against GSCs in vitro.

Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells.

Despite the great success of chimeric antigen receptor T (CAR-T)-cell therapy in the treatment of hematologic malignancies, CAR-T-cell therapy is limited in solid tumors, including hepatocellular carcinoma (HCC). NK group 2 member D (NKG2D) ligands (NKG2DL) are generally absent on the surface of normal cells but are overexpressed on malignant cells, offering good targets for CAR-T therapy. Indeed, analysis of The Cancer Genome Atlas and HCC tumor samples showed that the expression of most NKG2DLs was elevated in tumors compared with normal tissues. Thus, we designed a novel NKG2D-based CAR comprising the extracellular domain of human NKG2D, 4-1BB, and CD3ζ signaling domains (BBz). NKG2D-BBz CAR-T cells efficiently killed the HCC cell lines SMMC-7721 and MHCC97H in vitro, which express high levels of NKG2DLs, whereas they less efficiently killed NKG2DL-silenced SMMC-7721 cells or NKG2DL-negative Hep3B cells. Overexpression of MICA or ULBP2 in Hep3B improved the killing capacity of NKG2D-BBz CAR-T cells. T cells expressing the NKG2D-BBz CAR effectively eradicated SMMC-7721 HCC xenografts. Collectively, these results suggested that NKG2D-BBz CAR-T cells could potently eliminate NKG2DL-high HCC cells both in vitro and in vivo, thereby providing a promising therapeutic intervention for patients with NKG2DL-positive HCC.

Picea wilsonii transcription factor NAC2 enhanced plant tolerance to abiotic stress and participated in RFCP1-regulated flowering time.

KEY MESSAGE: Picea wilsonii transcription factor PwNAC2 enhanced plant tolerance to salt and drought stress through multiple signaling pathway and interacted with PwRFCP1 to participate in flowering regulation. NAC is one of the largest transcription factor families in plants, however, its role is not yet fully understood. Here, we identified a transcription factor PwNAC2 in Picea wilsonii, which localized in nucleus with transcriptional activity in C-terminal region and can form homodimer by itself. Expression analysis by real-time PCR showed that PwNAC2 was induced by multiple abiotic stresses and phytohormones stimuli. PwRFCP1 (Resemble-FCA-contain-PAT1 domain), an interaction protein of PwNAC2 was screened via yeast two hybrid. Luciferase complementation assay confirmed the interaction in vivo and bimolecular fluorescence complementation assay showed the interaction in nucleus. PwNAC2 overexpression retarded Arabidopsis hypocotyls growth which is closely related to light, whereas promotion of hypocotyls growth by PwRFCP1 is independent on light. Under drought or salt treatment, overexpression of PwNAC2 in Arabidopsis showed more vigorous seed germination and significant tolerance for seedlings by ROS scavenging, reducing of membrane damage, slower water loss and increased stomatal closure. ABA or CBF-pathway marker genes were substantially higher in PwNAC2 transgenic Arabidopsis. Overexpression of PwRFCP1 promotes flowering in transgenic Arabidopsis, whereas PwNAC2 delayed flowering by altering the expression of FT, SOC1 and FLC. In addtioin, PwRFCP1 overexpression plants showed no higher tolerance to stress treatment than Col-0. Collectively, our results indicate that PwNAC2 enhanced plant tolerance to abiotic stress through multiple signaling pathways and participated in PwRFCP1-regulated flowering time.