Drying without dying: A genome database for desiccation-tolerant plants and evolution of desiccation tolerance.

Desiccation is typically fatal, but a small number of land plants have evolved vegetative desiccation tolerance (VDT), allowing them to dry without dying through a process called anhydrobiosis. Advances in sequencing technologies have enabled the investigation of genomes for desiccation-tolerant plants over the past decade. However, a dedicated and integrated database for these valuable genomic resources has been lacking. Our prolonged interest in VDT plant genomes motivated us to create the "Drying without Dying" database, which contains a total of 16 VDT-related plant genomes (including 10 mosses) and incorporates 10 genomes that are closely related to VDT plants. The database features bioinformatic tools, such as blast and homologous cluster search, sequence retrieval, Gene Ontology term and metabolic pathway enrichment statistics, expression profiling, co-expression network extraction, and JBrowser exploration for each genome. To demonstrate its utility, we conducted tailored PFAM family statistical analyses, and we discovered that the drought-responsive ABA transporter AWPM-19 family is significantly tandemly duplicated in all bryophytes but rarely so in tracheophytes. Transcriptomic investigations also revealed that response patterns following desiccation diverged between bryophytes and angiosperms. Combined, the analyses provided genomic and transcriptomic evidence supporting a possible divergence and lineage-specific evolution of VDT in plants. The database can be accessed at http://desiccation.novogene.com. We expect this initial release of the "Drying without Dying" plant genome database will facilitate future discovery of VDT genetic resources.

The ScAPD1-like gene from the desert moss Syntrichia caninervis enhances resistance to Verticillium dahliae via phenylpropanoid gene regulation.

Soloist is a member of a distinct and small subfamily within the AP2/ERF transcriptional factor family that play important roles in plant biotic and abiotic stress responses. There are limited studies of Soloist genes and their functions are poorly understood. We characterized the abiotic and biotic stress tolerance function of the ScSoloist gene (designated as ScAPD1-like) from the desert moss Syntrichia caninervis. ScAPD1-like responded to multiple abiotic, biotic stresses and plant hormone treatments. ScAPD1-like protein located to the nucleus and bound to several DNA elements. Overexpression of ScAPD1-like in Arabidopsis did not alter abiotic stress resistance or inhibit Pseudomonas syringae pv. tomato (Pst) DC3000 infection. However, overexpression of ScAPD1-like significantly increased the resistance of transgenic Arabidopsis and S. caninervis to Verticillium dahliae infection, decreased reactive oxygen species accumulation and improved reactive oxygen species scavenging activity. ScAPD1-like overexpression plants altered the abundance of transcripts for lignin synthesis and promoted lignin accumulation in Arabidopsis. ScAPD1-like directly bind to RAV1, AC elements, and TATA-box in the promoters of AtPAL1 and AtC4H genes, respectively, in vitro. Chromatin immunoprecipitation-quantitative polymerase chain reaction assays demonstrated ScAPD1-like directly bound to PAL and C4H genes promoters in Arabidopsis and their homologs in S. caninervis. In S. caninervis, ScAPD1-like overexpression and RNAi directly regulated the abundance of ScPAL and ScC4H transcripts and modified the metabolites of phenylpropanoid pathway. We provide insight into the function of Soloist in plant defense mechanisms that likely occurs through activation of the phenylpropanoid biosynthesis pathway. ScAPD1-like is a promising candidate gene for breeding strategies to improve resistance to Verticillium wilt.

Nonmetal Atom Doping Induced Orbital Shifts and Charge Modulation at the Edge of Two-Dimensional Boron Carbonitride Leading to Enhanced Photocatalytic Nitrogen Reduction.

Electronic structure, particularly charge state analysis, plays a crucial role in comprehending catalytic mechanisms. This study focuses on metal-free boron carbonitride (BCN) nanosheets as a case study to investigate the impact of heteroatom doping on the charge state of active sites at the edge of two-dimensional (2D) metal-free nanomaterials. Our observations revealed that the doping induces a shift in the frontier py orbital near the Fermi level, accompanied by alterations in its charge state. These changes provide insights into the nitrogen adsorption descriptors and the critical hydrogenation step, ultimately leading to the proposal of a competitive charge transfer mechanism. Additionally, this exploration has led to the screening of five BCN-type structures (P@T1-C1, S@T1-B1, O@T1-B1, P@T1-B1C2, and P@T1-B1C3) with promising nitrogen reduction reaction (NRR) performances. The BCN structure (S@T1-B1) exhibited the lowest NRR overpotential reaching -0.2 V, which is associated with the proposed charge competition mechanism. Furthermore, the investigation delves into the key step hydrogenation mechanism, descriptors, and volcano diagrams of the conformational relationships. In addition, the proposed doping strategy endows the 2D-BCN with more sensitivity toward the solar spectrum, suggesting its application as a potential photocatalyst. Overall, this study establishes a strong foundation for the advancement of nonmetal-atom-doped BCN nanosheets in nitrogen reduction applications, while also providing a versatile framework for fine-tuning edge-site activity within the broader context of two-dimensional photo/electrocatalytic materials.

Multiphysical graph neural network (MP-GNN) for COVID-19 drug design.

Graph neural networks (GNNs) are the most promising deep learning models that can revolutionize non-Euclidean data analysis. However, their full potential is severely curtailed by poorly represented molecular graphs and features. Here, we propose a multiphysical graph neural network (MP-GNN) model based on the developed multiphysical molecular graph representation and featurization. All kinds of molecular interactions, between different atom types and at different scales, are systematically represented by a series of scale-specific and element-specific graphs with distance-related node features. From these graphs, graph convolution network (GCN) models are constructed with specially designed weight-sharing architectures. Base learners are constructed from GCN models from different elements at different scales, and further consolidated together using both one-scale and multi-scale ensemble learning schemes. Our MP-GNN has two distinct properties. First, our MP-GNN incorporates multiscale interactions using more than one molecular graph. Atomic interactions from various different scales are not modeled by one specific graph (as in traditional GNNs), instead they are represented by a series of graphs at different scales. Second, it is free from the complicated feature generation process as in conventional GNN methods. In our MP-GNN, various atom interactions are embedded into element-specific graph representations with only distance-related node features. A unique GNN architecture is designed to incorporate all the information into a consolidated model. Our MP-GNN has been extensively validated on the widely used benchmark test datasets from PDBbind, including PDBbind-v2007, PDBbind-v2013 and PDBbind-v2016. Our model can outperform all existing models as far as we know. Further, our MP-GNN is used in coronavirus disease 2019 drug design. Based on a dataset with 185 complexes of inhibitors for severe acute respiratory syndrome coronavirus (SARS-CoV/SARS-CoV-2), we evaluate their binding affinities using our MP-GNN. It has been found that our MP-GNN is of high accuracy. This demonstrates the great potential of our MP-GNN for the screening of potential drugs for SARS-CoV-2. Availability: The Multiphysical graph neural network (MP-GNN) model can be found in https://github.com/Alibaba-DAMO-DrugAI/MGNN. Additional data or code will be available upon reasonable request.

Molecular persistent spectral image (Mol-PSI) representation for machine learning models in drug design.

Artificial intelligence (AI)-based drug design has great promise to fundamentally change the landscape of the pharmaceutical industry. Even though there are great progress from handcrafted feature-based machine learning models, 3D convolutional neural networks (CNNs) and graph neural networks, effective and efficient representations that characterize the structural, physical, chemical and biological properties of molecular structures and interactions remain to be a great challenge. Here, we propose an equal-sized molecular 2D image representation, known as the molecular persistent spectral image (Mol-PSI), and combine it with CNN model for AI-based drug design. Mol-PSI provides a unique one-to-one image representation for molecular structures and interactions. In general, deep models are empowered to achieve better performance with systematically organized representations in image format. A well-designed parallel CNN architecture for adapting Mol-PSIs is developed for protein-ligand binding affinity prediction. Our results, for the three most commonly used databases, including PDBbind-v2007, PDBbind-v2013 and PDBbind-v2016, are better than all traditional machine learning models, as far as we know. Our Mol-PSI model provides a powerful molecular representation that can be widely used in AI-based drug design and molecular data analysis.

LC-MS/MS method for the quantification of cortisol of hepatocellular carcinoma.

The imbalance of steroid hormones is closely related to the occurrence and development of hepatocellular carcinoma (HCC). However, most research has focused on steroid hormone receptors, and reports about the relationship between the serum concentration of cortisol and the development of HCC are rare. The aim of this research was to establish a simple, specific, sensitive and reliable liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method for the quantitation of cortisol in human serum and to compare the level of cortisol in serum between 221 HCC patients and 183 healthy volunteers. The results showed that the correlation coefficients of the linear regression with a weighing factor of 1/x2 ranged from 0.9933 to 0.9984 over the range of 2-1,000 ng/ml. The inter- and intra-day precision and accuracy were <10%. The matrix effect and recovery of cortisol were 94.9-102.5% and 96.3-99.8%, respectively. The concentration of cortisol in HCC patients was significantly higher than that in healthy volunteers (p < 0.05) and was not affected by sex, age, menopause or α-fetoprotein (AFP) level. The present study reveals that elevated cortisol might promote the progression of HCC.

White matter and cortical gray matter microstructural abnormalities in new daily persistent headache: a NODDI study.

BACKGROUND: New daily persistent headache (NDPH) is a rare primary headache with unclear pathogenesis. Neuroimaging studies of NDPH are limited, and controversy still exists. Diffusion tensor imaging (DTI) is commonly used to study the white matter. However, lacking specificity, the potential pathological mechanisms of white matter microstructural changes remain poorly understood. In addition, the intricacy of gray matter structures impedes the application of the DTI model. Here, we applied an advanced diffusion model of neurite orientation dispersion and density imaging (NODDI) to study the white matter and cortical gray matter microstructure in patients with NDPH. METHODS: This study assessed brain microstructure, including 27 patients with NDPH, and matched 28 healthy controls (HCs) by NODDI. The differences between the two groups were assessed by tract-based spatial statistics (TBSS) and surface-based analysis (SBA), focusing on the NODDI metrics (neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF)). Furthermore, we performed Pearson's correlation analysis between the NODDI indicators and clinical characteristics. RESULTS: Compared to HCs, patients with NDPH had a reduction of density and complexity in several fiber tracts. For robust results, the fiber tracts were defined as comprising more than 100 voxels, including bilateral inferior fronto-occipital fasciculus (IFOF), left superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF), as well as right corticospinal tract (CST). Moreover, the reduction of neurite density was uncovered in the left superior and middle frontal cortex, left precentral cortex, and right lateral orbitofrontal cortex and insula. There was no correlation between the NODDI metrics of these brain regions and clinical variables or scales of relevance after the Bonferroni correction. CONCLUSIONS: Our research indicated that neurite loss was detected in both white matter and cortical gray matter of patients with NDPH.

Metabolomic Analysis of the Desert Moss Syntrichia caninervis Provides Insights into Plant Dehydration and Rehydration Response.

Desiccation-tolerant (DT) plants can survive extreme dehydration and tolerate the loss of up to 95% of their water content, making them ideal systems to determine the mechanism behind extreme drought stress and identify potential approaches for developing drought-tolerant crops. The desert moss Syntrichia caninervis is an emerging model for extreme desiccation tolerance that has benefited from high-throughput sequencing analyses, allowing identification of stress-tolerant genes; however, its metabolic response to desiccation is unknown. A liquid chromatography-mass spectrometry analysis of S. caninervis at six dehydration-rehydration stages revealed 912 differentially abundant compounds, belonging to 93 metabolic classes. Many (256) metabolites accumulated during rehydration in S. caninervis, whereas only 71 accumulated during the dehydration period, in contrast to the pattern observed in vascular DT plants. During dehydration, nitrogenous amino acids (l-glutamic acid and cysteinylglycine), alkaloids (vinleurosine) and steroids (physalin D) accumulated, whereas glucose 6-phosphate decreased. During rehydration, γ-aminobutyric acid, glucose 6-phosphate and flavonoids (karanjin and aromadendrin) accumulated, as did the plant hormones 12-oxo phytodienoic acid (12-OPDA) and trans-zeatin riboside. The contents ofl-arginine, maltose, turanose, lactulose and sucrose remained high throughout dehydration-rehydration. Syntrichia caninervis thus accumulates antioxidants to scavenge reactive oxygen species, accumulating nitrogenous amino acids and cytoprotective metabolites and decreasing energy metabolism to enter a protective state from dehydration-induced damage. During subsequent rehydration, many metabolites rapidly accumulated to prevent oxidative stress and restore physiological activities while repairing cells, representing a more elaborate rehydration repair mechanism than vascular DT plants, with a faster and greater accumulation of metabolites. This metabolic kinetics analysis in S. caninervis deepens our understanding of its dehydration mechanisms and provides new insights into the different strategies of plant responses to dehydration and rehydration.

A pilot study of multi-antigen stimulated cell therapy-I plus camrelizumab and apatinib in patients with advanced bone and soft-tissue sarcomas.

BACKGROUND: Cell-based  immunotherapy shows the therapeutic potential in sarcomas, in addition to angiogenesis-targeted tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI). Multi-antigen stimulated cell therapy-I (MASCT-I) technology is a sequential immune cell therapy for cancer, which composes of multiple antigen-loaded dendritic cell (DC) vaccines followed by the adoptive transfer of anti-tumor effector T-cells. METHODS: In this phase 1 study, we assessed MASCT-I plus camrelizumab (an ICI against PD-1) and apatinib (a highly selective TKI targeting VEGFR2) in patients with unresectable recurrent or metastatic bone and soft-tissue sarcoma after at least one line of prior systemic therapy. One MASCT-I course consisted of 3 DC subcutaneous injections, followed by 3 active T cell infusions administered 18-27 days after each DC injection. In schedule-I group, 3 DC injections were administered with a 28-day interval in all courses; in schedule-II group, 3 DC injections were administered with a 7-day interval in the first course and with a 28-day interval thereafter. All patients received intravenous camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg daily. RESULTS: From October 30, 2019, to August 12, 2021, 19 patients were enrolled and randomly assigned to schedule-I group (n = 9) and schedule-II group (n = 10). Of the 19 patients, 11 (57.9%) experienced grade 3 or 4 treatment-related adverse events. No treatment-related deaths occurred. Patients in schedule-II group showed similar objective response rate (ORR) with those in schedule-I group (30.0% versus 33.3%) but had higher disease control rate (DCR; 90.0% versus 44.4%) and longer median progression-free survival (PFS; 7.7 versus 4.0 months). For the 13 patients with soft-tissue sarcomas, the ORR was 30.8%, DCR was 76.9%, and median PFS was 12.9 months; for the 6 patients with osteosarcomas, the ORR was 33.3%, the DCR was 50.0%, and median PFS was 5.7 months. CONCLUSIONS: Overall, MASCT-I plus camrelizumab and apatinib was safe and showed encouraging efficacy in advanced bone and soft-tissue sarcoma, and schedule-II administration method was recommended. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04074564.

Exosomal miR-211-5p regulates glucose metabolism, pyroptosis, and immune microenvironment of melanoma through GNA15.

Despite the unprecedented advancement of cancer treatment, the prognosis for patients with metastatic stage of cancer remains poor. The challenge that underlines this clinical dilemma is the complexity of metastasis. The conventional experiment-driven discovery approaches (the "wet lab") yield overly simplified one-to-one mechanistic relationships that are inept of elucidating the complexity of metastasis. Metastasis research also suffers from the knowledge and skill deficiency of the individual investigators. The importance of the present study is the demonstration that the "dry-lab-driven discovery and wet-lab validation" approach can improve the efficiency of studying complex biological behaviors, and can yield more reliable, objective and comprehensive mechanistic findings that are have clinical significance. Specifically, we applied this approach to study the mechanisms that underline the involvement of exosomal miRNAs in transferring the metastatic capability between heterogenous melanoma cancer cells. We show that the highly metastatic melanoma tumor cells (POL) can transfer their metastatic competency to the low-metastatic melanoma tumor cells (OL) by exosomal miR-211-5p. The oncogenic activity of miR-211-5p is mediated by the target gene guanine nucleotide-binding protein subunit alpha-15 (GNA15) through modifying the immune function of the tumor microenvironment extrinsically; as well as through inhibiting pyroptosis and augmenting glycolysis within OL cells intrinsically. In addition, we show that exosomal sorting of miR-211-5p is like selective and is subjected to regulation by a transcriptional feedback loop between miR-211-5p and zinc finger FYVE-type containing 26 (ZFYVE26). Furthermore, the "8-genes pyroptosis Risk model" derived from LASSO regression analysis was verified as an independent prognostic factor for melanoma.

Diabetes in intraductal papillary mucinous neoplasm of the pancreas and its association with malignancy.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) have the potential to become malignant. Few studies have focused on the prevalence of the diabetes mellitus (DM) in IPMNs and its association with malignancy. We evaluated the association between DM and malignant IPMNs in this study. METHODS: A total of 226 patients with pathologically confirmed IPMNs were included. Demographic data, serum biochemical data, and imaging findings were collected. The malignant IPMNs were defined as those with high-grade dysplasia and associated invasive carcinoma. The association between DM and malignant IPMNs was studied using logistic regression analysis. RESULTS: The prevalence of DM was 17.7% for all type IPMNs and 31.7% for malignant IPMNs. Compared to patients without DM, those with DM had a 3.6-fold (odds ratio [OR]: 3.62; 95% confidence interval [CI]: 1.26-10.44) higher risk of invasive carcinoma and 2.5-fold (OR: 2.48; 95% CI: 1.06-5.77) higher risk of malignant IPMNs. Similar results were observed in main pancreatic duct (MPD) involved IPMNs. New-onset DM was associated with a 4.13-fold (OR: 4.13, 95% CI: 1.27-13.36) higher risk of invasive carcinoma. CONCLUSION: DM is associated with a higher risk of malignant IPMNs and invasive carcinoma, especially in patients with MPD-involved IPMNs.

Ultraviolet photodetector based on RbCu2I3microwire.

Copper-based halide perovskites have shown great potential in lighting and photodetection due to their excellent photoelectric properties, good stability and lead-free nature. However, as an important piece of copper-based perovskites, the synthesis and application of RbCu2I3have never been reported. Here, we demonstrate the synthesis of high-quality RbCu2I3microwires (MWs) by a fast-cooling hot saturated solution method. The prepared MWs exhibit an orthorhombic structure with a smooth surface. Optical measurements show the RbCu2I3MWs have a sharp ultraviolet absorption edge with 3.63 eV optical band gap and ultra-large stokes shift (300 nm) in photoluminescence. The subsequent photodetector based on a single RbCu2I3MW shows excellent ultraviolet detection performance. Under the 340 nm illumination, the device shows a specific detectivity of 5.0 × 109Jones and a responsivity of 380 mA·W-1. The synthesis method and physical properties of RbCu2I3could be a guide to the future optoelectronic application of the new material.

Genome-Wide Characterization and Expression Analysis of Transcription Factor Families in Desert Moss Syntrichia caninervis under Abiotic Stresses.

Transcription factor (TF) families play important roles in plant stress responses. S. caninervis is a new model moss for plant desiccation tolerance studies. Here, we report a high-confidence identification and characterization of 591 TFs representing 52 families that covered all chromosomes in S. caninervis. GO term and KEGG pathway analysis showed that TFs were involved in the regulation of transcription, DNA-templated, gene expression, binding activities, plant hormone signal transduction, and circadian rhythm. A number of TF promoter regions have a mixture of various hormones-related cis-regulatory elements. AP2/ERF, bHLH, MYB, and C2H2-zinc finger TFs were the overrepresented TF families in S. caninervis, and the detailed classification of each family is performed based on structural features. Transcriptome analysis revealed the transcript abundances of some ScAP2/ERF, bHLH, MYB, and C2H2 genes were accumulated in the treated S. caninervis under cold, dehydration, and rehydration stresses. The RT-qPCR results strongly agreed with RNA-seq analysis, indicating these TFs might play a key role in S. caninervis response to abiotic stress. Our comparative TF characterization and classification provide the foundations for functional investigations of the dominant TF genes involved in S. caninervis stress response, as well as excellent stress tolerance gene resources for plant stress resistance breeding.

Mapping brain functional networks topological characteristics in new daily persistent headache: a magnetoencephalography study.

BACKGROUND: The brain functional network topology in new daily persistent headache (NDPH) is not well understood. In this study, we aim to assess the cortical functional network topological characteristics of NDPH using non-invasive neural signal recordings. METHODS: Resting-state magnetoencephalography (MEG) was used to measure power fluctuations in neuronal oscillations from distributed cortical parcels in 35 patients with NDPH and 40 healthy controls (HCs). Their structural data were collected by 3T MRI. Functional connectivity (FC) of neural networks from 1 to 80 Hz frequency ranges was analyzed with topographic patterns and calculated network topological parameters with graph theory. RESULTS: In the delta (1-4 Hz) and beta (13-30 Hz) bands, the lateral occipital cortex and superior frontal gyrus FC were increased in NDPH groups compared to HCs. Graph theory analysis revealed that the NDPH had significantly increased global efficiency in the delta band and decreased nodal clustering coefficient (left medial orbitofrontal cortex) in the theta (4-8 Hz) band. The clinical characteristics had a significant correlation with network topological parameters. Age at onset of patients showed a positive correlation with global efficiency in the delta band. The degree of depression of patients showed a negative correlation with the nodal clustering coefficient (left medial orbitofrontal cortex) in the theta band. CONCLUSION: The FC and topology of NDPH in brain networks may be altered, potentially leading to cortical hyperexcitability. Moreover, medial orbitofrontal cortex is involved in the pathophysiological mechanism of depression in patients with NDPH. Increased FC observed in the lateral occipital cortex and superior frontal gyrus during resting-state MEG could serve as one of the imaging characteristics associated with NDPH.

To dry perchance to live: Insights from the genome of the desiccation-tolerant biocrust moss Syntrichia caninervis.

With global climate change, water scarcity threatens whole agro/ecosystems. The desert moss Syntrichia caninervis, an extremophile, offers novel insights into surviving desiccation and heat. The sequenced S. caninervis genome consists of 13 chromosomes containing 16 545 protein-coding genes and 2666 unplaced scaffolds. Syntenic relationships within the S. caninervis and Physcomitrella patens genomes indicate the S. caninervis genome has undergone a single whole genome duplication event (compared to two for P. patens) and evidence suggests chromosomal or segmental losses in the evolutionary history of S. caninervis. The genome contains a large sex chromosome composed primarily of repetitive sequences with a large number of Copia and Gypsy elements. Orthogroup analyses revealed an expansion of ELIP genes encoding proteins important in photoprotection. The transcriptomic response to desiccation identified four structural clusters of novel genes. The genomic resources established for this extremophile offer new perspectives for understanding the evolution of desiccation tolerance in plants.

Sec23a inhibits the self-renewal of melanoma cancer stem cells via inactivation of ER-phagy.

BACKGROUND: The genesis and developments of solid tumors, analogous to the renewal of healthy tissues, are driven by a subpopulation of dedicated stem cells, known as cancer stem cells (CSCs), that exhibit long-term clonal repopulation and self-renewal capacity. CSCs may regulate tumor initiation, growth, dormancy, metastasis, recurrence and chemoresistance. While autophagy has been proposed as a regulator of the stemness of CSCs, the underlying mechanisms requires further elucidation. METHODS: The CSC component in human melanoma cell lines M14 and A375 was isolated and purified by repetitive enrichments for cells that consistently display anchorage-independent spheroid growth. The stemness properties of the CSCs were confirmed in vitro by the expressions of stemness marker genes, the single-cell cloning assay and the serial spheroid formation assay. Subcutaneous tumor transplantation assay in BALB/c nude mice was performed to test the stemness properties of the CSCs in vivo. The autophagic activity was confirmed by the protein level of LC3 and P62, mRFP-LC3B punta and cytoplasmic accumulation of autolysosomes. The morphology of ER was detected with transmission electron microscopy. RESULTS: In the present study, by employing stable CSC cell lines derived from human melanoma cell lines M14 and A375, we show for the first time that Sec23a inhibits the self-renewal of melanoma CSCs via inactivation of ER-phagy. Mechanistically, inhibition of Sec23a reduces ER stress and consequently FAM134B-induced ER-phagy. Furthermore, TCGA data mining and analysis show that Sec23a is a favorable diagnostic and prognostic marker for human skin cutaneous melanoma. CONCLUSION: This study has elucidated a new mechanism underlying the regulation of autophagy on stemness, i.e. CSCs can exploit the SEC23A/ER-stress/FAM134B/ER-phagy axis for the self-renewal. These observations provide new ideas for exploration of the regulatory network of CSC self-renewal to develop CSCs-based therapy strategies for malignant tumors. Video Abstract.

Threshold of main pancreatic duct for malignancy in intraductal papillary mucinous neoplasm at head-neck and body-tail.

BACKGROUND: Main pancreatic duct (MPD) dilation is a high-risk stigmata/worrisome feature of malignancy in intraductal papillary mucinous neoplasms (IPMNs). The threshold of MPD diameter in predicting malignancy may be related to the lesion location. This study aimed to separately identify the thresholds of MPD for malignancy of IPMNs separately for the head-neck and body-tail. MATERIALS AND METHODS: A total of 185 patients with pathologically confirmed IPMNs were included. Patient demographic information, clinical data, and pathological features were obtained from the medical records. Those IPMNs with high-grade dysplasia or with associated invasive carcinoma were considered as malignant tumor. Radiological data including lesion location, tumor size, diameter of the MPD, mural nodule, and IPMN types (main duct, MD; branch duct, BD; and mixed type, MT), were collected on computed tomography or magnetic resonance imaging. Serum carbohydrate antigen 19-9 levels, serum carcinoembryonic antigen levels, and the medical history of diabetes mellitus, chronic cholecystitis, and pancreatitis were also collected. RESULTS: Malignant IPMNs were detected in 31.6% of 117 patients with lesions in the pancreatic head-neck and 20.9% of 67 patients with lesions in the pancreatic body-tail. In MPD-involved IPMNs, malignancy was observed in 54.1% of patients with lesions in the pancreatic head-neck and 30.8% of patients with lesions in the pancreatic body-tail (p < 0.05). The cutoff value of MPD diameter for malignancy was 6.5 mm for lesions in the head-neck and 7.7 mm for lesions in the body-tail in all type of IPMNs. In MPD-involved IPMNs, the threshold was 8.2 mm for lesion in pancreatic head-neck and 7.7 mm for lesions in the body-tail. Multivariate analysis confirmed that MPD diameter ≥ 6.5 mm (pancreatic head-neck) and MPD diameter ≥ 7.7 mm (pancreatic body-tail) were independent predictors of malignancy (p < 0.05). Similar results were observed in MPD-involved IPMNs using 8.2 mm as a threshold. CONCLUSION: The thresholds of the dilated MPD may be associated with IPMNs locations. Thresholds of 6.5 mm for lesions in the head-neck and 7.7 mm for lesions in the body-tail were observed. For MPD-involved IPMNs alone, threshold for lesions in the head-neck was close to that in the body-tail.

Melanoma stem cells promote metastasis via exosomal miR-1268a inactivation of autophagy.

BACKGROUND: Metastatic melanoma has a high mortality rate and poor survival. This is associated with efficient metastatic colonization, but the underlying mechanisms remain elusive. Communication between cancer stem cells (CSCs) and cancer cells plays an important role in metastatic dissemination. Whether cancer stem cells can alter the metastatic properties of non-CSC cells; and whether exosomal crosstalk can mediate such interaction, have not been demonstrated in melanoma prior to this report. RESULTS: The results revealed that exosomes secreted by highly metastatic melanoma CSCs (OL-SCs) promoted the invasiveness of the low metastatic melanoma cells (OL) and accelerated metastatic progression. miR-1268a was up-regulated in cells and exosomes of OL-SCs. Moreover, OL-SCs-derived exosomal miR-1268a, upon taking up by OL cells, promoted the metastatic colonization ability of OL cells in vitro and in vivo. In addition, the pro-metastatic activity of exosomal miR-1268a is achieved through inhibition of autophagy. CONCLUSION: Our study demonstrates that OL cells can acquire the "metastatic ability" from OL-SCs cells. OL-SCs cells achieves this goal by utilizing its exosomes to deliver functional miRNAs, such as miR-1268a, to the targeted OL cells which in turn augments metastatic colonization by inactivating the autophagy pathway in OL cells.

BaZFP1, a C2H2 Subfamily Gene in Desiccation-Tolerant Moss Bryum argenteum, Positively Regulates Growth and Development in Arabidopsis and Mosses.

C2H2 zinc finger protein (C2H2-ZFP) plays an important role in regulating plant growth, development, and response to abiotic stress. To date, there have been no analyses of the C2H2-ZFP family in desiccation-tolerant moss. In this study, we identified 57 BaZFP transcripts across the Bryum argenteum (B. argenteum) transcriptome. The BaZFP proteins were phylogenetically divided into four groups (I-IV). Additionally, we studied the BaZFP1 gene, which is a nuclear C2H2-ZFP and acts as a positive regulator of growth and development in both moss and Arabidopsis thaliana. The complete coding sequence of the BaZFP1 gene was isolated from B. argenteum cDNA, which showed a high expression level in a dehydration-rehydration treatment process. The overexpression of the BaZFP1 gene in the Physcomitrium patens and B. argenteum promoted differentiation and growth of gametophytes. Heterologous expression in Arabidopsis regulated the whole growth and development cycle. In addition, we quantitatively analyzed the genes related to growth and development in transgenic moss and Arabidopsis, including HLS1, HY5, ANT, LFY, FT, EIN3, MUS, APB4, SEC6, and STM1, and found that their expression levels changed significantly. This study may pave the way for substantial insights into the role of C2H2-ZFPs in plants as well as suggest appropriate candidate genes for crop breeding.

TGF-ß Signaling in Metastatic Colorectal Cancer (mCRC): From Underlying Mechanism to Potential Applications in Clinical Development.

Colorectal cancer (CRC) is a serious public health issue, and it has the leading incidence and mortality among malignant tumors worldwide. CRC patients with metastasis in the liver, lung or other distant sites always have poor prognosis. Thus, there is an urgent need to discover the underlying mechanisms of metastatic colorectal cancer (mCRC) and to develop optimal therapy for mCRC. Transforming growth factor-ß (TGF-ß) signaling plays a significant role in various physiologic and pathologic processes, and aberrant TGF-ß signal transduction contributes to mCRC progression. In this review, we summarize the alterations of the TGF-ß signaling pathway in mCRC patients, the functional mechanisms of TGF-ß signaling, its promotion of epithelial-mesenchymal transition, its facilitation of angiogenesis, its suppression of anti-tumor activity of immune cells in the microenvironment and its contribution to stemness of CRC cells. We also discuss the possible applications of TGF-ß signaling in mCRC diagnosis, prognosis and targeted therapies in clinical trials. Hopefully, these research advances in TGF-ß signaling in mCRC will improve the development of new strategies that can be combined with molecular targeted therapy, immunotherapy and traditional therapies to achieve better efficacy and benefit mCRC patients in the near future.