Human YKT6 forms priming complex with STX17 and SNAP29 to facilitate autophagosome-lysosome fusion.

Autophagy is crucial for degrading and recycling cellular components. Fusion between autophagosomes and lysosomes is pivotal, directing autophagic cargo to degradation. This process is driven by STX17-SNAP29-VAMP8 and STX7-SNAP29-YKT6 in mammalian cells. However, the interaction between STX17 and YKT6 and its significance remain to be revealed. In this study, we challenge the notion that STX17 and YKT6 function independently in autophagosome-lysosome fusion. YKT6, through its SNARE domain, forms a complex with STX17 and SNAP29 on autophagosomes, enhancing autophagy flux. VAMP8 displaces YKT6 from this complex, leading to the formation of the fusogenic complex STX17-SNAP29-VAMP8. We demonstrated that the YKT6-SNAP29-STX17 complex facilitates both lipid and content mixing driven by STX17-SNAP29-VAMP8, suggesting a priming role of YKT6 for efficient membrane fusion. Our results provide a potential regulation mechanism of autophagosome-lysosome fusion, highlighting the importance of YKT6 and its interactions with STX17 and SNAP29 in promoting autophagy flux.

Sorafenib Resistance Contributed by IL7 and MAL2 in Hepatocellular Carcinoma Can Be Overcome by Autophagy-Inducing Stapled Peptides.

Drug resistance poses a great challenge in systemic therapy for hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms associated with resistance to anti-cancer drugs, such as Sorafenib, remain unclear. In this study, we use transposon insertional mutagenesis to generate Sorafenib-resistant HCC cell lines in order to identify potential drug resistant causative genes. Interleukin 7 (IL7) and mal, T cell differentiation protein 2 (MAL2) were identified as candidate genes that promote survival by activating JAK/STAT and PI3K/AKT signaling pathways. Sorafenib-resistant cells exhibited higher clonogenic survival and lower drug sensitivity due to IL7 and MAL2 upregulation. Higher anti-apoptotic effect, clonogenic survival and increased PI3K/AKT/STAT3 activities were observed in IL7 and MAL2 co-overexpressing cells compared with controls or cells overexpressing IL7 or MAL2 individually. Given the critical role of MAL2 in endocytosis, we propose that MAL2 might facilitate the endocytic trafficking of IL7 and its cognate receptors to the plasma membrane, which leads to upregulated JAK/STAT and PI3K/AKT signaling pathways and Sorafenib resistance. Additionally, our previous studies showed that an autophagy-inducing stapled peptide promoted the endolysosomal degradation of c-MET oncogene and overcame adaptive Sorafenib resistance in c-MET+ HCC cells. In this study, we demonstrate that these stapled peptides readily induced autophagy and inhibited the proliferation of both wild-type and Sorafenib-resistant HCC cells co-overexpressing both IL7 and MAL2. Furthermore, these peptides showed synergistic cytotoxicity with Sorafenib in drug-resistant HCC cells co-overexpressing both IL7 and MAL2. Our studies suggest that targeting autophagy may be a novel strategy to overcome IL7/MAL2-mediated Sorafenib resistance in HCC.

Effects of Fungicides and Nontarget Pesticides on Accumulation of the Mycotoxin Deoxynivlenol in Wheat.

Deoxynivalenol (DON) is an important virulence factor of the Fusarium head blight of wheat and threatens the health of humans. The effect of fungicides on DON production after stressing wheat to produce H2O2 and the effect of nontarget pesticides on DON accumulation are largely unknown. Five pesticides were selected to explore the effect of pesticide-induced oxidative stress on DON production in vitro and in vivo. Epoxiconazole and hexaconazole significantly induced an increase in H2O2 in vitro, and H2O2 further stimulated the production of DON and the expression of the Tri5 gene. Imidacloprid, isoproturon, and mesosulfuron-methyl had no direct effect in vitro. All pesticides activated the activities of superoxide dismutase, catalase, and peroxidase in wheat and caused the excessive accumulation of H2O2. However, excessive H2O2 did not stimulate the accumulation of DON. Imidacloprid indirectly stimulated the production of DON in vivo, which may be due to its impact on the secondary metabolism of wheat. In brief, pesticide-induced H2O2 in vitro is an important factor in stimulating DON production, but the stressed physiological H2O2 in wheat is not sufficient to stimulate DON production. The bioaccumulation results indicated that imidacloprid and epoxiconazole increase the risk of DON contamination, especially under field spraying conditions.

An autophagy-inducing stapled peptide induces mitochondria dysfunction and triggers autotic cell death in triple-negative breast cancer.

Autophagy is a lysosome-dependent bulk degradation process essential for cell viability but excessive autophagy leads to a unique form of cell death termed autosis. Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with notable defect in its autophagy process. In previous studies, we developed stapled peptides that specifically targeted the essential autophagy protein Beclin 1 to induce autophagy and promote endolysosomal trafficking. Here we show that one lead peptide Tat-SP4 induced mild increase of autophagy in TNBC cells but showed potent anti-proliferative effect that could not be rescued by inhibitors of programmed cell death pathways. The cell death induced by Tat-SP4 showed typical features of autosis including sustained adherence to the substrate surface, rupture of plasma membrane and effective rescue by digoxin, a cardioglycoside that blocks the Na+/K+ ATPase. Tat-SP4 also induced prominent mitochondria dysfunction including loss of mitochondria membrane potential, elevated mitochondria reactive oxygen species and reduced oxidative phosphorylation. The anti-proliferative effect of Tat-SP4 was confirmed in a TNBC xenograft model. Our study uncovers three notable aspects of autosis. Firstly, autosis can be triggered by moderate increase in autophagy if such increase exceeds the endogenous capacity of the host cells. Secondly, mitochondria may play an essential role in autosis with dysregulated autophagy leading to mitochondria dysfunction to trigger autosis. Lastly, intrinsic autophagy deficiency and quiescent mitochondria bioenergetic profile likely render TNBC cells particularly susceptible to autosis. Our designed peptides like Tat-SP4 may serve as potential therapeutic candidates against TNBC by targeting this vulnerability.

The potent BECN2-ATG14 coiled-coil interaction is selectively critical for endolysosomal degradation of GPRASP1/GASP1-associated GPCRs.

ABBREVIATIONS: AMBRA1 autophagy and beclin 1 regulator 1; ATG14 autophagy related 14; ATG5 autophagy related 5; ATG7 autophagy related 7; BECN1 beclin 1; BECN2 beclin 2; CC coiled-coil; CQ chloroquine CNR1/CB1R cannabinoid receptor 1 DAPI 4',6-diamidino-2-phenylindole; dCCD delete CCD; DRD2/D2R dopamine receptor D2 GPRASP1/GASP1 G protein-coupled receptor associated sorting protein 1 GPCR G-protein coupled receptor; ITC isothermal titration calorimetry; IP immunoprecipitation; KD knockdown; KO knockout; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; NRBF2 nuclear receptor binding factor 2; OPRD1/DOR opioid receptor delta 1 PIK3C3/VPS34 phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15 phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K class III phosphatidylinositol 3-kinase; PtdIns3P phosphatidylinositol-3-phosphate; RUBCN rubicon autophagy regulator; SQSTM1/p62 sequestosome 1; UVRAG UV radiation resistance associated; VPS vacuolar protein sorting; WT wild type.

Oyster Mushroom Spherical Virus Crosses the Species Barrier and Is Pathogenic to a New Host Pleurotus pulmonarius.

Oyster mushroom spherical virus (OMSV) is a mycovirus with a positive-sense single-stranded RNA genome that infects the edible mushroom Pleurotus ostreatus. OMSV is horizontally transferred from an infected strain to a cured strain via mycelia. The infection results in significant inhibition of mycelial growth, malformation of fruiting bodies, and yield loss in oyster mushrooms. This study successfully transferred OMSV from P. ostreatus to Pleurotus pulmonarius. However, transmission was not successful in other Pleurotus species including P. citrinopileatus, P. eryngii, P. nebrodensis, and P. salmoneostramineus. The successful OMSV infection in P. pulmonarius was further verified with Western blot analysis using a newly prepared polyclonal antiserum against the OMSV coat protein. Furthermore, OMSV infection reduced the mycelial growth rate of P. pulmonarius. The OMSV-infected strain demonstrated abnormal performance including twisted mushrooms or irregular edge of the cap as well as reduced yield of fruiting bodies in P. pulmonarius, compared to the OMSV-free strain. This study is the first report on the infection and pathogenicity of OMSV to the new host P. pulmonarius. The data from this study therefore suggest that OMSV is a potential threat to P. pulmonarius.

Acousto-optic reconfigurable filter based on vector mode fusion in dispersion-compensating fiber.

An acousto-optic reconfigurable filter (AORF) is proposed and demonstrated based on vector mode fusion in dispersion-compensating fiber (DCF). With multiple acoustic driving frequencies, the resonance peaks of different vector modes in the same scalar mode group can be effectively fused into a single peak, which is utilized to obtain arbitrary reconfiguration of the proposed filter. In the experiment, the bandwidth of the AORF can be electrically tuned from 5 nm to 18 nm with superposition of different driving frequencies. The multi-wavelength filtering is further demonstrated by increasing the interval of the multiple driving frequencies. The bandpass/band-rejection can also be electrically reconfigured by setting the combination of driving frequencies. The proposed AORF gains the feature of reconfigurable filtering types, fast and wide tunability, and zero frequency shift, which is advantageous for high-speed optical communication networks, tunable lasers, fast optical spectrum analyzing and microwave photonics signal processing.

The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression.

Trypanosoma brucei is a protozoan parasite that causes human African trypanosomiasis. Its major surface antigen VSG is expressed from subtelomeric loci in a strictly monoallelic manner. We previously showed that the telomere protein TbRAP1 binds dsDNA through its 737RKRRR741 patch to silence VSGs globally. How TbRAP1 permits expression of the single active VSG is unknown. Through NMR structural analysis, we unexpectedly identify an RNA Recognition Motif (RRM) in TbRAP1, which is unprecedented for RAP1 homologs. Assisted by the 737RKRRR741 patch, TbRAP1 RRM recognizes consensus sequences of VSG 3'UTRs in vitro and binds the active VSG RNA in vivo. Mutating conserved RRM residues abolishes the RNA binding activity, significantly decreases the active VSG RNA level, and derepresses silent VSGs. The competition between TbRAP1's RNA and dsDNA binding activities suggests a VSG monoallelic expression mechanism in which the active VSG's abundant RNA antagonizes TbRAP1's silencing effect, thereby sustaining its full-level expression.

Perturbation of Autophagy by a Beclin 1-Targeting Stapled Peptide Induces Mitochondria Stress and Inhibits Proliferation of Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, with a dismal five-year survival rate of less than 10%. PDAC possesses prominent genetic alterations in the oncogene KRAS and tumor suppressors p53, SMAD4 and CDKN2A. However, efforts to develop targeted drugs against these molecules have not been successful, and novel therapeutic modalities for PDAC treatment are urgently needed. Autophagy is an evolutionarily conserved self-degradative process that turns over intracellular components in a lysosome-dependent manner. The role of autophagy in PDAC is complicated and context-dependent. Elevated basal autophagy activity has been detected in multiple human PDAC cell lines and primary tumors resected from patients. However, clinical trials using chloroquine (CQ) to inhibit autophagy failed to show therapeutic efficacy. Here we show that a Beclin 1-targeting stapled peptide (Tat-SP4) developed in our lab further enhanced autophagy in multiple PDAC cell lines possessing high basal autophagy activity. Tat-SP4 also triggered faster endolysosomal degradation of EGFR and induced significant mitochondria stress as evidenced by partial loss of Δψ, increased level of ROS and reduced OXPHOS activity. Tat-SP4 exerted a potent anti-proliferative effect in PDAC cell lines in vitro and prohibited xenograft tumor growth in vivo. Intriguingly, excessive autophagy has been reported to trigger a unique form of cell death termed autosis. Tat-SP4 does induce autosis-like features in PDAC cells, including mitochondria stress and non-apoptotic cell death. Overall, our study suggests that autophagy perturbation by a Beclin 1-targeting peptide and the resulting autosis may offer a new strategy for PDAC drug discovery.

Screening cell-cell communication in spatial transcriptomics via collective optimal transport.

Spatial transcriptomic technologies and spatially annotated single-cell RNA sequencing datasets provide unprecedented opportunities to dissect cell-cell communication (CCC). However, incorporation of the spatial information and complex biochemical processes required in the reconstruction of CCC remains a major challenge. Here, we present COMMOT (COMMunication analysis by Optimal Transport) to infer CCC in spatial transcriptomics, which accounts for the competition between different ligand and receptor species as well as spatial distances between cells. A collective optimal transport method is developed to handle complex molecular interactions and spatial constraints. Furthermore, we introduce downstream analysis tools to infer spatial signaling directionality and genes regulated by signaling using machine learning models. We apply COMMOT to simulation data and eight spatial datasets acquired with five different technologies to show its effectiveness and robustness in identifying spatial CCC in data with varying spatial resolutions and gene coverages. Finally, COMMOT identifies new CCCs during skin morphogenesis in a case study of human epidermal development.

An autophagy-inducing stapled peptide promotes c-MET degradation and overrides adaptive resistance to sorafenib in c-MET+ hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer cases and ranks as the second leading cause of cancer related death. Multiple receptor tyrosine kinases such as EGFR, FGFR and c-MET have been shown to drive tumorigenesis and progression of HCC. However, tyrosine kinase inhibitors (TKIs) that target these kinases, including the FDA-approved sorafenib, only offer limited clinical success. Resistance to sorafenib and other TKIs also readily emerge in HCC patients, further limiting the usage of these drugs. Novel therapeutic strategies are needed to address the urgent unmet medical need for HCC patients. Results: Autophagy is an evolutionally conserved lysosome-dependent degradation process that is also functionally implicated in HCC. We previously developed an autophagy-inducing stapled peptide (Tat-SP4) that induced autophagy and endolysosomal degradation of EGFR in lung cancer and breast cancer cells. Here we present data to show that Tat-SP4 also induced significant autophagic response in multiple HCC cell lines and promoted the endolysosomal degradation of c-MET to attenuate its downstream signaling activities although it didn't affect the intrinsically fast turnover of EGFR. Tat-SP4 also overrode adaptive resistance to sorafenib in c-MET+ HCC cells but employed the distinct mechanism of inducing non-apoptotic cell death. Conclusion: With its distinct mechanism of promoting autophagy and endolysosomal degradation of c-MET, Tat-SP4 may serve as a novel therapeutic agent that complement and synergize with sorafenib to enhance its clinical efficacy in HCC patients.

A Beclin 1-targeting stapled peptide synergizes with erlotinib to potently inhibit proliferation of non-small-cell lung cancer cells.

Epidermal Growth Factor Receptor (EGFR) is a major drug target for non-small-cell lung carcinoma (NSCLC). Tyrosine Kinase Inhibitors (TKIs) like erlotinib are potent inhibitors of EGFR and have achieved impressive clinical success against NSCLC. However, NSCLC cells readily develop resistance to TKIs by acquiring mutations in EGFR or other oncogenes. Novel strategies to inhibit EGFR are needed to overcome this urgent problem of TKI resistance. Beclin 1 is an essential autophagy protein and is intimately involved in tumorigenesis and EGFR signaling. Here we present data to show that a Beclin 1-targeting stapled peptide Tat-SP4 can inhibit the EGFR signaling pathway by enhancing the Beclin 1-mediated endolysosomal degradation of EGFR. This inhibition mechanism is orthogonal to that employed by TKIs and is effective against either wild-type or mutant EGFR. Tat-SP4 alone showed moderate anti-proliferative efficacy in NSCLC cells but synergized with erlotinib to potently inhibit NSCLC proliferation. These results suggest that Beclin 1-targeting stapled peptides may be used in combination with TKIs to enhance their efficacy, particularly for NSCLC subtypes refractory to current regiments.

The Effect of Risk Accumulation on Childhood Stunting: A Matched Case-Control Study in China.

Background: Childhood stunting is still a public health issue in developing countries. However, the traditional risk factors in underdeveloped areas are not suitable for developed areas. Moreover, childhood stunting is influenced by several aspects, including genetic factors, perinatal conditions, maternal conditions, and feeding practices, but researchers have not yet clearly determined which aspect of risk accumulation exerts the strongest effect on stunting. A matched case-control study was performed to assess the effect of different aspects of risk accumulation on childhood stunting. Methods: In total, 173 non-stunted children aged under 7 years were matched in our study from June 2015 to August 2015. The children's heights and weights were measured, and a self-administered questionnaire was used to collect information from the children and their parents. The risk factors were assigned to the following five aspects: genetic factors, family socioeconomic status, perinatal conditions, maternal conditions, and feeding practices. The risk accumulation (cumulative risk score) in each aspect was defined as the total number of risk factors that occurred in a certain aspect. A conditional logistic regression model was used to assess the effect of risk accumulation in different aspects on stunting, and a decision-tree model was used to predict the children's stunting based on the cumulative risk scores. Results: Risk accumulation in perinatal conditions, genetic factors, maternal conditions, and feeding practices was significant in the conditional logistic regression model (P < 0.05). Perinatal conditions showed the strongest association with stunting in both the regression analysis and the decision-tree model. The risk of stunting increased by 1.199 times if the cumulative risk score for perinatal conditions increased by one, and the probability of stunting was 75.8% if the cumulative risk score for perinatal conditions was ≥1. Conclusion: Risk accumulation in perinatal conditions, genetic factors, maternal conditions, and feeding practices substantially increased the probability of stunting in childhood. Perinatal conditions were the main aspect associated with stunting. Prevention and intervention measures should be adopted to avoid risk accumulation in stunting.

Unconventional tonicity-regulated nuclear trafficking of NFAT5 mediated by KPNB1, XPOT and RUVBL2.

NFAT5 is the only known mammalian tonicity-responsive transcription factor with an essential role in cellular adaptation to hypertonic stress. It is also implicated in diverse physiological and pathological processes. NFAT5 activity is tightly regulated by extracellular tonicity, but the underlying mechanisms remain elusive. Here, we demonstrate that NFAT5 enters the nucleus via the nuclear pore complex. We found that NFAT5 utilizes a unique nuclear localization signal (NFAT5-NLS) for nuclear import. siRNA screening revealed that only karyopherin ß1 (KPNB1), but not karyopherin α, is responsible for the nuclear import of NFAT5 via direct interaction with the NFAT5-NLS. Proteomics analysis and siRNA screening further revealed that nuclear export of NFAT5 under hypotonicity is driven by exportin-T (XPOT), where the process requires RuvB-like AAA-type ATPase 2 (RUVBL2) as an indispensable chaperone. Our findings have identified an unconventional tonicity-dependent nucleocytoplasmic trafficking pathway for NFAT5 that represents a critical step in orchestrating rapid cellular adaptation to change in extracellular tonicity. These findings offer an opportunity for the development of novel NFAT5 targeting strategies that are potentially useful for the treatment of diseases associated with NFAT5 dysregulation.

Quantitative multiplexed proteomics analysis reveals reshaping of the lysine 2-hydroxyisobutyrylome in Fusarium graminearum by tebuconazole.

BACKGROUNDS: Lysine 2-hydroxyisobutyrylation (Khib) is a newly discovered posttranslational modification (PTM) and has been identified in several prokaryotic and eukaryotic organisms. Fusarium graminearum, a major pathogen of Fusarium head blight (FHB) in cereal crops, can cause considerable yield loss and produce various mycotoxins that threaten human health. The application of chemical fungicides such as tebuconazole (TEC) remains the major method to control this pathogen. However, the distribution of Khib in F. graminearum and whether Khib is remodified in response to fungicide stress remain unknown. RESULTS: Here, we carried out a proteome-wide analysis of Khib in F. graminearum, identifying the reshaping of the lysine 2-hydroxyisobutyrylome by tebuconazole, using the most recently developed high-resolution LC-MS/MS technique in combination with high-specific affinity enrichment. Specifically, 3501 Khib sites on 1049 proteins were identified, and 1083 Khib sites on 556 modified proteins normalized to the total protein content were changed significantly after TEC treatment. Bioinformatics analysis showed that Khib proteins are involved in a wide range of biological processes and may be involved in virulence and deoxynivalenol (DON) production, as well as sterol biosynthesis, in F. graminearum. CONCLUSIONS: Here, we provided a wealth of resources for further study of the roles of Khib in the fungicide resistance of F. graminearum. The results enhanced our understanding of this PTM in filamentous ascomycete fungi and provided insight into the remodification of Khib sites during azole fungicide challenge in F. graminearum.

The Transcription Factor FgAtrR Regulates Asexual and Sexual Development, Virulence, and DON Production and Contributes to Intrinsic Resistance to Azole Fungicides in Fusarium graminearum.

Fusarium graminearum is the predominant causal agent of cereal Fusarium head blight disease (FHB) worldwide. The application of chemical fungicides such as azole antifungals is still the primary method for FHB control. However, to date, our knowledge of transcriptional regulation in the azole resistance of F. graminearum is quite limited. In this study, we identified and functionally characterized a Zn(II)2-Cys6 transcription factor FgAtrR in F. graminearum. We constructed a FgAtrR deletion mutant and found that deletion of FgAtrR resulted in faster radial growth with serious pigmentation defects, significantly reduced conidial production, and an inability to form perithecia. The pathogenicity of the ΔFgAtrR mutant on wheat spikes and corn silks was severely impaired with reduced deoxynivalenol production, while the tolerance to prochloraz and propiconazole of the deletion mutant was also significantly decreased. RNA-seq indicated that many metabolic pathways were affected by the deletion of FgAtrR. Importantly, FgAtrR could regulate the expression of the FgCYP51A and ABC transporters, which are the main contributors to azole resistance. These results demonstrated that FgAtrR played essential roles in asexual and sexual development, DON production, and pathogenicity, and contributed to intrinsic resistance to azole fungicides in F. graminearum. This study will help us improve the understanding of the azole resistance mechanism in F. graminearum.

Optimization of Beclin 1-Targeting Stapled Peptides by Staple Scanning Leads to Enhanced Antiproliferative Potency in Cancer Cells.

Beclin 1 is an essential autophagy gene and a haploinsufficient tumor suppressor. Beclin 1 is the scaffolding member of the Class III phosphatidylinositol-3-kinase complex (PI3KC3) and recruits two positive regulators Atg14L and UVRAG through its coiled-coil domain to upregulate PI3KC3 activity. Our previous work has shown that hydrocarbon-stapled peptides targeted to the Beclin 1 coiled-coil domain reduced Beclin 1 homodimerization and promoted the Beclin 1-Atg14L/UVRAG interaction. These peptides also induced autophagy and enhanced the endolysosomal degradation of cell surface receptors like EGFR. Here, we present the optimization of these Beclin 1-targeting peptides by staple scanning and sequence permutation. Placing the hydrocarbon staple closer to the Beclin 1-peptide interface enhanced their binding affinity by ∼10- to 30-fold. Optimized peptides showed potent antiproliferative efficacy in cancer cells that overexpressed EGFR and HER2 by inducing necrotic cell death but not apoptosis. Our Beclin 1-targeting stapled peptides may serve as effective therapeutic candidates for EGFR- or HER2-driven cancer.

LncRNA RHPN1-AS1 promotes the progression of nasopharyngeal carcinoma by targeting CELF2 expression.

This study aims to investigate the role of lncRNA RHPN1-AS1 in NPC and its potential regulatory mechanism. The expression of RHPN1-AS1 in tissues and cells was measured by qRT-PCR. The effect of RHPN1-AS1 silencing on biological functions of NPC cells was detected by CCK-8, colony formation, flow cytometry, wound healing, and transwell assays. The protein expression was measured by western blot. The RBPs of RHPN1-AS1 were predicted by Starbase and LncTar, and verify by RIP assay. ESTIMATE was used to analyze the relationship between CELF2 expression and tumor purity. GSEA was used to analyze the downstream signaling pathway of CELF2. In our study, RHPN1-AS1 was up-regulated in NPC tissues and cells. RHPN1-AS1 silencing inhibited cell viability, capacity of proliferation, migration and invasion, promoted apoptosis, decreased protein expression of Bcl-2, MMP2/9, increased protein expression of Bax, caspase-3, and TIMP2 of NPC cells. CELF2 was a target of RHPN1-AS1 and was down-regulated in NPC tissues and cells. CELF2 level was associated with tumor purity negatively. Low expression of CELF2 activated mTORC1 signaling pathway and increased protein expression of p-mTORC1/mTORC1 and p-P70S6K/P70S6K. RHPN1-AS1 silencing eliminated the activating effect of CELF2 silencing on mTORC1 signaling pathway. Moreover, CELF2 silencing reversed the inhibitory effect of RHPN1-AS1 on NPC progression. In conclusion, our findings indicated that RHPN1-AS1 plays an important role in NPC via activating mTORC1 signaling which is modulated by CELF2. RHPN1-AS1 may serve as a potential therapeutic target for NPC treatment.

Regulation of Antigenic Variation by Trypanosoma brucei Telomere Proteins Depends on Their Unique DNA Binding Activities.

Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, Variant Surface Glycoprotein (VSG), to evade the host immune response. Such antigenic variation is a key pathogenesis mechanism that enables T. brucei to establish long-term infections. VSG is expressed exclusively from subtelomere loci in a strictly monoallelic manner, and DNA recombination is an important VSG switching pathway. The integrity of telomere and subtelomere structure, maintained by multiple telomere proteins, is essential for T. brucei viability and for regulating the monoallelic VSG expression and VSG switching. Here we will focus on T. brucei TRF and RAP1, two telomere proteins with unique nucleic acid binding activities, and summarize their functions in telomere integrity and stability, VSG switching, and monoallelic VSG expression. Targeting the unique features of TbTRF and TbRAP1's nucleic acid binding activities to perturb the integrity of telomere structure and disrupt VSG monoallelic expression may serve as potential therapeutic strategy against T. brucei.

Transition Patterns of Weight Status and Their Predictive Lipid Markers Among Chinese Adults: A Longitudinal Cohort Study Using the Multistate Markov Model.

BACKGROUND: Obesity is well recognized as a risk factor for cardiometabolic diseases. The development of obesity is a dynamic process that can be described as a multistate process with an emphasis on transitions between weight states. However, it is still unclear what convenient biomarkers predict transitions between weight states. The aim of this study was to show the dynamic nature of weight status in adults stratified by age and sex and to explore blood markers of metabolic syndrome (MetS) that predict transitions between weight states. METHODS: This study involved 9795 individuals aged 18 to 56 at study entry who underwent at least two health check-ups in the eight-year period of study in the health check-up centre of our institution. Weight, height and biochemical indices were measured at each check-up. The participants were divided into four groups based on age and sex (young male, middle-aged male, young female and middle-aged female groups). A multistate Markov model containing 3 states (healthy weight, overweight and obesity) was adopted to study the longitudinal weight data. RESULTS: Young people were more likely to transit between weight states than middle-aged people, and middle-aged people were more resistant to recover from worse states. The mean sojourn time in obesity was greatest in the middle-aged male group (6.23 years), and the predicted rate of obesity beginning with healthy weight was greatest in the young male group (13.7%). In multivariate models, age group and triglyceride (TG) and high-density lipoprotein cholesterol (HDL) levels were significant for specific transitions in females, whereas age group and HDL levels were significant in males. In females, if HDL levels increased 1 mmol/L, the probability of progression from healthy weight to overweight decreased by 37.0% (HR= 0.63), and the probabilities of recovery (overweight to healthy weight and obesity to overweight) increased by 62.0% (HR= 1.62) and 1.23-fold (HR= 2.23), respectively. In males, if TG levels increased 1 mmol/L, the risk of progression from healthy weight to overweight increased by 24.0% (HR= 1.24). Each unit increase in HDL levels was associated with a 0.99-fold (HR= 1.99) increase in the chance of recovery from overweight to healthy weight and with a 0.37-fold (HR= 0.63) decrease in the risk of progression from healthy weight to overweight. CONCLUSION: The weight status of young people was less stable than that of middle-aged people. Males were more likely to become overweight and more resistant to recover from worse states than females. Young males with healthy weight were more likely to develop obesity than other healthy weight groups. Blood lipid levels, especially HDL, were predictors of weight transitions in adults. Prevention and intervention measures should be applied early.