Machine learning and multi-omics data reveal driver gene-based molecular subtypes in hepatocellular carcinoma for precision treatment.

The heterogeneity of Hepatocellular Carcinoma (HCC) poses a barrier to effective treatment. Stratifying highly heterogeneous HCC into molecular subtypes with similar features is crucial for personalized anti-tumor therapies. Although driver genes play pivotal roles in cancer progression, their potential in HCC subtyping has been largely overlooked. This study aims to utilize driver genes to construct HCC subtype models and unravel their molecular mechanisms. Utilizing a novel computational framework, we expanded the initially identified 96 driver genes to 1192 based on mutational aspects and an additional 233 considering driver dysregulation. These genes were subsequently employed as stratification markers for further analyses. A novel multi-omics subtype classification algorithm was developed, leveraging mutation and expression data of the identified stratification genes. This algorithm successfully categorized HCC into two distinct subtypes, CLASS A and CLASS B, demonstrating significant differences in survival outcomes. Integrating multi-omics and single-cell data unveiled substantial distinctions between these subtypes regarding transcriptomics, mutations, copy number variations, and epigenomics. Moreover, our prognostic model exhibited excellent predictive performance in training and external validation cohorts. Finally, a 10-gene classification model for these subtypes identified TTK as a promising therapeutic target with robust classification capabilities. This comprehensive study provides a novel perspective on HCC stratification, offering crucial insights for a deeper understanding of its pathogenesis and the development of promising treatment strategies.

Structural basis of ubiquitin modification by the Legionella effector SdeA.

Protein ubiquitination is a multifaceted post-translational modification that controls almost every process in eukaryotic cells. Recently, the Legionella effector SdeA was reported to mediate a unique phosphoribosyl-linked ubiquitination through successive modifications of the Arg42 of ubiquitin (Ub) by its mono-ADP-ribosyltransferase (mART) and phosphodiesterase (PDE) domains. However, the mechanisms of SdeA-mediated Ub modification and phosphoribosyl-linked ubiquitination remain unknown. Here we report the structures of SdeA in its ligand-free, Ub-bound and Ub-NADH-bound states. The structures reveal that the mART and PDE domains of SdeA form a catalytic domain over its C-terminal region. Upon Ub binding, the canonical ADP-ribosyltransferase toxin turn-turn (ARTT) and phosphate-nicotinamide (PN) loops in the mART domain of SdeA undergo marked conformational changes. The Ub Arg72 might act as a 'probe' that interacts with the mART domain first, and then movements may occur in the side chains of Arg72 and Arg42 during the ADP-ribosylation of Ub. Our study reveals the mechanism of SdeA-mediated Ub modification and provides a framework for further investigations into the phosphoribosyl-linked ubiquitination process.

Fouling behavior of nanofiltration membrane during the refining treatment of morphlines-dominant reverse osmosis concentrate.

Nanofiltration (NF) has been proven to be with great potential for the separation of morpholines with molecular weight less than 200 Da in refining reverse osmosis concentrate (ROC), but its application is significantly restricted by the membrane fouling, which can reduce the rejection and service time. To enable the long-term operation stability of nanofiltration, this work focuses on the fouling behavior of each substance in the hydrosaline organic solution on nanofiltration membrane, aiming to give insight into the fouling mechanism. To this end, in this work, the effects of salts (i.e NaCl and Na2SO4), organic substances (including N-(2-hydroxypropyl)morpholine(NMH) and 4-morpholineacetate(MHA)) and representative divalent ions (Ca2+ and Mg2+) on the performance and physicochemical properties of DK membrane were systematically investigated. The results show that both salts and organics can induce DK membrane swelling, leading to an increase of the mean effective pore size. After the filtration of Na2SO4-NaCl-H2O, the mean pore size increased by 0.002 nm, resulting in the decrease of the removal ratio of NMH and MHA for 3.82% and 13.10%, respectively. With static adsorption of NMH and MHA, the mean pore size of DK membrane increased by 0.005 and 0.003 nm. The swelling slowed the entrance of more organic molecules into membrane pores. Among them, MHA led to the terrible irreversible pore blocking. As the concentration of Ca2+ increased, gypsum scaling was formed on the membrane surface. During this process, NMH and MHA played different roles, i.e. NMH accelerated the CaSO4 crystallization while MHA inhibited. As a conclusion, the fouling behavior of substances in the high saline organic wastewater on DK membrane were systematically revealed with the fouling mechanisms proposed, which could provide an insightful guidance for membrane fouling control and cleaning in the treatment of high salinity and organic wastewater.

Impact of the COVID-19 pandemic on children's sleep habits: an ECHO study.

BACKGROUND: Sleep in childhood is affected by behavioral, environmental, and parental factors. We propose that these factors were altered during the COVID-19 pandemic. This study investigates sleep habit changes during the pandemic in 528 children 4-12 years old in the US, leveraging data from the Environmental Influences on Child Health Outcomes (ECHO) Program. METHODS: Data collection occurred in July 2019-March 2020 (pre-pandemic) and two pandemic periods: December 2020-April 2021 and May-August 2021. Qualitative interviews were performed in 38 participants. RESULTS: We found no changes in sleep duration, but a shift to later sleep midpoint during the pandemic periods. There was an increase in latency at the first pandemic collection period but no increase in the frequency of bedtime resistance, and a reduced frequency of naps during the pandemic. Qualitative interviews revealed that parents prioritized routines to maintain sleep duration but were more flexible regarding timing. Children from racial/ethnic minoritized communities slept less at night, had later sleep midpoint, and napped more frequently across all collection periods, warranting in-depth investigation to examine and address root causes. CONCLUSIONS: The COVID-19 pandemic significantly impacted children sleep, but parental knowledge of the importance of sleep might have played a significant protective role. IMPACT: During the COVID-19 pandemic, US children changed their sleep habits, going to bed and waking up later, but their sleep duration did not change. Sleep latency was longer. Parental knowledge of sleep importance might have played a protective role. Regardless of data collection periods, children from racial/ethnic minoritized communities slept less and went to bed later. This is one of the first study on this topic in the US, including prospective pre-pandemic qualitative and quantitative data on sleep habits. Our findings highlight the pandemic long-term impact on childhood sleep. Results warrants further investigations on implications for overall childhood health.

Using the NEISS database to understand pressure cooker related injuries in the USA.

OBJECTIVE: To determine the incidence of pressure cooker related injuries in US hospital emergency departments. To quantify injury patterns associated with pressure cookers and inform prevention recommendation messaging. METHODS: The National Electronic Injury Surveillance System (NEISS) was queried to identify injuries associated with pressure cookers between 1 January 2003 and 31 December 2019. Case narratives were reviewed to identify precipitating or contributing factors of pressure cooker related injuries. Negative binomial regression was employed to test for trends over time. RESULTS: The NEISS query identified 759 actual pressure cooker injuries between 2003 and 2019, yielding a national estimate of 28 337 (95% CI 24 588 to 32,086) injuries treated in US emergency departments, 1667 cases annually. Analysis of case narratives resulted in the identification of four predominant precipitating or contributing factors to injury: burning agent, struck by product, injured while opening and other. CONCLUSION: NEISS is a valuable tool for determining injury incidence and understanding common injury patterns associated with specific products. Consumers and manufacturers of pressure cookers can develop safety strategies targeted at preventing the product's main injury risks.

Effect on genetic diversity of the absence of intraspecies preference in 2 sympatric Reticulitermes termite species (Isoptera: Rhinotermitidae).

The recombinant genotypes that can be produced when closely related species mate improve the genetic diversity of the population. Among closely related species, the link between interspecific reproduction behaviors and genetic diversity has barely been studied. Reticulitermes chinensis and R. flaviceps, which live close to each other, were used as research subjects in our study to find out how preferring conspecifics affects reproductive behavior between species. We discovered that neither R. chinensis nor R. flaviceps displayed preference behavior for conspecifics. Males of R. chinensis and R. flaviceps chased and groomed not only intraspecific females but also interspecific females. In a brief period of time, 2 mating behaviors, intra- and interspecific mating, were also observed. There were no significant differences in the duration of each behavior (tandem, grooming, and mating) between interspecies and intraspecies partners. Moreover, genetic analysis showed both interspecific mating and intraspecific mating can produce living offspring when the 2 types of mating occur in a colony. Our findings showed that there was no obvious intraspecific preference between the 2 species of termite Reticulitermes when it came to tandem, grooming, and mating, which not only makes it easier for interspecific hybridization to occur but also sheds light on the genetic diversity.

Two-Dimensional Coordination Polymer Showing Spin-Crossover Behavior with a 64 K Wide Hysteresis Loop.

A two-dimensional grid-like coordination polymer, [Fe(NCBH3)2(Py2ttz)2]·4CHCl3 (1·4CHCl3, Py2ttz = 2,5-di(pyridin-4-yl)thiazolo[5,4-d]thiazole), showed one-step complete spin crossover with unexpectedly large hysteresis loop of 64 K wide and temperature-induced excited spin-state trapping effect below 91 K.

A natural halogenated fluoride adenosine analog 5'-fluorodeoxy adenosine induced anticolon cancer activity in vivo and in vitro.

Adenosine (ADO) and its analogs have been introduced into the anticancer clinical trials, especial for the ADO derivatives with fluoride. The biosynthesis of fluorinase produces a fluorine-containing ADO analog 5'-fluorodeoxy adenosine (5'-FDA). The toxicity and application of 5'-FDA has not been evaluated, which limits the application of ADO analogs. In order to study its potential mechanism, we carried out the following experiments. In our research, 5'-FDA displayed good antitumor activity in colon cancer cells and two colon cancer models. As a result, 5'-FDA concentration-dependently inhibited the proliferation, migration, and invasion in colon cancer cells through its proapoptosis and cell cycle arrest pathway. Furthermore, 5'-FDA inhibited the growth of colon cancer and its pulmonary metastasis in CT26 inbred mice without affecting their body weight. It was found that 5'-FDA remarkably increased the protein levels of Caspase 3 and cleaved-Caspase 9 and decreased Cyclin A2 and CDK2 via the regulation of p53 signaling pathway, and increased the protein levels of Caspase 8 and cleaved-Caspase 8 which participated in apoptosis pathway. All in all, 5'-FDA displayed excellent therapeutic effects on colon cancer and its pulmonary metastasis. We believed that our study provided a theoretical basis for further preclinical research of 5'-FDA in the treatment of cancer.

Cryotherapy on Subjective Sleep Quality, Muscle, and Inflammatory Response in Chinese Middle- and Long-Distance Runners After Muscle Damage.

ABSTRACT: Qu, C, Wu, Z, Xu, M, Lorenzo, S, Dong, Y, Wang, Z, Qin, F, and Zhao, J. Cryotherapy on subjective sleep quality, muscle, and inflammatory response in Chinese middle- and long-distance runners after muscle damage. J Strength Cond Res 36(10): 2883-2890, 2022-The purpose of this investigation was to explore the effects of cold-water immersion (CWI), contrast-water therapy (CWT), and whole-body cryotherapy (CRY) on subjective sleep quality, muscle damage markers, and inflammatory markers in middle- and long-distance runners after muscle damage. Twelve male runners from Beijing Sport University completed a muscle damage exercise protocol and were treated with different recovery methods (CWI, CWT, CRY, or control [CON]) immediately after exercise and at 24-, 48-, and 72-h postexercise. The Pittsburgh Sleep Quality Index questionnaire score, lactate dehydrogenase (LDH) activity, myoglobin (Mb) activity, interleukin-6 (IL-6) activity, and soluble intercellular adhesion molecule-1 (sICAM-1) activity were measured at 7 time points (preexercise; immediately postexercise; and at 1-, 24-, 48-, 72-, and 96-h postexercise). Pittsburgh Sleep Quality Index scores indicated that the CRY condition had improved sleep quality compared with the CON and CWI conditions (p < 0.05). In terms of LDH activity, the CRY and CWT conditions had improved recovery compared with the CON and CWI conditions (p < 0.05). In terms of Mb activity, the CRY condition exhibited improved recovery compared with that of the CON and CWI conditions (p < 0.05), and the CWT condition showed better recovery than that of the CON condition (p < 0.05). In terms of IL-6 activity, the CRY condition showed improved recovery compared with the CWI condition (p < 0.05). Finally, in terms of sICAM-1 activity, the CRY condition had enhanced recovery compared with the other 3 conditions (p < 0.05). The results from this study suggest that CRY improves subjective sleep quality and reduces muscle damage and inflammatory responses in middle- and long-distance runners. In addition, CWT reduced muscle damage and inflammatory responses, but its effects on the other parameters were inconclusive.

Determinants of preference for future living arrangement in disabled elders: a cross-sectional study of elderly residents in Kunshan, China.

BACKGROUND: The rapid increase in the number of disabled elders and great economic and social changes call for a synchronised development of long-term care services. The aim of this study was to identify the factors determining the preference for future living arrangements, forecasting the demand for long-term care services. METHODS: A cross-sectional survey was conducted in Kunshan between June and July 2018. The stratified sampling method was used in this survey. The multinomial logistic regression model was used to explore the influencing factors. RESULTS: The most preferred future living arrangement was to live at home. Individual income, number of children alive, life satisfaction and medical insurance were significantly associated with the preference for future living arrangement. CONCLUSIONS: Our study suggested that home-based long-term care should be promoted to meet the expectations of the elderly and caregivers, and special attention should be given to the elderly with low individual income.

The remarkable hypoxia tolerance in Brandt's voles (Lasiopodomys brandtii).

Oxygen (O2 ) is essential for the survival of most animal species; however, O2 levels are lower than normal in certain spatiotemporal circumstances. Therefore, animals have to develop some strategies to face and adapt to this plight. This study compared the differences in survival, behavior, and hippocampal neurons under hypoxic conditions between Brandt's voles (Lasiopodomys brandtii) and Kunming mice (Mus musculus). Brandt's voles had longer survival times than did Kunming mice in 5%-6.5% O2 levels. Significant differences were observed in mortality between Brandt's voles and Kunming mice after 6 hr of exposure to 5%-7% O2 levels. The novel object recognition test (NORT) and neuronal nuclei staining revealed the presence of species-dependent learning deficits and neuron loss under hypoxic conditions. NORT and neuronal nuclei staining showed that the Kunming mice exposed to 7.5% O2 levels had significant learning deficits and neuronal loss compared with normoxia Kunming mice. Conversely, Brandt's voles exposed to 7.5% O2 levels had no significant learning deficits and neuronal loss compared with the normoxia group. Therefore, hypoxia showed significant effects on survival, cognitive behavior, and neuronal loss of the two species. Moreover, Brandt's voles showed stronger hypoxia tolerance than Kunming mice, and Brandt's voles hypoxia tolerance may root in their adaptive evolution to highland habitat environment. This research is meaningful for studying hypoxic adaptation in animals, and will promote the development of therapies for some illnesses such as stroke and cardiac arrest.

A Mixed-Method Approach of Pre-Cooling Enhances High-Intensity Running Performance in the Heat.

We investigated whether single or combined methods of pre-cooling could affect high-intensity exercise performance in a hot environment. Seven male athletes were subjected to four experimental conditions for 30 min in a randomised order. The four experimental conditions were: 1) wearing a vest cooled to a temperature of 4 ℃ (Vest), 2) consuming a beverage cooled to a temperature of 4 ℃ (Beverage), 3) simultaneous usage of vest and consumption of beverage (Mix), and 4) the control trial without pre-cooling (CON). Following those experimental conditions, they exercised at a speed of 80% VO2max until exhaustion in the heat (38.1 ± 0.6 ℃, 55.3 ± 0.3% RH). Heart rate (HR), rectal temperature (Tcore), skin temperature (Tskin), sweat loss (SL), urine specific gravity (USG), levels of sodium (Na+) and potassium (K+), rating of perceived exertion (RPE), thermal sensation (TS), and levels of blood lactic acid ([Bla]) were monitored. Performance was improved using the mixed pre-cooling strategy (648.43 ± 77.53 s, p = 0.016) compared to CON (509.14 ± 54.57 s). Tcore after pre-cooling was not different (Mix: 37.01 ± 0.27 ℃, Vest: 37.19 ± 0.33 ℃, Beverage: 37.03 ± 0.35 ℃) in all cooling conditions compared to those of CON (37.31 ±0.29 ℃). A similar Tcore values was achieved at exhaustion in all trials (from 38.10 ℃ to 39.00 ℃). No difference in the level of USG was observed between the conditions. Our findings suggest that pre-cooling with a combination of cold vest usage and cold fluid intake can improve performance in the heat.

LMTRDA: Using logistic model tree to predict MiRNA-disease associations by fusing multi-source information of sequences and similarities.

Emerging evidence has shown microRNAs (miRNAs) play an important role in human disease research. Identifying potential association among them is significant for the development of pathology, diagnose and therapy. However, only a tiny portion of all miRNA-disease pairs in the current datasets are experimentally validated. This prompts the development of high-precision computational methods to predict real interaction pairs. In this paper, we propose a new model of Logistic Model Tree for predicting miRNA-Disease Association (LMTRDA) by fusing multi-source information including miRNA sequences, miRNA functional similarity, disease semantic similarity, and known miRNA-disease associations. In particular, we introduce miRNA sequence information and extract its features using natural language processing technique for the first time in the miRNA-disease prediction model. In the cross-validation experiment, LMTRDA obtained 90.51% prediction accuracy with 92.55% sensitivity at the AUC of 90.54% on the HMDD V3.0 dataset. To further evaluate the performance of LMTRDA, we compared it with different classifier and feature descriptor models. In addition, we also validate the predictive ability of LMTRDA in human diseases including Breast Neoplasms, Breast Neoplasms and Lymphoma. As a result, 28, 27 and 26 out of the top 30 miRNAs associated with these diseases were verified by experiments in different kinds of case studies. These experimental results demonstrate that LMTRDA is a reliable model for predicting the association among miRNAs and diseases.

Zn-Catalyzed Cyanation of Aryl Iodides.

We report the first example of zinc-catalyzed cyanation of aryl iodides with formamide as the cyanogen source. The transformation was promoted by the bisphosphine Nixantphos ligand. Under optimized conditions, a variety of electron-donating and electron-withdrawing aryl iodides were converted into nitrile products in good to excellent yields. This approach is an exceedingly simple and benign method for the synthesis of aryl nitriles and is likely to proceed via a dinuclear Zn-concerted catalysis.

JA-Ile-macrolactone 5b Induces Tea Plant (Camellia sinensis) Resistance to Both Herbivore Ectropis obliqua and Pathogen Colletotrichum camelliae.

Jasmonates (JAs), the group of lipid-derived hormones, were found to control the defense responses in a myriad of plants. Meaningfully, the macrolactones of 12-hydroxy jasmonate isoleucine (12OH-JA-Ile) were reported to induce the defensive response of wild tobacco. However, little to nothing has been known about the elicitation effect of JA-Ile-macrolactones on woody plants to harmful organisms, let alone its underlying mechanisms. Here, we first optimized the synthetic routine using mild toxic reagent isobutyl chloroformate instead of ethyl chloroformate for conjugation, and we used acetonitrile (MeCN) instead of ethyl alcohol for the better dissolution of p-toluenesulfonic acid (p-TsOH) to gain JA-Ile-macrolactones. JA-Ile-macrolactone 5b-treated tea plants significantly inhibited the larvae weight gain of Ectropis obliqua larvae and the lesions caused by Colletotrichum camelliae. Furthermore, the expression level of CsOPR3 was significantly upregulated in 5b-treated leaves. Meanwhile, 5b reduced the accumulation of eriodictyol 7-O-glucuronide (EDG) in tea plants, which was confirmed to promote the growth rate of E. obliqua larvae by artificial diet assay. In conclusion, our study proved that the exogenous application of 5b could induce the tea plant resistance both to herbivore E. obliqua and pathogen C. camelliae, and EDG was identified as one of the secondary metabolites that could influence the growth rate of E. obliqua, but it did not directly influence the infection of C. camelliae in vitro. Further research should be carried out to clarify the mechanism through which 5b induces tea plant resistance to C. camelliae.

Design, Optimization and Improvement of FBG Flexible Sensor for Slope Displacement Profiles Measurement.

The accurate measurement of slope displacement profiles using a fiber Bragg grating flexible sensor is limited due to the influence of accumulative measurement errors. The measurement errors vary with the deformation forms of the sensor, which dramatically affects the measurement accuracy of the slope displacement profiles. To tackle the limitations and improve the measurement precision of displacement profiles, a segmental correction method based on strain increments clustering was proposed. A K-means clustering algorithm was used to automatically identify the deformation segments of a flexible sensor with different bending shapes. Then, the particle swarm optimization method was adopted to determine the correction coefficients corresponding to different deformation segments. Both finite element simulations and experiments were performed to validate the superiority of the proposed method. The experimental results indicated that the mean absolute errors (MAEs) percentages of the reconstructed displacements using the proposed method for six different bending shapes were 1.87%, 5.28%, 6.98%, 7.62%, 4.16% and 8.31%, respectively, which had improved the accuracy by 26.83%, 18.94%, 29.49%, 26.35%, 7.39%, and 19.65%, respectively. Therefore, it was confirmed that the proposed correction method was competent for effectively mitigating the measurement errors and improving the measurement accuracy of slope displacement profiles, and it presented a vital significance and application promotion value.

Related factors of quality of life of type 2 diabetes patients: a systematic review and meta-analysis.

BACKGROUND: Diabetes is a chronic disease, and it could affect both health and quality of life (QOL). A lot of studies have reported some predictors of QOL of type 2 diabetes patients. While their results were not completely consistent. So the aim of our study was finding out the related factors (including characteristics related to the disease, life styles and mental health factors) of QOL of type 2 diabetes patients. METHODS: We searched Cochrane library, EmBase, PubMed and CNKI databases for published studies that evaluated the related factors of QOL of type 2 diabetes patients by using a proper statistic method and had effect sizes (OR or ß) and 95% confidence intervals from January 1st 2000 to May 31st 2016. Any study types were acceptable, and we excluded the reviews, letters, editorials and pooled analyses. The data were analyzed using STATA software (Version 12.0; Stata Corporation). Effect sizes and 95% confidence intervals were calculated to evaluate the relationship between these factors and QOL. RESULTS: Eighteen studies were included into our systematic review and meta-analysis, totaling 57,109 type 2 diabetes patients. Do more physical exercises (The pooled ORs ranged from 0.635 to 0.825 for different scales, less than 1.00), glucose check more frequently [pooled OR (95%CI): 0.175 (0.041, 0.756)] were associated with a better QOL. Presence of complications (The pooled ORs ranged from 1.462 to 3.038 for different scales, more than 1.00), presence of hypertension [pooled OR (95%CI): 1.389 (1.173, 1644)], longer duration of diabetes [pooled OR (95%CI): 1.865 (1.088, 3.197)], diet with more red meat [pooled OR (95%CI): 2.085 (1.063, 4.089)] and depression (The pooled ORs ranged from 3.003 to 11.473 for different scales, higher than 1.00) were associated with a worse QOL. CONCLUSION: The results of this study show that physical exercise, glucose check frequently, complications, hypertension, duration of diabetes, diet with more red meat, and depression were associated with the QOL of type 2 diabetes patients.

Design and Optimization of FBG Implantable Flexible Morphological Sensor to Realize the Intellisense for Displacement.

The measurement accuracy of the intelligent flexible morphological sensor based on fiber Bragg grating (FBG) structure was limited in the application of geotechnical engineering and other fields. In order to improve the precision of intellisense for displacement, an FBG implantable flexible morphological sensor was designed in this study, and the classification morphological correction method based on conjugate gradient method and extreme learning machine (ELM) algorithm was proposed. This study utilized finite element simulations and experiments, in order to analyze the feasibility of the proposed method. Then, following the corrections, the results indicated that the maximum relative error percentages of the displacements at measuring points in different bending shapes were determined to be 6.39% (Type 1), 7.04% (Type 2), and 7.02% (Type 3), respectively. Therefore, it was confirmed that the proposed correction method was feasible, and could effectively improve the abilities of sensors for displacement intellisense. In this paper, the designed intelligent sensor was characterized by temperature self-compensation, bending shape self-classification, and displacement error self-correction, which could be used for real-time monitoring of deformation field in rock, subgrade, bridge, and other geotechnical engineering, presenting the vital significance and application promotion value.

Crystal structure of the nitrile-specifier protein NSP1 from Arabidopsis thaliana.

As important components of the glucosinolate-myrosinase system, specifier proteins mediate plant defense against herbivory and pathogen attacks. After tissue disruption, glucosinolates are hydrolyzed by myrosinases to instable aglucones, which will rearrange to form defensive isothiocyanates. Nevertheless, this reaction could be redirected to form other products by specifier proteins. Up to now, identified specifier proteins include epithiospecifier proteins (ESPs), thiocyanate forming proteins (TFPs), and nitrile-specifier proteins (NSPs). Recently, the structures of ESP and TFP have been reported. However, both the structure and the catalytic mechanism of NSPs remain enigmatic. Here, we solved the crystal structure of the NSP1 protein from Arabidopsis thaliana (AtNSP1). Structural comparisons with ESP and TFP proteins revealed several structural features of AtNSP1 different from those of the two proteins. Subsequent molecular docking studies showed that the R292 residue in AtNSP1 displayed a conformation different from those of the corresponding residues in ESP and TFP proteins, which might account for the product specificity and catalytic mechanism of AtNSP1. Taken together, the present study provides important insights into the molecular mechanisms underlying the different product spectrums between NSPs and the other two types of specifier proteins, and shed light on the future studies of the detailed mechanisms of other specifier proteins.

RBM5 inhibits tumorigenesis of gliomas through inhibition of Wnt/ß-catenin signaling and induction of apoptosis.

BACKGROUND: Gliomas are one of the most common malignant brain tumors and bring a big threat to human life as traditional therapy is unsatisfactory. RBM5 was a RNA-binding motif protein and was reported as a tumor suppressor. But the role of RBM5 in gliomas was unknown. METHODS: The mRNA level of RBM5 was determined in gliomas tissues and cell lines by real-time quantitative PCR (qRT-PCR) assay while the association of RBM5 expression with prognosis was analyzed by Kaplan-Meier method and compared by log-rank test. Lentivirus was used to overexpress RBM5 in gliomas cells. MTT and BrdU incorporation assay were used to determine cell proliferation and DNA synthesis when the ability of cell migration and invasion was analyzed by transwell assay with/without Matrigel. Cell apoptosis rate was determined with fluorescence-activated cell sorting (FACS) method. Then, expression of apoptosis molecules and critical members in Wnt/ß-catenin pathway were detected by western blot analysis. RESULTS: RBM5 was shown to be downregulated in gliomas tissues and gliomas cell lines. And decreased RBM5 expression was clinically correlated with tumor stage, patient age, and poor prognosis of gliomas patients. The proliferation and DNA synthesis was dramatically inhibited when RBM5 was overexpressed in SHG44 or U251 cells. Also, the ability of cell migration and invasion was disrupted. Then, the level of ß-catenin and Cyclin D1 significantly decreased when DKK1 and P-GSK-3ß increased reversely in SHG44 cells, which suggested that RBM5 inhibited canonical Wnt/ß-catenin signaling. Meanwhile, we demonstrated that caspase3-mediated apoptotic pathway was activated by RBM5 as Bax, TNF-α, and cleaved caspase3 were greatly upregulated while antiapoptotic molecule Bcl-2 was downregulated. Additionally, that apoptotic rate increased significantly from less than 1 to 32% in RBM5-overexpressed SHG44 cells further supported the pro-apoptosis role of RBM5 in gliomas cells. CONCLUSIONS: RBM5 plays a suppressor role in human gliomas by inhibiting Wnt/ß-catenin signaling and inducing cell apoptosis. This study improves our knowledge about the carcinogenesis and progression of human gliomas, which would greatly contribute to the therapy for gliomas patients.