A male germ-cell-specific ribosome controls male fertility.

Ribosomes are highly sophisticated translation machines that have been demonstrated to be heterogeneous in the regulation of protein synthesis1,2. Male germ cell development involves complex translational regulation during sperm formation3. However, it remains unclear whether translation during sperm formation is performed by a specific ribosome. Here we report a ribosome with a specialized nascent polypeptide exit tunnel, RibosomeST, that is assembled with the male germ-cell-specific protein RPL39L, the paralogue of core ribosome (RibosomeCore) protein RPL39. Deletion of RibosomeST in mice causes defective sperm formation, resulting in substantially reduced fertility. Our comparison of single-particle cryo-electron microscopy structures of ribosomes from mouse kidneys and testes indicates that RibosomeST features a ribosomal polypeptide exit tunnel of distinct size and charge states compared with RibosomeCore. RibosomeST predominantly cotranslationally regulates the folding of a subset of male germ-cell-specific proteins that are essential for the formation of sperm. Moreover, we found that specialized functions of RibosomeST were not replaceable by RibosomeCore. Taken together, identification of this sperm-specific ribosome should greatly expand our understanding of ribosome function and tissue-specific regulation of protein expression pattern in mammals.

A novel protein encoded by circRsrc1 regulates mitochondrial ribosome assembly and translation during spermatogenesis.

BACKGROUND: Circular RNAs (circRNAs) are a large class of mammalian RNAs. Several protein products translated by circRNAs have been reported to be involved in the development of various tissues and systems; however, their physiological functions in male reproduction have yet not been explored. RESULTS: Here, we report an endogenous circRNA (circRsrc1) that encodes a novel 161-amino-acid protein which we named Rsrc1-161aa through circRNA sequencing coupled with mass spectrometry analysis on mouse testicular tissues. Deletion of Rsrc1-161aa in mice impaired male fertility with a significant decrease in sperm count and motility due to dysfunctions of mitochondrial energy metabolism. A series of in vitro rescue experiments revealed that circRsrc1 regulates mitochondrial functions via its encoded protein Rsrc1-161aa. Mechanistically, Rsrc1-161aa directly interacts with mitochondrial protein C1qbp and enhances its binding activity to mitochondrial mRNAs, thereby regulating the assembly of mitochondrial ribosomes and affecting the translation of oxidative phosphorylation (OXPHOS) proteins and mitochondrial energy metabolism. CONCLUSIONS: Our studies reveal that Rsrc1-161aa protein encoded by circRsrc1 regulates mitochondrial ribosome assembly and translation during spermatogenesis, thereby affecting male fertility.

Early prediction of mortality at sepsis diagnosis time in critically ill patients by using interpretable machine learning.

This study applied machine learning for the early prediction of 30-day mortality at sepsis diagnosis time in critically ill patients. Retrospective study using data collected from the Medical Information Mart for Intensive Care IV database. The data of the patient cohort was divided on the basis of the year of hospitalization, into training (2008-2013), validation (2014-2016), and testing (2017-2019) datasets. 24,377 patients with the sepsis diagnosis time < 24 h after intensive care unit (ICU) admission were included. A gradient boosting tree-based algorithm (XGBoost) was used for training the machine learning model to predict 30-day mortality at sepsis diagnosis time in critically ill patients. Model performance was measured in both discrimination and calibration aspects. The model was interpreted using the SHapley Additive exPlanations (SHAP) module. The 30-day mortality rate of the testing dataset was 17.9%, and 39 features were selected for the machine learning model. Model performance on the testing dataset achieved an area under the receiver operating characteristic curve (AUROC) of 0.853 (95% CI 0.837-0.868) and an area under the precision-recall curves of 0.581 (95% CI 0.541-0.619). The calibration plot for the model revealed a slope of 1.03 (95% CI 0.94-1.12) and intercept of 0.14 (95% CI 0.04-0.25). The SHAP revealed the top three most significant features, namely age, increased red blood cell distribution width, and respiratory rate. Our study demonstrated the feasibility of using the interpretable machine learning model to predict mortality at sepsis diagnosis time.

Molecular Dynamics Simulations of the Short-Chain Fluorocarbon Surfactant PFHXA and the Anionic Surfactant SDS at the Air/Water Interface.

The research and development of alternatives to long-chain fluorocarbon surfactants are desperately needed because they are extremely toxic, difficult to break down, seriously harm the environment, and limit the use of conventional aqueous film-forming foam fire extinguishing agents. In this study, mixed surfactant systems containing the short-chain fluorocarbon surfactant perfluorohexanoic acid (PFHXA) and the hydrocarbon surfactant sodium dodecyl sulfate (SDS) were investigated by molecular dynamics simulation to investigate the microscopic properties at the air/water interface at different molar ratios. Some representative parameters, such as surface tension, degree of order, density distribution, radial distribution function, number of hydrogen bonds, and solvent-accessible surface area, were calculated. Molecular dynamics simulations show that compared with a single type of surfactant, mixtures of surfactants provide superior performance in improving the interfacial properties of the gas-liquid interface. A dense monolayer film is formed by the strong synergistic impact of the two surfactants. Compared to the pure SDS system, the addition of PFHXA caused SDS to be more vertically oriented at the air/water interface with a reduced tilt angle, and a more ordered structure of the mixed surfactants was observed. Hydrogen bonding between SDS headgroups and water molecules is enhanced with the increasing PFHXA. The surface activity is arranged in the following order: PFHXA/SDS = 1:1 > PFHXA/SDS = 3:1 > PFHXA/SDS = 1:3. These results indicate that a degree of synergistic relationship exists between PFHXA and SDS at the air/water interface.

Phosphoproteomic Analysis of Neonatal Regenerative Myocardium Revealed Important Roles of Checkpoint Kinase 1 via Activating Mammalian Target of Rapamycin C1/Ribosomal Protein S6 Kinase b-1 Pathway.

BACKGROUND: In mammals, regenerative therapy after myocardial infarction is hampered by the limited regenerative capacity of adult heart, whereas a transient regenerative capacity is maintained in the neonatal heart. Systemic phosphorylation signaling analysis on ischemic neonatal myocardium might be helpful to identify key pathways involved in heart regeneration. Our aim was to define the kinase-substrate network in ischemic neonatal myocardium and to identify key pathways involved in heart regeneration after ischemic insult. METHODS: Quantitative phosphoproteomics profiling was performed on infarct border zone of neonatal myocardium, and kinase-substrate network analysis revealed 11 kinases with enriched substrates and upregulated phosphorylation levels, including checkpoint kinase 1 (CHK1) kinase. The effect of CHK1 on cardiac regeneration was tested on Institute of Cancer Research CD1 neonatal and adult mice that underwent apical resection or myocardial infarction. RESULTS: In vitro, CHK1 overexpression promoted whereas CHK1 knockdown blunted cardiomyocyte proliferation. In vivo, inhibition of CHK1 hindered myocardial regeneration on resection border zone in neonatal mice. In adult myocardial infarction mice, CHK1 overexpression on infarct border zone upregulated mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway, promoted cardiomyocyte proliferation, and improved cardiac function. Inhibiting mammalian target of rapamycin activity by rapamycin blunted the neonatal cardiomyocyte proliferation induced by CHK1 overexpression in vitro. CONCLUSIONS: Our study indicates that phosphoproteome of neonatal regenerative myocardium could help identify important signaling pathways involved in myocardial regeneration. CHK1 is found to be a key signaling responsible for neonatal regeneration. Myocardial overexpression of CHK1 could improve cardiac regeneration in adult hearts by activating the mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway. Thus, CHK1 might serve as a potential novel target in myocardial repair after myocardial infarction.

TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa.

Flagella and cilia are critical cellular organelles that provide a means for cells to sense and progress through their environment. The central component of flagella and cilia is the axoneme, which comprises the "9+2" microtubule arrangement, dynein arms, radial spokes, and the nexin-dynein regulatory complex (N-DRC). Failure to properly assemble components of the axoneme leads to defective flagella and in humans leads to a collection of diseases referred to as ciliopathies. Ciliopathies can manifest as severe syndromic diseases that affect lung and kidney function, central nervous system development, bone formation, visceral organ organization, and reproduction. T-Complex-Associated-Testis-Expressed 1 (TCTE1) is an evolutionarily conserved axonemal protein present from Chlamydomonas (DRC5) to mammals that localizes to the N-DRC. Here, we show that mouse TCTE1 is testis-enriched in its expression, with its mRNA appearing in early round spermatids and protein localized to the flagellum. TCTE1 is 498 aa in length with a leucine rich repeat domain at the C terminus and is present in eukaryotes containing a flagellum. Knockout of Tcte1 results in male sterility because Tcte1-null spermatozoa show aberrant motility. Although the axoneme is structurally normal in Tcte1 mutant spermatozoa, Tcte1-null sperm demonstrate a significant decrease of ATP, which is used by dynein motors to generate the bending force of the flagellum. These data provide a link to defining the molecular intricacies required for axoneme function, sperm motility, and male fertility.

The Protein Phosphorylation Landscape of Mouse Spermatids during Spermiogenesis.

The characteristic tadpole shape of sperm is formed from round spermatids via spermiogenesis, a process which results in dramatic morphological changes in the final stage of spermatogenesis in the testis. Protein phosphorylation, as one of the most important post-translational modifications, can regulate spermiogenesis; however, the phosphorylation events taking place during this process have not been systematically analyzed. In order to better understand the role of phosphorylation in spermiogenesis, large-scale phosphoproteome profiling is performed using IMAC and TiO2 enrichment. In total, 13 835 phosphorylation sites, in 4196 phosphoproteins, are identified in purified mouse spermatids undergoing spermiogenesis in two biological replicates. Overall, 735 testis-specific proteins are identified to be phosphorylated, and are expressed at high levels during spermiogenesis. Gene ontology analysis shows enrichment of the identified phosphoproteins in terms of histone modification, cilium organization, centrosome and the adherens junction. Further characterization of the kinase-substrate phosphorylation network demonstrates enrichment of phosphorylation substrates related to the regulation of spermiogenesis. This global protein phosphorylation landscape of spermiogenesis shows wide phosphoregulation across a diverse range of processes during spermiogenesis and can help to further characterize the process of sperm generation. All MS data are available via ProteomeXchange with the identifier PXD011890.

Deficiency of TPPP2, a factor linked to oligoasthenozoospermia, causes subfertility in male mice.

Oligoasthenozoospermia is a major cause of male infertility; however, its etiology and pathogenesis are unclear and may be associated with specific gene abnormalities. This study focused on Tppp2 (tubulin polymerization promoting protein family member 2), whose encoded protein localizes in elongating spermatids at stages IV-VIII of the seminiferous epithelial cycle in testis and in mature sperm in the epididymis. In human and mouse sperm, in vitro inhibition of TPPP2 caused significantly decreased motility and ATP content. Studies on Tppp2 knockout (KO) mice demonstrated that deletion of TPPP2 resulted in male subfertility with a significantly decreased sperm count and motility. In Tppp2-/- mice, increased irregular mitochondria lacking lamellar cristae, abnormal expression of electron transfer chain molecules, lower ATP levels, decreased mitochondrial membrane potential and increased apoptotic index were observed in sperm, which could be the potential causes for its oligoasthenozoospermia phenotype. Moreover, we identified a potential TPPP2-interactive protein, eEf1b (eukaryotic translation elongation factor 1 beta), which plays an important role in protein translation extension. Thus, TPPP2 is probably a potential pathogenic factor in oligoasthenozoospermia. Deficiency of TPPP2 might affect the translation of specific proteins, altering the structure and function of sperm mitochondria, and resulting in decreased sperm count, motility and fertility.

Epigenetic silencing of ASPP1 confers 5-FU resistance in clear cell renal cell carcinoma by preventing p53 activation.

Inactivation of p53 has been shown to correlate with drug resistance in tumors. However, in clear cell renal cell carcinoma (ccRCC), p53 is rarely mutated, yet the tumors remain highly insensitive to the conventional chemotherapeutic drugs. The underlying mechanisms responsible for the non-genetic p53 inactivation remain obscure. Here, we report, for the first time, that Apoptosis Stimulating of P53 Protein 1 (ASPP1) was remarkably downregulated at both mRNA (about 3.9-fold) and protein (about 4.9-fold) levels in ccRCC human specimens in comparison with the paired normal controls. In addition, lower ASPP1 was closely related to the higher grade of tumors and shorter life expectancy of ccRCC patients, both with p < 0.001. We also find that CpG island hypermethylation at promoter region contributed to the suppression of ASPP1 expression in ccRCC that contained relatively low levels of ASPP1. Further functional studies demonstrated that forced expression ASPP1 not only significantly inhibited the growth rate of ccRCC, but also promoted sensitivity of ccRCC to the conventional chemotherapeutic drug 5-fluorouracil (5-FU)-induced apoptosis. Moreover, ASPP1 expression was accompanied with the apoptosis-prone alterations of p53 targets expression and p53 target PIG3 luciferase reporter activation. In contrast, ASPP1 knockdown promoted cell growth and prevent 5-FU-induced p53 activation and apoptosis. In conclusion, our results suggest that ASPP1 silencing is one of dominate mechanisms in inhibiting wild type p53 in ccRCC. ASPP1, therefore, may be potentially used as a promising biomarker for prognosis and therapeutic intervention in ccRCC.

Reactive Transport Model of Sulfur Cycling as Impacted by Perchlorate and Nitrate Treatments.

Microbial souring in oil reservoirs produces toxic, corrosive hydrogen sulfide through microbial sulfate reduction, often accompanying (sea)water flooding during secondary oil recovery. With data from column experiments as constraints, we developed the first reactive-transport model of a new candidate inhibitor, perchlorate, and compared it with the commonly used inhibitor, nitrate. Our model provided a good fit to the data, which suggest that perchlorate is more effective than nitrate on a per mole of inhibitor basis. Critically, we used our model to gain insight into the underlying competing mechanisms controlling the action of each inhibitor. This analysis suggested that competition by heterotrophic perchlorate reducers and direct inhibition by nitrite produced from heterotrophic nitrate reduction were the most important mechanisms for the perchlorate and nitrate treatments, respectively, in the modeled column experiments. This work demonstrates modeling to be a powerful tool for increasing and testing our understanding of reservoir-souring generation, prevention, and remediation processes, allowing us to incorporate insights derived from laboratory experiments into a framework that can potentially be used to assess risk and design optimal treatment schemes.

Deep Bidirectional Recurrent Neural Networks Ensemble for Remaining Useful Life Prediction of Aircraft Engine.

Remaining useful life (RUL) prediction of aircraft engine (AE) is of great importance to improve its reliability and availability, and reduce its maintenance costs. This article proposes a novel deep bidirectional recurrent neural networks (DBRNNs) ensemble method for the RUL prediction of the AEs. In this method, several kinds of DBRNNs with different neuron structures are built to extract hidden features from sensory data. A new customized loss function is designed to evaluate the performance of the DBRNNs, and a series of the RUL values is obtained. Then, these RUL values are reencapsulated into a predicted RUL domain. By updating the weights of elements in the domain, multiple regression decision tree (RDT) models are trained iteratively. These models integrate the predicted results of different DBRNNs to realize the final RUL prognostics with high accuracy. The proposed method is validated by using C-MAPSS datasets from NASA. The experimental results show that the proposed method has achieved more superior performance compared with other existing methods.

High-performance broadband flexible photodetector based on Gd3Fe5O12-assisted double van der Waals heterojunctions.

Flexible photodetectors are fundamental components for developing wearable systems, which can be widely used for medical detection, environmental monitoring and flexible imaging. However, compared with 3D materials, low-dimensional materials have degraded performance, a key challenge for current flexible photodetectors. Here, a high-performance broadband photodetector has been proposed and fabricated. By combining the high mobility of graphene (Gr) with the strong light-matter interactions of single-walled carbon nanotubes (SWCNTs) and molybdenum disulfide (MoS2), the flexible photodetector exhibits a greatly improved photoresponse covering the visible to near-infrared range. Additionally, a thin layer of gadolinium iron garnet (Gd3Fe5O12, GdlG) film is introduced to improve the interface of the double van der Waals heterojunctions to reduce the dark current. The SWCNT/GdIG/Gr/GdIG/MoS2 flexible photodetector exhibits a high photoresponsivity of 47.375 A/W and a high detectivity of 1.952 × 1012 Jones at 450 nm, a high photoresponsivity of 109.311 A/W and a high detectivity of 4.504 × 1012 Jones at 1080 nm, and good mechanical stability at room temperature. This work demonstrates the good capacity of GdIG-assisted double van der Waals heterojunctions on flexible substrates and provides a new solution for constructing high-performance flexible photodetectors.

Insights of microalgal municipal wastewater treatment at low temperatures: Performance, microbiota patterns, and cold-adaptation of tubular and aeration column photobioreactors.

In order to refine the treatment of microalgae consortium (MC) for municipal wastewater (MWW) during the winter, this study investigated the effectiveness of tubular and aeration column photobioreactors (TPBR and APBR) in wastewater treatment plant (WWTP) during winter by two start-up modes: microalgae/microalgae-activated sludge (AS). The operation results showed that under 5.7-13.1 °C, TPBR enhanced the assimilation of N and P pollutant by microalgal accumulation, meeting the Chinese discharge standard within 24 h (NH4+-N, TP, and COD ≤8.0, 0.5, and 50 mg·L-1). The microbial community profiles were identified and showed that inoculating AS under low-temperature still promoted bacterial interspecific association, but influenced by the inhibition of microbial diversity by the homogeneous circulation of TPBR, the nitrogen transfer function of MC was lower than that of APBR at low temperatures, except nitrogen fixation (K02588), nitrosification (K10944, K10945, and K10946), assimilatory nitrate reduction (K00366), and ammonification (K01915 and K05601). And the intermittent aeration in the APBR was still beneficial in increasing microbial diversity, which was more beneficial for reducing COD through microbial collaboration. In the treatment, the cryotolerant MGPM were Delftia, Romboutsia, Rhizobiales, and Bacillus, and the cold stress-related genes that were highly up-regulated were defense signaling molecules (K03671 and K00384), cold shock protein gene (K03704), and cellular protector (K01784) were present in both PBRs. This study provided a reference for the feasibility of the low temperature treatment of MC with the different types of PBR, which improved the application of wastewater treatment in more climatic environments.

Early prediction of delirium upon intensive care unit admission: Model development, validation, and deployment.

STUDY OBJECTIVE: To develop, validate, and deploy models for predicting delirium in critically ill adult patients as early as upon intensive care unit (ICU) admission. DESIGN: Retrospective cohort study. SETTING: Single university teaching hospital in Taipei, Taiwan. PATIENTS: 6238 critically ill patients from August 2020 to August 2021. MEASUREMENTS: Data were extracted, pre-processed, and split into training and testing datasets based on the time period. Eligible variables included demographic characteristics, Glasgow Coma Scale, vital signs parameters, treatments, and laboratory data. The predicted outcome was delirium, defined as any positive result (a score ≥ 4) of the Intensive Care Delirium Screening Checklist that was assessed by primary care nurses in each 8-h shift within 48 h after ICU admission. We trained models to predict delirium upon ICU admission (ADM) and at 24 h (24H) after ICU admission by using logistic regression (LR), gradient boosted trees (GBT), and deep learning (DL) algorithms and compared the models' performance. MAIN RESULTS: Eight features were extracted from the eligible features to train the ADM models, including age, body mass index, medical history of dementia, postoperative intensive monitoring, elective surgery, pre-ICU hospital stays, and GCS score and initial respiratory rate upon ICU admission. In the ADM testing dataset, the incidence of ICU delirium occurred within 24 h and 48 h was 32.9% and 36.2%, respectively. The area under the receiver operating characteristic curve (AUROC) (0.858, 95% CI 0.835-0.879) and area under the precision-recall curve (AUPRC) (0.814, 95% CI 0.780-0.844) for the ADM GBT model were the highest. The Brier scores of the ADM LR, GBT, and DL models were 0.149, 0.140, and 0.145, respectively. The AUROC (0.931, 95% CI 0.911-0.949) was the highest for the 24H DL model and the AUPRC (0.842, 95% CI 0.792-0.886) was the highest for the 24H LR model. CONCLUSION: Our early prediction models based on data obtained upon ICU admission could achieve good performance in predicting delirium occurred within 48 h after ICU admission. Our 24-h models can improve delirium prediction for patients discharged >1 day after ICU admission.

Proteomic profiling of the endogenous peptides of MRSA and MSSA.

Staphylococcus aureus is a Gram-positive bacterium that can cause diverse skin and soft tissue infections. Methicillin-resistant Staphylococcus aureus (MRSA) can cause more severe infections than methicillin-susceptible Staphylococcus aureus (MSSA). Nevertheless, the physiological and metabolic regulation of MSSA and MRSA has not been well studied. In light of the increased interest in endogenous peptides and recognition of the important roles that they play, we studied the endogenous peptidome of MSSA and MRSA. We identified 1,065 endogenous peptides, among which 435 were differentially expressed (DE), with 292 MSSA-abundant endogenous peptides and 35 MRSA-abundant endogenous peptides. MSSA-abundant endogenous peptides have significantly enriched "VXXXK" motif of at the C-terminus. MSSA-abundant endogenous peptides are involved in penicillin-binding and immune responses, whereas MRSA-abundant endogenous peptides are associated with antibiotic resistance and increased toxicity. Our characterization of the peptidome of MSSA and MRSA provides a rich resource for future studies to explore the functional regulation of drug resistance in S. aureus and may also help elucidate the mechanisms of its pathogenicity and the development of treatments.

A novel random forest approach to revealing interactions and controls on chlorophyll concentration and bacterial communities during coastal phytoplankton blooms.

Increasing occurrence of harmful algal blooms across the land-water interface poses significant risks to coastal ecosystem structure and human health. Defining significant drivers and their interactive impacts on blooms allows for more effective analysis and identification of specific conditions supporting phytoplankton growth. A novel iterative Random Forests (iRF) machine-learning model was developed and applied to two example cases along the California coast to identify key stable interactions: (1) phytoplankton abundance in response to various drivers due to coastal conditions and land-sea nutrient fluxes, (2) microbial community structure during algal blooms. In Example 1, watershed derived nutrients were identified as the least significant interacting variable associated with Monterey Bay phytoplankton abundance. In Example 2, through iRF analysis of field-based 16S OTU bacterial community and algae datasets, we independently found stable interactions of prokaryote abundance patterns associated with phytoplankton abundance that have been previously identified in laboratory-based studies. Our study represents the first iRF application to marine algal blooms that helps to identify ocean, microbial, and terrestrial conditions that are considered dominant causal factors on bloom dynamics.

Modulation of optical focusing by using optimized zone plate structures.

The focusing properties of the optimized zone plate structures which have upper and lower zones with different thicknesses are studied by the three-dimensional finite-difference time-domain method. Two kinds of materials are chosen, including silver representing metal and BK7 glass representing dielectric. An optimization algorithm is applied to tune the parameters of zone plate structures. Several optimized zone plate structures with smaller circular-shape focus are presented. By using the angular spectrum representation method, we found that the cases with smaller focal sizes have larger high-k components; however, the intensities of side lobes also become larger in comparison with the main beam. It is also found that the phase differences between different spatial field components can have the influences on focusing properties. A special case with two focuses is shown by changing the cost function of the same optimization algorithm. Our findings suggest that the optimized zone plate structures can reconstruct the light intensity distribution and have a great potential for the applications in imaging, lithography, and data storage.

Medulloblastoma-derived tumor stem-like cells acquired resistance to TRAIL-induced apoptosis and radiosensitivity.

OBJECTS: Medulloblastoma (MB) is the most malignant primary brain tumor in early childhood that contains cellular and functional heterogeneity. Recent evidence has demonstrated that the tumor stem cells (TSC) may explain the radiochemoresistance of brain tumors, including MB. The aim of the present study is to investigate the possible role of TNF-related apoptosis-inducing ligand (TRAIL) in viability and tumorigenicity of MB cells and MB-derived TSC. METHODS: MB-associated TSC were isolated and cultured by serum-free medium with bFGF and EGF. The parental MB cells and MB-TSC cells were treated with TRAIL in different concentrations and assessed for cell viability, invasion ability, colony forming ability, and radiotherapy effect. RESULTS: We enrich a subpopulation of MB-TSC cells using tumor spheroid formation approach. MB-TSC display enhanced self-renewal and highly expressed "stemness" genes (CD133, Sox-2, Bmi1, Nestin). Additionally, MB-TSC showed significant resistance to TRAIL-induced apoptosis and radiosensitivity compared to the parental MB cells due antiapoptotic gene (c-FLIP, Caspase 8, Bcl-2, and Bax) upregulation. CONCLUSIONS: Our data suggest that MB-TSC are resistant to TRAIL-induced apoptosis and tumorigenic properties. Understanding the molecular mechanisms by which to operate the physiological characteristics in MB-TSC cells offers attractive approach for MB treatment.

Appropriate locations of fixed bearings of continuous beams considering rail-bridge thermal interaction.

Due to the rail-bridge thermal interaction, the high additional axial force in continuously welded rails on continuous bridges may lead to rail buckling or breaking. However, there is little research on the influence of the location of the fixed bearing of continuous beam on the additional force of rail. In order to study the influence of bridge bearing arrangement on the additional longitudinal force of CWR, the thermal interaction model is established for rail, and simple and continuous beams considering nonlinear stiffness and the methods are proposed to determine the locations of fixed bearings of continuous beams corresponding to the maximum additional forces in rail reaching minimum values. Multiple continuous beams with several different lengths and simple beams with three types of bearing arrangements are taken into account to find the effect laws of the locations of the fixed bearings of continuous beams on the maximum additional forces in rail. The results show that as long as the same number of continuous beams, the ratios of the distances of adjacent two fixed bearings to the distance between the two fixed bearings of the simple beams neighbour to the first and last continuous beams respectively are approximately equal to each other. Furthermore the appropriate locations of the fixed bearings of continuous beams are recommended. The results can guide designing the location of the fixed bearing of continuous railway bridge while reducing the additional axial force in continuously welded rails due to bridge thermal effect.