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Abstract Background Cyclic-dependent kinase (CDK) 4/6 kinases, as the critical drivers of the cell cycle, are involved in the tumor progression of various malignancies. Pharmacologic inhibitors of CDK4/6 have shown significant clinical prospects in treating hormone receptor-positive and human epidermal growth factor receptor-negative (HR + /HER2-) breast cancer (BC) patients. However, acquired resistance to CDK4/6 inhibitors (CDK4/6i), as a common issue, has developed rapidly. It is of great significance that the identification of novel therapeutic targets facilitates overcoming the CDK4/6i resistance. PARP1, an amplified gene for CDK4/6i-resistant patients, was found to be significantly upregulated during the construction of CDK4/6i-resistant strains. Whether PARP1 drives CDK4/6i resistance in breast cancer is worth further study. Method PARP1 and p-YB-1 protein levels in breast cancer cells and tissues were quantified using Western blot (WB) analysis, immunohistochemical staining (IHC) and immunofluorescence (IF) assays. Bioinformatics analyses of Gene Expression Profiling Interactive Analysis (GEPIA), Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) datasets were applied to explore the relationship between YB-1/PARP1 protein levels and CDK4/6i IC50. Cell Counting Kit-8 (CCK-8) and crystal violet staining assays were performed to evaluate cell proliferation rates and drug killing effects. Flow cytometry assays were conducted to assess apoptosis rates and the G1/S ratio in the cell cycle. An EdU proliferation assay was used to detect the DNA replication ratio after treatment with PARP1 and YB-1 inhibitors. A ChIP assay was performed to assess the interaction of the transcription factor YB-1 and associated DNA regions. A double fluorescein reporter gene assay was designed to assess the influence of WT/S102A/S102E YB-1 on the promoter region of PARP1. Subcutaneous implantation models were applied for in vivo tumor growth evaluations. Results Here, we reported that PARP1 was amplified in breast cancer cells and CDK4/6i-resistant patients, and knockdown or inhibition of PARP1 reversed drug resistance in cell experiments and animal models. In addition, upregulation of transcription factor YB-1 also occurred in CDK4/6i-resistant breast cancer, and YB-1 inhibition can regulate PARP1 expression. p-YB-1 and PARP1 were upregulated when treated with CDK4/6i based on the WB and IF results, and elevated PARP1 and p-YB-1 were almost simultaneously observed during the construction of MCF7AR-resistant strains. Inhibition of YB-1 or PAPR1 can cause decreased DNA replication, G1/S cycle arrest, and increased apoptosis. We initially confirmed that YB-1 can bind to the promoter region of PARP1 through a ChIP assay. Furthermore, we found that YB-1 phosphorylated at S102 was crucial for PARP1 transcription according to the double fluorescein reporter gene assay. The combination therapy of YB-1 inhibitors and CDK4/6i exerted a synergistic antitumor effect in vitro and in vivo. The clinical data suggested that HR + /HER2- patients with low expression of p-YB-1/PARP1 may be sensitive to CDK4/6i in breast cancer. Conclusion These findings indicated that a ‘‘YB-1/PARP1’’ loop conferred resistance to CDK4/6 inhibitors. Furthermore, interrupting the loop can enhance tumor killing in the xenograft tumor model, which provides a promising strategy against drug resistance in breast cancer.

BackgroundThe clinical impact of washed microbiota transplantation (WMT) from healthy donors in sleep disorder (SD) patients is unclear. This study aimed to investigate the effect of WMT in SD patients.MethodsThe clinical data were collected from patients with different indications receiving 1–3 courses of WMT, divided into two groups by 7 points of PSQI scale. The score of PQSI and SF-36 scale was used to assess the improvement in sleep quality and life quality among patients with sleep disorders following WMT. Finally, 16S rRNA gene amplicon sequencing was performed on fecal samples of patients with sleep disorders before and after WMT.ResultsWMT significantly improved sleep quality in patients with sleep disorder in the short and medium term. WMT significantly improved sleep latency, sleep time and total score in the short term. WMT significantly improved sleep quality and total score in the medium term. In terms of sleep quality and sleep latency, the improvement value also increased with the increase of treatment course, and the improvement effect of multiple treatment course was better than that of single and double treatment course. In the total score, the improvement effect of double and multiple treatment was better than that of single treatment. WMT also improved quality of life in the sleep disorder group. WMT significantly improved general health, vitality, social function and mental health in the short term. WMT significantly improved role-physical, general health, vitality, and mental health in the medium term. WMT regulated the disturbed gut microbiota in patients with sleep disorders. In the normal sleep group, WMT had no effect on the decline of sleep quality in the short, medium and long term, and had an improving effect on the quality of life.ConclusionWMT could significantly improve sleep quality and life quality in patients with sleep disorders with no adverse events. The improvement in sleep quality resulting from WMT could lead to an overall enhancement in life quality. WMT could be a potentially effective treatment for patients with sleep disorders by regulating the gut microbiota.

Cell membrane surface tension has emerged as a pivotal biophysical factor governing cell behavior and fate. This review systematically delineates recent advances in techniques for cell membrane surface tension quantification, mechanosensing mechanisms, and regulatory roles of cell membrane surface tension in modulating major cellular processes. Micropipette aspiration, tether pulling, and newly developed fluorescent probes enable the measurement of cell membrane surface tension with spatiotemporal precision. Cells perceive cell membrane surface tension via conduits including mechanosensitive ion channels, curvature-sensing proteins (e.g. BAR domain proteins), and cortex-membrane attachment proteins (e.g. ERM proteins). Through membrane receptors like integrins, cells convert mechanical cues into biochemical signals. This conversion triggers cytoskeletal remodeling and extracellular matrix interactions in response to environmental changes. Elevated cell membrane surface tension suppresses cell spreading, migration, and endocytosis while facilitating exocytosis. Moreover, reduced cell membrane surface tension promotes embryonic stem cell differentiation and cancer cell invasion, underscoring cell membrane surface tension as a regulator of cell plasticity. Outstanding questions remain regarding cell membrane surface tension regulatory mechanisms and roles in tissue development/disease in vivo. Emerging tools to manipulate cell membrane surface tension with high spatiotemporal control in combination with omics approaches will facilitate the elucidation of cell membrane surface tension-mediated effects on signaling networks across various cell types/states. This will accelerate the development of cell membrane surface tension-based biomarkers and therapeutics for regenerative medicine and cancer. Overall, this review provides critical insights into cell membrane surface tension as a potent orchestrator of cell function, with broader impacts across mechanobiology.

Abstract Latency is a major barrier towards virus elimination in HIV-1-infected individuals. Yet, the mechanisms that contribute to the maintenance of HIV-1 latency are incompletely understood. Here we describe the Schlafen 12 protein (SLFN12) as an HIV-1 restriction factor that establishes a post-transcriptional block in HIV-1-infected cells and thereby inhibits HIV-1 replication and virus reactivation from latently infected cells. The inhibitory activity is dependent on the HIV-1 codon usage and on the SLFN12 RNase active sites. Within HIV-1-infected individuals, SLFN12 expression in PBMCs correlated with HIV-1 plasma viral loads and proviral loads suggesting a link with the general activation of the immune system. Using an RNA FISH-Flow HIV-1 reactivation assay, we demonstrate that SLFN12 expression is enriched in infected cells positive for HIV-1 transcripts but negative for HIV-1 proteins. Thus, codon-usage dependent translation inhibition of HIV-1 proteins participates in HIV-1 latency and can restrict the amount of virus release after latency reversal.

Understanding the cytological pattern of genome size and ploidy level of the bermudagrass (Cynodon dactylon) is vital to explore the evolution pattern and breeding of the species. To study the diversification of the cytological pattern of bermudagrass along the longitudinal gradient, the genome size and ploidy level were measured and explored with the relationship to climate factors. The corresponding ploidy level was verified through the mitotic chromosome counts method. Bermudagrass accessions ploidy level included diploids, triploid, tetraploid, pentaploid and hexaploid with a basic chromosome number of x = 9. The major ploidy level was tetraploid (45%) and aneuploidy was commonly discovered in collected regions. Mean genome size of bermudagrasswas was estimated to be 1.31 pg/1Cx along longitudinal gradient. The 1Cx values of diploid were higher than that of triploid and tetraploid, while the tetraploid had minimum basic genome size. In the current study, we observed that genome downsizing exists in tetraploids of Cynodon dactylon. Tetraploids have a wider distribution than other ploidy levels, especially in arid areas, occupying a relatively high proportion. In addition, at the same ploidy level, genome size was remarkably variable in the current study. The coefficient of determination analysis showed that longitude and mean annual rainfall were significantly correlated to genome size rather than ploidy level. This cytological study will be helpful for further genetic mechanisms and molecular characteristics to landscape adaptation of bermudagrass.

Schlafen11 (encoded by the SLFN11 gene) has been shown to inhibit the accumulation of HIV-1 proteins. We show that the SLFN11 gene is under positive selection in simian primates and is species-specific in its activity against HIV-1. The activity of human Schlafen11 is relatively weak compared to that of some other primate versions of this protein, with the versions encoded by chimpanzee, orangutan, gibbon, and marmoset being particularly potent inhibitors of HIV-1 protein production. Interestingly, we find that Schlafen11 is functional in the absence of infection and reduces protein production from certain non-viral (GFP) and even host (Vinculin and GAPDH) transcripts. This suggests that Schlafen11 may just generally block protein production from non-codon optimized transcripts. Because Schlafen11 is an interferon-stimulated gene with a broad ability to inhibit protein production from many host and viral transcripts, its role may be to create a general antiviral state in the cell. Interestingly, the strong inhibitors such as marmoset Schlafen11 consistently block protein production better than weak primate Schlafen11 proteins, regardless of the virus or host target being analyzed. Further, we show that the residues to which species-specific differences in Schlafen11 potency map are distinct from residues that have been targeted by positive selection. We speculate that the positive selection of SLFN11 could have been driven by a number of different factors, including interaction with one or more viral antagonists that have yet to be identified.

Abstract Background Previous studies have demonstrated the role of N6-methyladenosine (m6A) RNA methylation in various biological processes, our research is the first to elucidate its specific impact on LCAT mRNA stability and adipogenesis in poultry. Results The 6 100-day-old female chickens were categorized into high (n = 3) and low-fat chickens (n = 3) based on their abdominal fat ratios, and their abdominal fat tissues were processed for MeRIP-seq and RNA-seq. An integrated analysis of MeRIP-seq and RNA-seq omics data revealed 16 differentially expressed genes associated with to differential m6A modifications. Among them, ELOVL fatty acid elongase 2 (ELOVL2), pyruvate dehydrogenase kinase 4 (PDK4), fatty acid binding protein 9 (PMP2), fatty acid binding protein 1 (FABP1), lysosomal associated membrane protein 3 (LAMP3), lecithin-cholesterol acyltransferase (LCAT) and solute carrier family 2 member 1 (SLC2A1) have ever been reported to be associated with adipogenesis. Interestingly, LCAT was down-regulated and expressed along with decreased levels of mRNA methylation methylation in the low-fat group. Mechanistically, the highly expressed ALKBH5 gene regulates LCAT RNA demethylation and affects LCAT mRNA stability. In addition, LCAT inhibits preadipocyte proliferation and promotes preadipocyte differentiation, and plays a key role in adipogenesis. Conclusions In conclusion, ALKBH5 mediates RNA stability of LCAT through demethylation and affects chicken adipogenesis. This study provides a theoretical basis for further understanding of RNA methylation regulation in chicken adipogenesis.

Abstract Background Brain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many solid tumors, has been reported to be involved in the progression of multiple tumors. However, its potential involvement in BM of NSCLC and the underlying mechanism remain unknown. Methods The expression of MSLN was validated in clinical tissue and serum samples using immunohistochemistry and enzyme-linked immunosorbent assay. The ability of NSCLC cells to penetrate the blood-brain barrier (BBB) was examined using an in vitro Transwell model and an ex vivo multi-organ microfluidic bionic chip. Immunofluorescence staining and western blotting were used to detect the disruption of tight junctions. In vivo BBB leakiness assay was performed to assess the barrier integrity. MET expression and activation was detected by western blotting. The therapeutic efficacy of drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) on BM was evaluated in animal studies. Results MSLN expression was significantly elevated in both serum and tumor tissue samples from NSCLC patients with BM and correlated with a poor clinical prognosis. MSLN significantly enhanced the brain metastatic abilities of NSCLC cells, especially BBB extravasation. Mechanistically, MSLN facilitated the expression and activation of MET through the c-Jun N-terminal kinase (JNK) signaling pathway, which allowed tumor cells to disrupt tight junctions and the integrity of the BBB and thereby penetrate the barrier. Drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) effectively blocked the development of BM and prolonged the survival of mice. Conclusions Our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.

This study aimed to enhance the mechanical properties of calcium sulfoaluminate cement grouting materials (HCSA) by investigating the effects of ordinary Portland cement (OPC) content, the ratio of quicklime to gypsum, and the dosage of sodium aluminate on the compressive strength of the OPC-CSA composite system. The results indicate that as the OPC content increases, the compressive strength of the blended cement initially increases and then decreases, reaching a maximum at a 60% OPC replacement ratio within the experimental group. The addition of an appropriate amount of OPC to the CSA composite system effectively prevents the regression of compressive strength. With an increase in quicklime content, the compressive strength of the samples at various ages first increases and then decreases, with the optimal ratio of quicklime to gypsum found to be 2:8. Furthermore, sodium aluminate, used as an activator, when increased in dosage, leads to an initial increase followed by a decrease in the compressive strength of OPC-CSA samples, with an optimal incorporation rate of 0.75%, significantly enhancing the strength of the blended cement. In the orthogonal experiments, the dosage of sodium aluminate was identified as the most influential factor affecting the compressive strength of the composite grouting materials.

Abstract Background Resistance to pemetrexed (PEM), a rare chemotherapeutic agent that can efficiently cross the blood-brain barrier, limits the therapeutic efficacy for patients with lung cancer brain metastasis (BM). Aldo-keto reductase family 1 B10 (AKR1B10) was recently found to be elevated in lung cancer BM. The link between AKR1B10 and BM-acquired PEM is unknown. Methods PEM drug-sensitivity was assessed in the preclinical BM model of PC9 lung adenocarcinoma cells and the BM cells with or without AKR1B10 interference in vitro and in vivo. Metabolic reprogramming of BM attributed to AKR1B10 was identified by chromatography-mass spectrometry (GC-MS) metabolomics, and the mechanism of how AKR1B10 mediates PEM chemoresistance via a way of modified metabolism was revealed by RNA sequencing as well as further molecular biology experimental approaches. Results The lung cancer brain metastatic subpopulation cells (PC9-BrM3) exhibited significant resistance to PEM and silencing AKR1B10 in PC9-BrM3 increased the PEM sensitivity in vitro and in vivo. Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle. Conclusions Our finding demonstrates that AKR1B10/glycolysis/H4K12la/CCNB1 promotes acquired PEM chemoresistance in lung cancer BM, providing novel strategies to sensitize PEM response in the treatment of lung cancer patients suffering from BM.

Abstract Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune‐related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota‐derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition.

Abstract Background Aggressive brain tumours, whether primary gliomas or secondary metastases, are characterised by hypervascularisation and are fatal. Recent research has emphasised the crucial involvement of endothelial cells (ECs) in all brain tumour genesis and development events, with various patterns and underlying mechanisms identified. Main body Here, we highlight recent advances in knowledge about the contributions of ECs to brain tumour development, providing a comprehensive summary including descriptions of interactions between ECs and tumour cells, the heterogeneity of ECs and new models for research on ECs in brain malignancies. We also discuss prospects for EC targeting in novel therapeutic approaches. Conclusion Interventions targeting ECs, as an adjunct to other therapies (e.g. immunotherapies, molecular‐targeted therapies), have shown promising clinical efficacy due to the high degree of vascularisation in brain tumours. Developing precise strategies to target tumour‐associated vessels based on the heterogeneity of ECs is expected to improve anti‐vascular efficacy.

Abstract The structural parameters of multibell underreamed anchors play a crucial role in anchoring performance. The parameters of multibell underreamed anchor investigations are helpful when exploring optimized anchor structures. Based on the results of small-scale physical modelling tests, two types of multibell underreamed anchors were adopted under vertical uplifting loads. Numerical investigations were employed to study the effect of bell spacing, underream structure and bell dimension on the ultimate uplift bearing capacity. After an analysis of the anchorage mechanism, the anchoring efficiency was evaluated by the anchoring force provided by the unit concrete usage of the anchor, and the structural parameter λ equal to the surface area ratios of the expanded bell cone to the straight shaft between bells was defined. Then, the anchoring efficiency optimized structural parameters were presented. An analysis of model tests and simulation results showed that compared to concave bell surfaces, the convex shape could enhance the ultimate bearing capacity of a multibell underreamed anchor. There is an optimal value for the spacing of neighbouring bells, and there are three models of mechanisms for multibell anchors pulling out. When λ ∈ [1, 1.8], the multibell anchors can perform most efficiently to achieve their structural advantages.

Abstract This study fabricated a wire-tube bipolar precharger with one power supply to reduce the amount of charge accumulated on fabric filters and improve collection efficiency in a hybrid electrostatic filtration system. Theoretical analyses revealed that electrons and negative and positive ions were produced under one negative power supply in the bipolar precharger simultaneously. Charged particles of opposite polarity, which escaped from the electric field with gas flow, deposited on the filter. Thus, the accumulative charge on fabric filter reduced due to charge neutralization. The influence of unipolar and bipolar prechargers on charge accumulation on the filter was experimental investigated. According to the maximum corona current, the optimized basic wire-tube electrode configuration was 120 mm in span of the tubes, 80 mm in wire-tube spacing, and 25 mm in tube diameter. The current on the filter, which was one order of magnitude lower than that in the precharger, was quadratic to the applied voltage on the precharger, and proportional to the gas velocity. Under gas velocities between 0.1 and 0.3 m s−1, despite the corona current of the bipolar precharger was approximately 5% higher than that of the unipolar precharger, the accumulative charge on fabric filter surfaces was approximately 40%–50% lower than that of the filtration system with a unipolar precharger. The incorporation of a bipolar precharger into hybrid electrostatic filtration systems is a promising approach for reducing the risk of back corona and spark damage to the filter bag.

The evolution and stability of fracturing in the cyclothymic deposition of phosphate rocks are strongly affected by the viscoelasticity and structural form of the rock-forming minerals. Presently, there is no standardized method that has been widely accepted to accurately quantify the elastic-plastic deformation and fracturing of such striped structural rock nor reflect the role of the different lithogenous minerals in phosphate rocks when subjected to viscoelastic strain loading. In this study, integrated mathematical equations were formulated for modelling the mechanical and fracture behaviour of cyclothymic deposition in structured phosphate rocks. These constitutive equations were developed based on Maxwell’s Theory after the elastic modulus and damping coefficient of the rock-forming mineral from the mechanical testing were substituted into the derived-equations. In these new models, the apatite stripes and dolomite stripes were incorporated into the transverse isotropic model through the analysis of structural characteristics of the phosphate rock. Through experimental validation, the response curves of the creep and stress relaxation tests were found to be consistent with the deformation curves generated by modelling using the mathematical equations. Overall, the formulated model along with the corresponding equations was found to exhibit good applicability properties to describe phosphate’s mechanical and fracture behaviour under low horizontal compressive stresses. In the study, the creep mechanism in phosphate rocks were satisfactorily analysed from the angles of microscopic morphology, cracks evolution, and inter-crystalline strength. The hard brittle apatite was found to be surrounded and separated by high creep variant dolomite. Furthermore, the analysis showed that dolomite crystals possessing high creep properties dominated the distribution and evolution of secondary structures in the phosphate rock, under the condition of long-term low-stress loading.

The macro policy of the stock market is an important market information. The implementation goal of the macro policy of the stock market is mainly to improve the effectiveness of the stock market. However, whether this effectiveness has achieved the goal is worth verifying through empirical data. The exertion of this information utility is closely related to the effectiveness of the stock market. Use the run test method in statistics to collect and sort out the daily data of stock price index in recent 30 years, the linkage between 75 macro policy events and 35 trading days of market efficiencies before and after the macro event are tested since 1992 to 2022. The results show that 50.66% of the macro policies are positively linked to the effectiveness of the stock market, while 49.34% of the macro policies have reduced the effectiveness of the market operation. This shows that the effectiveness of China's stock market is not high, and the nonlinear characteristics are obvious, so the policy formulation of the stock market needs further improvement.

Abstract Background Transmembrane proteins are vital for intercellular signalling and play important roles in the control of cell fate. However, their physiological functions and mechanisms of action in myogenesis and muscle disorders remain largely unexplored. It has been found that transmembrane protein 182 (TMEM182) is dramatically up‐regulated during myogenesis, but its detailed functions remain unclear. This study aimed to analyse the function of TMEM182 during myogenesis and muscle regeneration. Methods RNA sequencing, quantitative real‐time polymerase chain reaction, and immunofluorescence approaches were used to analyse TMEM182 expression during myoblast differentiation. A dual‐luciferase reporter assay was used to identify the promoter region of the TMEM182 gene, and a chromatin immunoprecipitation assay was used to investigate the regulation TMEM182 transcription by MyoD. We used chickens and TMEM182‐knockout mice as in vivo models to examine the function of TMEM182 in muscle growth and muscle regeneration. Chickens and mouse primary myoblasts were used to extend the findings to in vitro effects on myoblast differentiation and fusion. Co‐immunoprecipitation and mass spectrometry were used to identify the interaction between TMEM182 and integrin beta 1 (ITGB1). The molecular mechanism by which TMEM182 regulates myogenesis and muscle regeneration was examined by Transwell migration, cell wound healing, adhesion, glutathione‐S‐transferse pull down, protein purification, and RNA immunoprecipitation assays. Results TMEM182 was specifically expressed in skeletal muscle and adipose tissue and was regulated at the transcriptional level by the myogenic regulatory factor MyoD1. Functionally, TMEM182 inhibited myoblast differentiation and fusion. The in vivo studies indicated that TMEM182 induced muscle fibre atrophy and delayed muscle regeneration. TMEM182 knockout in mice led to significant increases in body weight, muscle mass, muscle fibre number, and muscle fibre diameter. Skeletal muscle regeneration was accelerated in TMEM182‐knockout mice. Furthermore, we revealed that the inhibitory roles of TMEM182 in skeletal muscle depend on ITGB1, an essential membrane receptor involved in cell adhesion and muscle formation. TMEM182 directly interacted with ITGB1, and this interaction required an extracellular hybrid domain of ITGB1 (aa 387–470) and a conserved region (aa 52–62) within the large extracellular loop of TMEM182. Mechanistically, TMEM182 modulated ITGB1 activation by coordinating the association between ITGB1 and laminin and regulating the intracellular signalling of ITGB1. Myogenic deletion of TMEM182 increased the binding activity of ITGB1 to laminin and induced the activation of the FAK‐ERK and FAK‐Akt signalling axes during myogenesis. Conclusions Our data reveal that TMEM182 is a novel negative regulator of myogenic differentiation and muscle regeneration.

Abstract Machine learning algorithms may address prognostic inaccuracy among clinicians by identifying patients at risk of short-term mortality and facilitating earlier discussions about hospice enrollment, discontinuation of therapy, or other management decisions. In the present study, we used prospective predictions from a real-time machine learning prognostic algorithm to identify two trajectories of all-cause mortality risk for decedents with cancer. We show that patients with an unpredictable trajectory, where mortality risk rises only close to death, are significantly less likely to receive guideline-based end-of-life care and may not benefit from the integration of prognostic algorithms in practice.

Rock mass failure is gradually becoming more common as the number of geotechnical engineering projects continues to increase. In this paper, the probability density distributions of initial and peak frequency events in the acoustic emission (AE) from two types of rock (phosphate rock and granite) undergoing failure are analyzed. Feature events (FEs) in this AE are proposed and obtained. The probabilities of events with an initial frequency of 1,000 kHz and peak frequency of 625 kHz are found to be higher than those with other frequencies. The evolutionary behavior of the cumulative probability distributions (CPDs) of the FEs as the rocks fail is subsequently investigated. The characteristic FEs of the AE and their CPD evolution behavior in the two rocks are then compared and contrasted. The CPD curves derived for both types of rock consist of four stages: slow rise—concave rise—rapid rise—slow rise. The differences related to the FEs for the two rocks are also found. The duration of the last stage (near rock failure) is quite different for phosphate rock and granite. The peak frequencies of the FEs are the highest and the smallest in the two rocks, respectively. Our method of analyzing the AE data and results provide a theoretical method for analyzing the stability of rock masses and predicting their failure.

AbstractRoof fall in phosphate mines seriously endangers the safety of the mining activity. In this paper, the risk of roof fall occurring in phosphate mines is evaluated using the underground phosphate mine in Shanshuya, China, as an engineering background. The factors affecting roof fall in phosphate mines are analyzed, and an index system for evaluating the risk of roof fall in phosphate mine is established. Four evaluation models are employed to evaluate the risk of roof fall occurring: a set pair analysis model based on combination weights, a comprehensive fuzzy model based on hierarchical analysis, an approximately ideal ranking model based on entropy weight, and a gray relational analysis model. The evaluation results of the first two models are moderate risk with a bias toward intense risk. And the evaluation results of the last two models are slight risk with a bias toward moderate risk and moderate risk with a bias toward slight risk, respectively. The suitability of each of the evaluation models is analyzed which reveals that the evaluation results obtained using the different models are inconsistent. A combined evaluation method based on the four original evaluation models is subsequently proposed. Application of the combined evaluation method to the Shanshuya phosphate mine produces results that the roof fall risk is moderate with a bias toward slight risk. It is consistent with the actual situation in this phosphate mine. The results of the study can be used to provide technical support to engineers evaluating the risk of roof fall occurring in similar phosphate mines.

Safe and effective mining of phosphate rock plays an important role in the sustainable development of phosphorus resources. The mechanical properties and failure process of phosphate rock under different mining rates remain unclear, further restricting the safe and efficient mining of phosphate rock. In this paper, infrared radiation and uniaxial compression tests of phosphate rock under different loading rates, e.g., 0.0005, 0.001, 0.005, and 0.01 mm/s, were conducted to investigate the failure process of phosphate rock. Energy evolution and infrared radiation characteristics of the phosphate rock damage process were analyzed using nondestructive, real-time, and noncontact infrared thermal imaging technology. The results show that the higher the loading rate of phosphate rock, the more obvious the high-temperature zone and high-temperature point of phosphate rock in the loading process. At failure, the friction and slippage between internal cracks are intense, showing that the infrared radiation temperature difference increases with the increase of loading rate. As loading rate increases, the energy release time of phosphate rock before damage is reduced, resulting in more energy stored in the rock as evinced by its infrared radiation characteristics, finally resulting in greater damage. The increase of loading rate reduces the dissipation energy of phosphate rock before failure so that more energy remains in the rock mass through the weak surface of the grain boundary. The results of this work will be helpful in enhancing theoretical support for prevention and control of dynamic disasters in phosphate mines.

BackgroundWhile health systems have implemented multifaceted interventions to improve physician and patient communication in serious illnesses such as cancer, clinicians vary in their response to these initiatives. In this secondary analysis of a randomized trial, we identified phenotypes of oncology clinicians based on practice pattern and demographic data, then evaluated associations between such phenotypes and response to a machine learning (ML)-based intervention to prompt earlier advance care planning (ACP) for patients with cancer.Methods and findingsBetween June and November 2019, we conducted a pragmatic randomized controlled trial testing the impact of text message prompts to 78 oncology clinicians at 9 oncology practices to perform ACP conversations among patients with cancer at high risk of 180-day mortality, identified using a ML prognostic algorithm. All practices began in the pre-intervention group, which received weekly emails about ACP performance only; practices were sequentially randomized to receive the intervention at 4-week intervals in a stepped-wedge design. We used latent profile analysis (LPA) to identify oncologist phenotypes based on 11 baseline demographic and practice pattern variables identified using EHR and internal administrative sources. Difference-in-differences analyses assessed associations between oncologist phenotype and the outcome of change in ACP conversation rate, before and during the intervention period. Primary analyses were adjusted for patients' sex, age, race, insurance status, marital status, and Charlson comorbidity index. The sample consisted of 2695 patients with a mean age of 64.9 years, of whom 72% were White, 20% were Black, and 52% were male. 78 oncology clinicians (42 oncologists, 36 advanced practice providers) were included. Three oncologist phenotypes were identified: Class 1 (n = 9) composed primarily of high-volume generalist oncologists, Class 2 (n = 5) comprised primarily of low-volume specialist oncologists; and 3) Class 3 (n = 28), composed primarily of high-volume specialist oncologists. Compared with class 1 and class 3, class 2 had lower mean clinic days per week (1.6 vs 2.5 [class 3] vs 4.4 [class 1]) a higher percentage of new patients per week (35% vs 21% vs 18%), higher baseline ACP rates (3.9% vs 1.6% vs 0.8%), and lower baseline rates of chemotherapy within 14 days of death (1.4% vs 6.5% vs 7.1%). Overall, ACP rates were 3.6% in the pre-intervention wedges and 15.2% in intervention wedges (11.6 percentage-point difference). Compared to class 3, oncologists in class 1 (adjusted percentage-point difference-in-differences 3.6, 95% CI 1.0 to 6.1, p = 0.006) and class 2 (adjusted percentage-point difference-in-differences 12.3, 95% confidence interval [CI] 4.3 to 20.3, p = 0.003) had greater response to the intervention.ConclusionsPatient volume and time availability may be associated with oncologists' response to interventions to increase ACP. Future interventions to prompt ACP should prioritize making time available for such conversations between oncologists and their patients.

Leptospirosis is an important zoonosis that is caused by pathogenic Leptospira, which is considered to be a re-emerging infectious disease in many countries. Rodents are the most important reservoirs for both human and animal infection. An epidemiological survey of pathogenic Leptospira in rodents is important for the prevention and control of leptospirosis. In this study, a total of 964 rodents were captured from six cities in Hubei Province, and two pathogenic Leptospira species (L. interrogans and L. borgpetersenii) were detected using nested PCR with an overall prevalence of 4.8%. L. interrogans was distributed in five sampling sites, which may be the dominant species of pathogenic Leptospira in Hubei Province. In addition, Rattus norvegicus showed a relatively high infection rate, which may play an important role in the transmission and infection of pathogenic Leptospira. This study reveals the prevalence of pathogenic Leptospira in wild rodents in Hubei Province, suggesting that the risk of leptospirosis infection in Hubei Province still exists.

The Ras and Rab interactor 2 (RIN2) gene, which encodes RAS and Rab interacting protein 2, can interact with GTP-bound Rab5 and participate in early endocytosis. This study found a 61-bp insertion/deletion (indel) in the RIN2 intron region, and 3 genotypes II, ID, and DD were observed. Genotype analysis of mutation sites was performed on 665 individuals from F2 population and 8 chicken breeds. It was found that the indel existed in each breed and that yellow feathered chickens were mainly of the DD genotype. Correlation analysis of growth and carcass traits in the F2 population of Xinghua and White Recessive Rock chickens showed that the 61-bp indel was significantly correlated with abdominal fat weight, abdominal fat rate, fat width, and hatching weight (P < 0.05). RIN2 mRNA was expressed in all the tested tissues, and its expression in abdominal fat was higher than that in other tissues. In addition, the expression of the RIN2 mRNA in the abdominal fat of the DD genotype was significantly higher than that of the II genotype (P < 0.05). The transcriptional activity results showed that the luciferase activity of the pGL3-DD vector was significantly higher than that of the pGL3-II vector (P < 0.01). Moreover, the results indicate that the polymorphisms in transcription factor binding sites (TFBSs) of 61-bp indel may affect the transcriptional activity of RIN2, and thus alter fat traits in chicken. The results of this study showed that the 61-bp indel was closely related to abdominal fat-related and hatching weight traits of chickens, which may have reference value for molecular marker-assisted selection of chickens.

Lipid biosynthesis is a complex process, which is regulated by multiple factors including lncRNA. However, the role of lncRNA in chicken abdominal fat accumulation is still unclear. In this research, we collected liver tissues from six high abdominal fat rate Sanhuang broilers and six low abdominal fat rate Sanhuang broilers to perform lncRNA sequencing and small RNA sequencing. A total of 2,265 lncRNAs, 245 miRNAs, and 5,315 mRNAs were differently expressed. Among of them, 1,136 differently expressed genes were enriched in the metabolic process. A total of 36 differently expressed genes, which were considered as differently expressed lncRNAs’ targets, were enriched in the metabolic process. In addition, we also found out that eight differently expressed miRNAs could target 19 differently expressed genes. FNIP2 and PEX5L were shared in a cis-regulatory network and a differently expressed miRNA target relationship network. LncRNA-FNIP2/miR-24-3p/FNIP2 axis was considered as a potential candidate that may participate in lipid synthesis. Experimentally, the objective reality of lncRNA-FNIP2/miR-24-3p/FNIP2 axis was clarified and the regulation effect of lncRNA-FNIP2/miR-24-3p/FNIP2 axis on synthesis was validated. In brief, our study reveals a potential novel regulatory mechanism that lncRNA-FNIP2/miR-24-3p/FNIP2 axis was considered as being involved in lipid synthesis during chicken adipogenesis in liver.

Sex-linked dwarf (SLD) chicken, which is caused by a recessive mutation of the growth hormone receptor (GHR), has been widely used in the Chinese broiler industry. However, it has been found that the SLD chicken has more abdominal fat deposition than normal chicken. Excessive fat deposition not only reduced the carcass quality of the broilers but also reduced the immunity of broilers to diseases. To find out the key genes and the precise regulatory pathways that were involved in the GHR mutation-induced excessive fat deposition, we used high-fat diet (HFD) and normal diet to feed the SLD chicken and normal chicken and analyzed the differentially expressed genes (DEGs) among the four groups. Results showed that the SLD chicken had more abdominal fat deposition and larger adipocytes size than normal chicken and HFD can promote abdominal fat deposition and induce adipocyte hypertrophy. RNA sequencing results of the livers and abdominal fats from the above chickens revealed that many DEGs between the SLD and normal chickens were enriched in fat metabolic pathways, such as peroxisome proliferator-activated receptor (PPAR) signaling, extracellular matrix (ECM)-receptor pathway, and fatty acid metabolism. Importantly, by constructing and analyzing the GHR-downstream regulatory network, we found that suppressor of cytokine signaling 2 (SOCS2) and cytokine-inducible SH2-containing protein (CISH) may involve in the GHR mutation-induced abdominal fat deposition in chicken. The ectopic expression of SOCS2 and CISH in liver-related cell line leghorn strain M chicken hepatoma (LMH) cell and immortalized chicken preadipocytes (ICP) revealed that these two genes can regulate fatty acid metabolism, adipocyte differentiation, and lipid droplet accumulation. Notably, overexpression of SOCS2 and CISH can rescue the hyperactive lipid metabolism and excessive lipid droplet accumulation of primary liver cell and preadipocytes that were isolated from the SLD chicken. This study found some genes and pathways involved in abdominal fat deposition of the SLD chicken and reveals that SOCS2 and CISH are two key genes involved in the GHR mutation-induced excessive fat deposition of the SLD chicken.

In engineering blasting, the determination of the range of rock blasting fracture zone has important guiding significance for blasting construction. This paper proposes a method that can accurately and directly obtain the range of rock blasting fracture zone. Based on the theory of elastic wave propagation, test rods which are made of appropriate material are selected and prepared. A certain number of boreholes are drilled for subsequent insertion of the test rods along the direction perpendicular to the free surface of the excavation at a certain distance from the blast hole. Based on the field blasting test results, the deepest fracture position of the test rod is used as the boundary of the blasting fracture zone, and the range of the rock blasting fracture zone is obtained. A numerical analysis model is established according to the Mohr–Coulomb constitutive relationship and the Von Mises yield criterion. Then, the range of the fracture zone and the maximum horizontal radius of the fracture zone are analyzed and obtained. The numerical analysis results are compared with the field measured data. It is demonstrated that the range of the fracture zone obtained by the numerical simulation is in good agreement with the blasting test results of the pre-embedded test rods. The research results can provide references for the safety control of blasting and excavation of rock slopes.

RAB39B is located on the X chromosome and encodes the RAB39B protein that belongs to the RAB family. Mutations in RAB39B are known to be associated with X-linked intellectual disability (XLID), Parkinson’s disease, and autism. However, the patho/physiological functions of RAB39B remain largely unknown. In the present study, we established Rab39b knockout (KO) mice, which exhibited overall normal birth rate and morphologies as wild type mice. However, Rab39b deficiency led to reduced anxiety and impaired learning and memory in 2 months old mice. Deletion of Rab39b resulted in impairments of synaptic structures and functions, with reductions in NMDA receptors in the postsynaptic density (PSD). RAB39B deficiency also compromised autophagic flux at basal level, which could be overridden by rapamycin-induced autophagy activation. Further, treatment with rapamycin partially rescued impaired memory and synaptic plasticity in Rab39b KO mice, without affecting the PSD distribution of NMDA receptors. Together, these results suggest that RAB39B plays an important role in regulating both autophagy and synapse formation, and that targeting autophagy may have potential for treating XLID caused by RAB39B loss-of-function mutations.

To explore the regulatory mechanism of abdominal fat deposition in broilers, 100-day-old Sanhuang chickens (n = 12) were divided into high-fat and low-fat groups, according to the abdominal fat ratio size. Total RNA isolated from the 12 abdominal fat tissues was used for miRNA and mRNA sequencing. Results of miRNA and mRNA sequencing revealed that miR-429-3p was highly expressed in high-fat chicken whereas LPIN1 expression was downregulated. Further, we determined that miR-429-3p promoted preadipocyte proliferation and differentiation, whereas LPIN1 exerted an opposite effect. Notably, we found that the miR-429-3p/LPIN1 axis facilitated PPARγ pathway activation, which is closely associated with the progression of adipogenesis. In conclusion, our results provide evidence that a novel miR-429-3p/LPIN1 axis is involved in the regulation of adipogenesis, which may have a guiding role in the improvement of breeding for abdominal fat traits in broiler chickens.