Engineering medium-range order and polyamorphism in a nanostructured amorphous alloy

Like crystalline materials, the properties of amorphous materials can be tailored by tuning the local atomic-to-nanoscale structural configurations. Polyamorphism is evident by the coexistence of kinetically stabilized amorphous structures with tailorable short-to-medium-range orders, providing a viable means to engineer the degree of local order and heterogeneity. Here, we report experimental evidence of the coexistence of liquid-like and solid-like amorphous phases in a Ni$_{82}$P$_{18}$ amorphous alloy with enhanced thermal stability and plasticity prepared by pulsed electrodeposition. The two amorphous phases, of comparable volume fraction of ~50% each, have similar short-range order but are distinguished by packing at the medium-range length scale (>6 Å). Upon heating, a structure crossover at ~450 K was observed, where the liquid-like structure transforms to the solid-like structure, as evidenced by the enthalpy release and an anomalous contraction of atomic structure over the medium-range length scale, due to the metastable nature of the liquid-like structure

Continuous and low-energy 125I seed irradiation changes DNA methyltransferases expression patterns and inhibits pancreatic cancer tumor growth

<p>Abstract</p> <p>Background</p> <p>Iodine 125 (¹²⁵I) seed irradiation is an effective treatment for unresectable pancreatic cancers. However, the radiobiological mechanisms underlying brachytherapy remain unclear. Therefore, we investigated the influence of continuous and low-energy ¹²⁵I irradiation on apoptosis, expression of DNA methyltransferases (DNMTs) and cell growth in pancreatic cancers.</p> <p>Materials and methods</p> <p>For <it>in vitro </it>¹²⁵I seed irradiation, SW-1990 cells were divided into three groups: control (0 Gy), 2 Gy, and 4 Gy. To create an animal model of pancreatic cancer, the SW 1990 cells were surgically implanted into the mouse pancreas. At 10 d post-implantation, the 30 mice with pancreatic cancer underwent ¹²⁵I seed implantation and were separated into three groups: 0 Gy, 2 Gy, and 4 Gy group. At 48 or 72 h after irradiation, apoptosis was detected by flow cytometry; changes in DNMTs mRNA and protein expression were assessed by real-time PCR and western blotting analysis, respectively. At 28 d after ¹²⁵I seed implantation, <it>in vivo </it>apoptosis was evaluated with TUNEL staining, while DNMTs protein expression was detected with immunohistochemical staining. The tumor volume was measured 0 and 28 d after ¹²⁵I seed implantation.</p> <p>Results</p> <p>¹²⁵I seed irradiation induced significant apoptosis, especially at 4 Gy. DNMT1 and DNMT3b mRNA and protein expression were substantially higher in the 2 Gy group than in the control group. Conversely, the 4 Gy cell group exhibited significantly decreased DNMT3b mRNA and protein expression relative to the control group. There were substantially more TUNEL positive in the ¹²⁵I seed implantation treatment group than in the control group, especially at 4 Gy. The 4 Gy seed implantation group showed weaker staining for DNMT1 and DNMT3b protein relative to the control group. Consequently, ¹²⁵I seed implantation inhibited cancer growth and reduced cancer volume.</p> <p>Conclusion</p> <p>¹²⁵I seed implantation kills pancreatic cancer cells, especially at 4 Gy. ¹²⁵I-induced apoptosis and changes in DNMT1 and DNMT3b expression suggest potential mechanisms underlying effective brachytherapy.</p

Identifying the risk factors of ICU-acquired fungal infections: clinical evidence from using machine learning

BackgroundFungal infections are associated with high morbidity and mortality in the intensive care unit (ICU), but their diagnosis is difficult. In this study, machine learning was applied to design and define the predictive model of ICU-acquired fungi (ICU-AF) in the early stage of fungal infections using Random Forest.ObjectivesThis study aimed to provide evidence for the early warning and management of fungal infections.MethodsWe analyzed the data of patients with culture-positive fungi during their admission to seven ICUs of the First Affiliated Hospital of Chongqing Medical University from January 1, 2015, to December 31, 2019. Patients whose first culture was positive for fungi longer than 48 h after ICU admission were included in the ICU-AF cohort. A predictive model of ICU-AF was obtained using the Least Absolute Shrinkage and Selection Operator and machine learning, and the relationship between the features within the model and the disease severity and mortality of patients was analyzed. Finally, the relationships between the ICU-AF model, antifungal therapy and empirical antifungal therapy were analyzed.ResultsA total of 1,434 cases were included finally. We used lasso dimensionality reduction for all features and selected six features with importance ≥0.05 in the optimal model, namely, times of arterial catheter, enteral nutrition, corticosteroids, broadspectrum antibiotics, urinary catheter, and invasive mechanical ventilation. The area under the curve of the model for predicting ICU-AF was 0.981 in the test set, with a sensitivity of 0.960 and specificity of 0.990. The times of arterial catheter (p = 0.011, OR = 1.057, 95% CI = 1.053–1.104) and invasive mechanical ventilation (p = 0.007, OR = 1.056, 95%CI = 1.015–1.098) were independent risk factors for antifungal therapy in ICU-AF. The times of arterial catheter (p = 0.004, OR = 1.098, 95%CI = 0.855–0.970) were an independent risk factor for empirical antifungal therapy.ConclusionThe most important risk factors for ICU-AF are the six time-related features of clinical parameters (arterial catheter, enteral nutrition, corticosteroids, broadspectrum antibiotics, urinary catheter, and invasive mechanical ventilation), which provide early warning for the occurrence of fungal infection. Furthermore, this model can help ICU physicians to assess whether empiric antifungal therapy should be administered to ICU patients who are susceptible to fungal infections

Genus_Ruminococcus and order_Burkholderiales affect osteoporosis by regulating the microbiota-gut-bone axis

BackgroundThis study aimed to clarify the relationship between the gut microbiota and osteoporosis combining Mendelian randomization (MR) analysis with animal experiments.MethodsWe conducted an analysis on the relationship between differential bacteria and osteoporosis using open-access genome-wide association study (GWAS) data on gut microbe and osteoporosis obtained from public databases. The analysis was performed using two-sample MR analysis, and the causal relationship was examined through inverse variance weighting (IVW), MR Egger, weighted median, and weighted mode methods. Bilateral oophorectomy was employed to replicate the mouse osteoporosis model, which was assessed by micro computed tomography (CT), pathological tests, and bone transformation indexes. Additionally, 16S rDNA sequencing was conducted on fecal samples, while SIgA and indexes of IL-6, IL-1β, and TNF-α inflammatory factors were examined in colon samples. Through immunofluorescence and histopathology, expression levels of tight junction proteins, such as claudin-1, ZO-1, and occludin, were assessed, and conduct correlation analysis on differential bacteria and related environmental factors were performed.ResultsA positive correlation was observed between g_Ruminococcus1 and the risk of osteoporosis, while O_Burkholderiales showed a negative correlation with the risk of osteoporosis. Furthermore, there was no evidence of heterogeneity or pleiotropy. The successful replication of the mouse osteoporosis model was assessed, and it was found that the abundance of the O_Burkholderiales was significantly reduced, while the abundance of g_Ruminococcus was significantly increased in the ovariectomized (OVX)-mice. The intestinal SIgA level of OVX mice decreased, the expression level of inflammatory factors increased, barrier damage occurred, and the content of LPS in the colon and serum significantly increased. The abundance level of O_Burkholderiales is strongly positively correlated with bone formation factors, gut barrier indicators, bone density, bone volume fraction, and trabecular bone quantity, whereas it was strongly negatively correlated with bone resorption factors and intestinal inflammatory factors, The abundance level of g_Ruminococcus shows a strong negative correlation with bone formation factors, gut barrier indicators, and bone volume fraction, and a strong positive correlation with bone resorption factors and intestinal inflammatory factors.ConclusionO_Burkholderiales and g_Ruminococcus may regulate the development of osteoporosis through the microbiota-gut-bone axis

Complete Sequencing and Pan-Genomic Analysis of Lactobacillus delbrueckii subsp. bulgaricus Reveal Its Genetic Basis for Industrial Yogurt Production

Lactobacillus delbrueckii subsp. bulgaricus (Lb. bulgaricus) is an important species of Lactic Acid Bacteria (LAB) used for cheese and yogurt fermentation. The genome of Lb. bulgaricus 2038, an industrial strain mainly used for yogurt production, was completely sequenced and compared against the other two ATCC collection strains of the same subspecies. Specific physiological properties of strain 2038, such as lysine biosynthesis, formate production, aspartate-related carbon-skeleton intermediate metabolism, unique EPS synthesis and efficient DNA restriction/modification systems, are all different from those of the collection strains that might benefit the industrial production of yogurt. Other common features shared by Lb. bulgaricus strains, such as efficient protocooperation with Streptococcus thermophilus and lactate production as well as well-equipped stress tolerance mechanisms may account for it being selected originally for yogurt fermentation industry. Multiple lines of evidence suggested that Lb. bulgaricus 2038 was genetically closer to the common ancestor of the subspecies than the other two sequenced collection strains, probably due to a strict industrial maintenance process for strain 2038 that might have halted its genome decay and sustained a gene network suitable for large scale yogurt production

E2F1-Mediated Upregulation of p19INK4d Determines Its Periodic Expression during Cell Cycle and Regulates Cellular Proliferation

BACKGROUND: A central aspect of development and disease is the control of cell proliferation through regulation of the mitotic cycle. Cell cycle progression and directionality requires an appropriate balance of positive and negative regulators whose expression must fluctuate in a coordinated manner. p19INK4d, a member of the INK4 family of CDK inhibitors, has a unique feature that distinguishes it from the remaining INK4 and makes it a likely candidate for contributing to the directionality of the cell cycle. p19INK4d mRNA and protein levels accumulate periodically during the cell cycle under normal conditions, a feature reminiscent of cyclins. METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we demonstrate that p19INK4d is transcriptionally regulated by E2F1 through two response elements present in the p19INK4d promoter. Ablation of this regulation reduced p19 levels and restricted its expression during the cell cycle, reflecting the contribution of a transcriptional effect of E2F1 on p19 periodicity. The induction of p19INK4d is delayed during the cell cycle compared to that of cyclin E, temporally separating the induction of these proliferative and antiproliferative target genes. Specific inhibition of the E2F1-p19INK4d pathway using triplex-forming oligonucleotides that block E2F1 binding on p19 promoter, stimulated cell proliferation and increased the fraction of cells in S phase. CONCLUSIONS/SIGNIFICANCE: The results described here support a model of normal cell cycle progression in which, following phosphorylation of pRb, free E2F induces cyclin E, among other target genes. Once cyclinE/CDK2 takes over as the cell cycle driving kinase activity, the induction of p19 mediated by E2F1 leads to inhibition of the CDK4,6-containing complexes, bringing the G1 phase to an end. This regulatory mechanism constitutes a new negative feedback loop that terminates the G1 phase proliferative signal, contributing to the proper coordination of the cell cycle and provides an additional mechanism to limit E2F activity

Epstein–Barr Virus DNase (BGLF5) induces genomic instability in human epithelial cells

Epstein–Barr Virus (EBV) DNase (BGLF5) is an alkaline nuclease and has been suggested to be important in the viral life cycle. However, its effect on host cells remains unknown. Serological and histopathological studies implied that EBV DNase seems to be correlated with carcinogenesis. Therefore, we investigate the effect of EBV DNase on epithelial cells. Here, we report that expression of EBV DNase induces increased formation of micronucleus, an indicator of genomic instability, in human epithelial cells. We also demonstrate, using γH2AX formation and comet assay, that EBV DNase induces DNA damage. Furthermore, using host cell reactivation assay, we find that EBV DNase expression repressed damaged DNA repair in various epithelial cells. Western blot and quantitative PCR analyses reveal that expression of repair-related genes is reduced significantly in cells expressing EBV DNase. Host shut-off mutants eliminate shut-off expression of repair genes and repress damaged DNA repair, suggesting that shut-off function of BGLF5 contributes to repression of DNA repair. In addition, EBV DNase caused chromosomal aberrations and increased the microsatellite instability (MSI) and frequency of genetic mutation in human epithelial cells. Together, we propose that EBV DNase induces genomic instability in epithelial cells, which may be through induction of DNA damage and also repression of DNA repair, subsequently increases MSI and genetic mutations, and may contribute consequently to the carcinogenesis of human epithelial cells

The Current State of Proteomics in GI Oncology

Proteomics refers to the study of the entire set of proteins in a given cell or tissue. With the extensive development of protein separation, mass spectrometry, and bioinformatics technologies, clinical proteomics has shown its potential as a powerful approach for biomarker discovery, particularly in the area of oncology. More than 130 exploratory studies have defined candidate markers in serum, gastrointestinal (GI) fluids, or cancer tissue. In this article, we introduce the commonly adopted proteomic technologies and describe results of a comprehensive review of studies that have applied these technologies to GI oncology, with a particular emphasis on developments in the last 3 years. We discuss reasons why the more than 130 studies to date have had little discernible clinical impact, and we outline steps that may allow proteomics to realize its promise for early detection of disease, monitoring of disease recurrence, and identification of targets for individualized therapy

Potential of Core-Collapse Supernova Neutrino Detection at JUNO

JUNO is an underground neutrino observatory under construction in Jiangmen, China. It uses 20kton liquid scintillator as target, which enables it to detect supernova burst neutrinos of a large statistics for the next galactic core-collapse supernova (CCSN) and also pre-supernova neutrinos from the nearby CCSN progenitors. All flavors of supernova burst neutrinos can be detected by JUNO via several interaction channels, including inverse beta decay, elastic scattering on electron and proton, interactions on C12 nuclei, etc. This retains the possibility for JUNO to reconstruct the energy spectra of supernova burst neutrinos of all flavors. The real time monitoring systems based on FPGA and DAQ are under development in JUNO, which allow prompt alert and trigger-less data acquisition of CCSN events. The alert performances of both monitoring systems have been thoroughly studied using simulations. Moreover, once a CCSN is tagged, the system can give fast characterizations, such as directionality and light curve