Polo-like kinase 1 (Plk1) overexpression enhances ionizing radiation-induced cancer formation in mice

Polo-like kinase 1 (Plk1), a serine/threonine protein kinase normally expressed in mitosis, is frequently up-regulated in multiple types of human tumors regardless of the cell cycle stage. However, the causal relationship between Plk1 up-regulation and tumorigenesis is incompletely investigated. To this end, using a conditional expression system, here we generated Plk1 transgenic mouse lines to examine the role of Plk1 in tumorigenesis. Plk1 overexpression in mouse embryonic fibroblasts prepared from the transgenic mice led to aberrant mitosis followed by aneuploidy and apoptosis. Surprisingly, Plk1 overexpression had no apparent phenotypes in the mice. Given that no malignant tumor formation was observed even after a long period of Plk1 overexpression, we reasoned that additional factors are required for tumorigenesis in Plk1-overexpressing mice. Because Plk1 can directly participate in the regulation of the DNA damage response (DDR) pathway, we challenged Plk1-overexpressing mice with ionizing radiation (IR) and found that Plk1-overexpressing mice are much more sensitive to IR than their wild-type littermates. Analysis of tumor development in the Plk1-overexpressing mice indicated a marked decrease in the time required for tumor emergence after IR. At the molecular level, Plk1 overexpression led to reduced phosphorylation of the serine/threonine kinases ATM and Chk2 and of histone H2AX after IR treatment both in vivo and in vitro Furthermore, RNA-Seq analysis suggested that Plk1 elevation decreases the expression of several DDR genes. We conclude that Plk1 overexpression may contribute to tumor formation by both inducing chromosomal instability and suppressing the DDR pathway

SPatiotemporal-ENcoded acoustic radiation force imaging of focused ultrasound

Neuromodulation technology has provided novel therapeutic approaches for diseases caused by neural circuit dysfunction. Transcranial focused ultrasound (FU) is an emerging neuromodulation approach that combines noninvasiveness with relatively sharp focus, even in deep brain regions. It has numerous advantages such as high precision and good safety in neuromodulation, allowing for modulation of both peripheral and central nervous systems. To ensure accurate treatment targeting in FU neuromodulation, a magnetic resonance acoustic radiation force imaging (MR-ARFI) sequence is crucial for the visualization of the focal point. Currently, the commonly used 2D Spin Echo ARFI (2D SE-ARFI) sequence suffers from the long acquisition time, while the echo planar imaging ARFI (EPI-ARFI) sequence with a shorter acquisition time is vulnerable to the magnetic field inhomogeneities. To address these problems, we proposed a spatiotemporal-encoded acoustic radiation force imaging sequence (i.e., SE-SPEN-ARFI, shortened to SPEN-ARFI) in this study. The displacement at the focal spot obtained was highly consistent with that of the SE-ARFI sequence. Our research shows that SPEN-ARFI allows for rapid image acquisition and has less image distortions even under great field inhomogeneities. Therefore, a SPEN-ARFI sequence is a practical alternative for the treatment planning in ultrasound neuromodulation

Co-Targeting Plk1 and DNMT3a in Advanced Prostate Cancer

Because there is no effective treatment for late-stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A new network-based systems biology approach, XDeath, is developed to detect crosstalk of signaling pathways associated with PCa progression. This unique integrated network merges gene causal regulation networks and protein-protein interactions to identify novel co-targets for PCa treatment. The results show that polo-like kinase 1 (Plk1) and DNA methyltransferase 3A (DNMT3a)-related signaling pathways are robustly enhanced during PCa progression and together they regulate autophagy as a common death mode. Mechanistically, it is shown that Plk1 phosphorylation of DNMT3a leads to its degradation in mitosis and that DNMT3a represses Plk1 transcription to inhibit autophagy in interphase, suggesting a negative feedback loop between these two proteins. Finally, a combination of the DNMT inhibitor 5-Aza-2\u27-deoxycytidine (5-Aza) with inhibition of Plk1 suppresses PCa synergistically

Revealing the superior corrosion protection of the passive film on selective laser melted 316L SS in a phosphate-buffered saline solution

This study investigated the passivation behaviour of wrought 316L stainless steel (SS) and 316L manufactured by the Selective Laser Melting (SLM) process in phosphate-buffered saline (PBS). The 3D printing laser power influenced microstructure, passive film and corrosion resistance of SLM 316L SS were studied, and compared with the results of wrought 316L SS. The results indicated that a smaller corrosion current density and improved breakdown potential (Eb) of SLM 316L SS was associated with a higher proportion of Cr2O3 in the passive film at OCP conditions. The Transmission Electron Microscopy (TEM) proved that the passive film on SLM 316L SS was continuous and compact at 600 mV vs. Ag/AgCl applied potential. The increase in the applied potential resulted in a high content of hydroxide being recorded in the passive film. The results also suggest preferential facets of (1 1 0) and abundant grain/sub-grain boundaries for SLM 316L SS, as well as the increased work of separation and growth rate of the passive film from the substrate. Wrought 316L SS demonstrated preferred facets of (1 1 1)-γ and larger grains. There are confirmed via X-Ray Diffraction (XRD), Electron Backscatter Diffraction (EBSD) and the first-principle calculation

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

A systematic review and meta-analysis: the therapeutic and preventive effect of Lactobacillus reuteri DSM 17,938 addition in children with diarrhea

Abstract Objective To summarize the effect of adding Lactobacillus reuteri in the treatment plan for diarrheal disease in children, and analyze the potential of probiotics in preventing the occurrence of diarrheal disease. Methods Search for randomized controlled trials of Lactobacillus reuteri for the treatment and prevention of diarrhea in the Pubmed, Web of science, Medline, and Cochrane databases. Data such as the number of diarrhea patients, time, length of stay, clinical symptoms and effect of diarrhea prevention were extracted for meta-analysis. Relative risk and confidence interval (RR and 95% CI) were used as outcome indicators. Results 963 participants in the 9 RCTs came from multiple countries/regions. Compared with placebo/no intervention, the number of diarrhea patients in the Lactobacillus reuteri group was significantly reduced on the day 1 (RR = 0.87, 95%CI: 0.78–0.97) and day 2 (RR = 0.61, 95%CI: 0.44–0.83). Cumulative statistics analysis showed that the effect was stable and significant starting on the 4th day after treatment. A few studies have shown that Lactobacillus reuteri can reduce the time of diarrhea, the number of days with watery stools, and days of hospital stay. However, it has no effect on the occurrence of nosocomial diarrhea (RR = 1.11, 95%CI: 0.68–1.83), rotavirus diarrhea (RR = 1.46, 95%CI: 0.78–2.72), antibiotic-related diarrhea (RR = 1.76, 95%CI: 0.77–4.05), and diarrhea (RR = 1.35, 95%CI: 0.95–1.92). Conclusion Addition of Lactobacillus reuteri in the treatment plan has a significant effect on reducing the number of diarrhea and reducing the symptoms of diarrhea, but has no obvious effect on the prevention of diarrhea. Combining probiotics and improving the ability of probiotics to respond is the focus of attention

Enhancement of nutrient bioaccessibility and functional property of chicken bone powder through steam explosion

There are technological and nutritional challenges to efficient use of chicken bone in foods, due to its low bioaccessibility and techno-functionality. The impacts of steam explosion (SE), autoclave, steam treatment on the powder characteristics and the effect of SE on the physicochemical properties and bioaccessibility of chicken bone powders were investigated. X-ray diffraction and Fourier transform infrared spectroscopy indicated that SE treatment might increase crystallinity, partial loss of organic substance, but not completely destroyed its crystal type. SE had a smaller particle size of chicken bone powder with time and energy saving compared with other treatments, and it was conducive to improving the color acceptability. Compared with native chicken bone powder, SE significantly decreased the average particle size of powder by 79.23 %, whereas its specific surface of unit volume increased by 119.98 %. And SE improved the techno-functionality which evaluated by water holding capacity (4.19 %), oil holding capacity (10.53 %), water solubility index (117.64 %) and ABTS radical scavenging activity (14.05 %). The higher protein digestibility, calcium and major amino acids contents in chicken bone powder during digestion showed SE upgraded the bioaccessibility. The results were suggestive that steam explosion was an efficient process for preparing bone powder with improved techno-functionality and noticeable bioaccessibility

Effects of Driving Pressure-Guided Ventilation on Postoperative Pulmonary Complications in Prone-Positioned Patients Undergoing Spinal Surgery: A Randomized Controlled Clinical Trial

Background Prolonged spinal surgery in the prone position may lead to postoperative pulmonary complications (PPCs). We aimed to compare the effects of driving pressure-guided ventilation versus conventional protective ventilation on postoperative pulmonary complications in patients undergoing spinal surgery in the prone position. We hypothesized that driving pressure-guided ventilation would be associated with a decreased incidence of PPC. Methods We enrolled 78 patients into this single-center, double-blind, randomized controlled trial. The driving pressure (DP) group (n = 40) received a tidal volume of 6 ml/kg of predicted body weight, individualized positive end-expiratory pressure (PEEP) which produced the lowest driving pressure (plateau pressure-PEEP), and a recruitment maneuver. The protective ventilation (PV) group (n = 38) received the same tidal volume and recruitment maneuver but with a fixed PEEP of 5 cm H2O. Our primary outcome was postoperative pulmonary complications based on Lung Ultrasound Scores (LUS) at the end of the surgery and the simplified Clinical Pulmonary Infection Score (sCPIS) on postoperative days (POD) 1 and 3. Results DP patients had lower LUS and POD1 sCPIS than the PV group (p  0.05). The visual pain score (VAS) in postoperative days, drainage, and lengths of stay (LOS) were also similar between the two groups (p > 0.05). Conclusions Driving pressure-guided ventilation during spinal surgery with a prolonged prone patient position may reduce the incidence of early postoperative pulmonary complications, compared with conventional protective ventilation

Calibrate Ligand-ligand Interaction on Nanocrystals via the Dynamic Volume of Chain Segments

The intermolecular ligand-ligand interaction is crucial for the surface chemistry, solution properties, and self-assembly processes of colloidal nanocrystals (NCs). The studies on the ligand-ligand interaction are hampered by the disordered and dynamic nature of the surface, the low electron contrast of organic moieties, and the non-characteristic weak intermolecular forces. Solid-state nuclear magnetic resonance (NMR) can provide site-specific information on organic ligands and especially the motional behavior of chain segments. In this work, we develop an advanced solid-state NMR measurement and modelling strategy to quantify the “dynamic volume” of chain segments. The dynamic volume depicts the accessible space of a chain segment under the confinement of neighboring molecules, and is inversely proportional to the intermolecular interaction energy. The ligand-ligand interaction energies have been obtained for NCs with alkanoate ligands of different lengths. We show that the calculated ligand-ligand interaction energy determines solution dispersity and the melting transitions of NCs. This dynamic volume concept can be extended beyond experimental NMR measurements and offer semi-empirical predictions of the interaction energies for arbitrary selections of alkanoate ligands. Our study not only advances the quantitative understanding of ligand-ligand interaction on NCs but also establishes novel tactics to calibrate weak intermolecular interactions