Research on the Influence of Core Sensing Components on the Performance of Galvanic Dissolved Oxygen Sensors.

The galvanic dissolved oxygen sensor finds widespread applications in multiple critical fields due to its high precision and excellent stability. As its core sensing components, the oxygen-permeable membrane, electrode, and electrolyte significantly impact the sensor's performance. To systematically investigate the comprehensive effects of these core sensing components on the performance of galvanic dissolved oxygen sensors, this study selected six types of oxygen-permeable membranes made from two materials (Perfluoroalkoxy Polymer (PFA) and Fluorinated Ethylene Propylene Copolymer (FEP)) with three thicknesses (0.015 mm, 0.03 mm, and 0.05 mm). Additionally, five concentrations of KCl electrolyte were configured, and four different proportions of lead-tin alloy electrodes were chosen. Single-factor and crossover experiments were conducted using the OxyGuard dissolved oxygen sensor as the experimental platform. The experimental results indicate that under the same membrane thickness conditions, PFA membranes provide a higher output voltage compared to FEP membranes. Moreover, the oxygen permeability of FEP membranes is more significantly affected by temperature. Furthermore, the oxygen permeability of the membrane is inversely proportional to its thickness; the thinner the membrane, the better the oxygen permeability, resulting in a corresponding increase in sensor output voltage. When the membrane thickness is reduced from 0.05 mm to 0.015 mm, the sensor output voltage for PFA and FEP membranes increases by 86% and 74.91%, respectively. However, this study also observed that excessively thin membranes might compromise measurement accuracy. In a saturated, dissolved oxygen environment, the sensor output voltage corresponding to the six oxygen-permeable membranes used in the experiment exhibits a highly linear inverse relationship with temperature (correlation coefficient ≥ 98%). Meanwhile, the lead-tin ratio of the electrode and electrolyte concentration have a relatively minor impact on the sensor output voltage, demonstrating good stability at different temperatures (coefficient of variation ≤ 0.78%). In terms of response time, it is directly proportional to the thickness of the oxygen-permeable membrane, especially for PFA membranes. When the thickness increases from 0.015 mm to 0.05 mm, the response time extends by up to 2033.33%. In contrast, the electrode material and electrolyte concentration have a less significant effect on response time. To further validate the practical value of the experimental results, the best-performing combination of core sensing components from the experiments was selected to construct a new dissolved oxygen sensor. A performance comparison test was conducted between this new sensor and the OxyGuard dissolved oxygen sensor. The results showed that both sensors had the same response time (49 s). However, in an anaerobic environment, the OxyGuard sensor demonstrated slightly higher accuracy by 2.44%. This study not only provides a deep analysis of the combined effects of oxygen-permeable membranes, electrodes, and electrolytes on the performance of galvanic dissolved oxygen sensors but also offers scientific evidence and practical guidance for optimizing sensor design.

Nicotinamide mononucleotide as a therapeutic agent to alleviate multi-organ failure in sepsis.

BACKGROUND: Sepsis-caused multi-organ failure remains the major cause of morbidity and mortality in intensive care units with limited therapeutics. Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD+), has been recently reported to be protective in sepsis; however, its therapeutic effects remain to be determined. This study sought to investigate the therapeutic effects of NMN in septic organ failure and its underlying mechanisms. METHODS: Sepsis was induced by feces-injection-in-peritoneum in mice. NMN was given after an hour of sepsis onset. Cultured neutrophils, macrophages and endothelial cells were incubated with various agents. RESULTS: We demonstrate that administration of NMN elevated NAD+ levels and reduced serum lactate levels, oxidative stress, inflammation, and caspase-3 activity in multiple organs of septic mice, which correlated with the attenuation of heart dysfunction, pulmonary microvascular permeability, liver injury, and kidney dysfunction, leading to lower mortality. The therapeutic effects of NMN were associated with lower bacterial burden in blood, and less ROS production in septic mice. NMN improved bacterial phagocytosis and bactericidal activity of macrophages and neutrophils while reducing the lipopolysaccharides-induced inflammatory response of macrophages. In cultured endothelial cells, NMN mitigated mitochondrial dysfunction, inflammation, apoptosis, and barrier dysfunction induced by septic conditions, all of which were offset by SIRT3 inhibition. CONCLUSION: NAD+ repletion with NMN prevents mitochondrial dysfunction and restrains bacterial dissemination while limiting inflammatory damage through SIRT3 signaling in sepsis. Thus, NMN may represent a therapeutic option for sepsis.

A Novel Betulinic Acid Analogue: Synthesis, Solubility, Antitumor Activity and Pharmacokinetic Study in Rats.

Betulinic acid (BA) and betulin (BE) are naturally pentacyclic triterpenes with documented biological activities, especially antitumor and anti-inflammatory activity. However, their bioavailability in vivo is not satisfactory in terms of medical applications. Thus, to improve the solubility and bioavailability so as to improve the efficacy, 28-O-succinyl betulin (SBE), a succinyl derivative of BE, was synthesized and its solubility, in vitro and in vivo anti-tumor activities, the apoptosis pathway as well as the pharmacokinetic properties were investigated. The results showed that SBE exhibited significantly higher solubility in most of the tested solvents, and showed a maximum solubility of 7.19 ± 0.66 g/L in n-butanol. In vitro and in vivo anti-tumor activity assays indicated both BA and SBE exhibited good anti-tumor activities, and SBE demonstrated better potential compared to BA. An increase in the ratio of Bad/Bcl-xL and activation of caspase 9 was found in SBE treated Hela cells, suggesting that the intrinsic mitochondrial pathway is involved in SBE induced apoptosis. Compared with BA, SBE showed much-improved absorption and bioavailability in pharmacokinetic studies.

MLKL-mediated necroptosis is a target for cardiac protection in mouse models of type-1 diabetes.

BACKGROUND: Cardiomyocyte death contributes to cardiac pathology of diabetes. Studies have shown that the RIPK3/MLKL necroptosis signaling is activated in diabetic hearts. Deletion of RIPK3 was reported to attenuate myocardial injury and heart dysfunction in streptozocin (STZ)-induced diabetic mice, suggesting a potential role of necroptosis in diabetic cardiomyopathy. This study characterized cardiomyocyte necroptosis in diabetic hearts and investigated whether MLKL-mediated necroptosis is a target for cardiac protection in diabetes. METHODS: Type 1 diabetes was induced in RIPK3 knockout, MLKL knockout and wild-type mice. Akita Type-1 diabetic mice were injected with shRNA for MLKL. Myocardial function was assessed by echocardiography. Immuno-histological analyses determined cardiomyocyte death and fibrosis in the heart. Cultured adult mouse cardiomyocytes were incubated with high glucose in the presence of various drugs. Cell death and phosphorylation of RIPK3 and MLKL were analysed. RESULTS: We showed that the levels of phosphorylated RIPK3 and MLKL were higher in high glucose-stimulated cardiomyocytes and hearts of STZ-induced type-1 diabetic mice, akita mice and type-1 diabetic monkeys when compared to non-diabetic controls. Inhibition of RIPK3 by its pharmacological inhibitor or gene deletion, or MLKL deletion prevented high glucose-induced MLKL phosphorylation and attenuated necroptosis in cardiomyocytes. In STZ-induced type-1 diabetic mice, cardiomyocyte necroptosis was present along with elevated cardiac troponin I in serum and MLKL oligomerization, and co-localized with phosphorylated MLKL. Deletion of RIPK3 or MLKL prevented MLKL phosphorylation and cardiac necroptosis, attenuated serum cardiac troponin I levels, reduced myocardial collagen deposition and improved myocardial function in STZ-injected mice. Additionally, shRNA-mediated down-regulation of MLKL reduced cardiomyocyte necroptosis in akita mice. Interestingly, incubation with anti-diabetic drugs (empagliflozin and metformin) prevented phosphorylation of RIPK3 and MLKL, and reduced cell death in high glucose-induced cardiomyocytes. CONCLUSIONS: We have provided evidence that cardiomyocyte necroptosis is present in diabetic hearts and that MLKL-mediated cardiomyocyte necroptosis contributes to diabetic cardiomyopathy. These findings highlight MLKL-mediated necroptosis as a target for cardiac protection in diabetes.

Perinatal Risk Factors Influencing Neonatal Hypoxic Ischemic Encephalopathy in Southern China: A Case-Control Study.

OBJECTIVE: In this study, our objective was to explore the relevant influencing factors of neonatal hypoxic-ischemic encephalopathy (HIE) in Southern China and provide scientific basis for improving the quality of life for neonates. STUDY DESIGN: A retrospective analysis of 306 cases with HIE neonates who were admitted during April 2015 to October 2017 was conducted. A total of 306 non-HIE patients admitted to the same hospital during the same period were also included as controls. The basic clinical characteristics were analyzed, and the risk factors for HIE were assessed by logistic regression analysis. RESULTS: Univariate analysis showed that the differences in medicals during pregnancy, placenta previa, fetal distress during labor, cesarean section, amniotic fluid contamination, abnormal labor stage, and Apgar showed significantly different in the case group and the control group (p < 0.05). The multivariate logistic regression analysis revealed that the placenta previa, medicals during pregnancy, fetal distress, abnormal labor stage, Apgar's score, amniotic fluid contamination, and cesarean section were independent risk factors for HIE. CONCLUSION: The placenta previa, medicals during pregnancy, fetal distress, and abnormal labor stage can increase the risk of HIE. Early detection, early diagnosis, and treatment might make great achievement in improving the life quality of HIE neonates.

Betulinic acid derivatives can protect human Müller cells from glutamate-induced oxidative stress.

Müller cells are the predominant retinal glial cells. One of the key roles of Müller cells is in the uptake of the neurotransmitter glutamate and in its conversion to glutamine. Müller cell dysfunction due to oxidative stress elicited by high glutamate concentrations can lead to toxicity, which promote the pathogenesis of retinal diseases like diabetic retinopathy and glaucoma. This study investigated the anti-oxidant activity and mechanisms of betulinic acid (BA) and its derivatives in human Müller cells. Human MIO-M1 Müller cells were pre-treated in the presence or absence of BA, BE as well as their derivatives (named H3-H20) followed by incubation with glutamate. Cell viability was evaluated with the MTT and calcein-AM assays. Reactive oxygen species (ROS) production in MIO-M1 cells was measured using CM-H2DCFDA and flow cytometry. The activation of cellular apoptosis and necrosis was analyzed with annexin V/PI staining and flow cytometry. The modulation of signaling pathways involved in glutamate-mediated cytotoxicity and ROS production was evaluated by immunoblotting. The BA derivatives H3, H5 and H7 exhibited minimal cytotoxicity and significant anti-oxidant activity. These compounds significantly suppressed ROS production and attenuated cellular necrosis elicited by glutamate-induced oxidative stress. The protective effects of H3, H5 and H7 in MIO-M1 cells were associated with the attenuation of Akt, Erk, and JNK signaling. The BA analogues H3, H5 and H7 are protective against glutamate-induced oxidative stress in human Müller cells, and elicit their actions by modulation of the Erk, Akt and JNK signaling pathways. These agents are potential candidate molecules for the prevention or treatment of human retinal diseases.

A derivative of betulinic acid protects human Retinal Pigment Epithelial (RPE) cells from cobalt chloride-induced acute hypoxic stress.

The Retinal Pigment Epithelium (RPE) is a monolayer of cells located above the choroid. It mediates human visual cycle and nourishes photoreceptors. Hypoxia-induced oxidative stress to RPE is a vital cause of retinal degeneration such as the Age-related Macular Degeneration. Most of these retinal diseases are irreversible with no efficient treatment, therefore protecting RPE cells from hypoxia stress is an important way to prevent or slow down the progression of retinal degeneration. Betulinic acid (BA) and betulin (BE) are pentacyclic triterpenoids with anti-oxidative property, but little is known about their effect on RPE cells. We investigated the protective effect of BA, BE and their derivatives against cobalt chloride-induced hypoxia stress in RPE cells. Human ARPE-19 cells were exposed to BA, BE and their eighteen derivatives (named as H3H20) that we customized through replacing moieties at C3 and C28 positions. We found that cobalt chloride reduced cell viability, increased Reactive Oxygen Species (ROS) production as well as induced apoptosis and necrosis in ARPE-19 cells. Interestingly, the pretreatment of 3-O-acetyl-glycyl- 28-O-glycyl-betulinic acid effectively protected cells from acute hypoxia stress induced by cobalt chloride. Our immunoblotting results suggested that this derivative attenuated the cobalt chloride-induced activation of Akt, Erk and JNK pathways. All findings were further validated in human primary RPE cells. In summary, this BA derivate has protective effect against the acute hypoxic stress in human RPE cells and may be developed into a candidate agent effective in the prevention of prevalent retinal diseases.

An LC-MS/MS method for the determination of salidroside and its metabolite p-tyrosol in rat liver tissues.

CONTEXT: Salidroside and its metabolite p-tyrosol are two major phenols in the genus Rhodiola L. (Crassulaceae). They have been confirmed to possess various pharmacological properties and are used for the prophylaxis and therapeutics of many diseases. Several analytical methods have been developed for the determination of the two compounds in plant materials and biological plasma matrices. However, these methods are not optimal for biological samples containing complex organic interferences, such as liver and brain tissues. OBJECTIVE: This study aimed to further develop and validate a simple and specific LC-MS/MS method for the determination of salidroside and its metabolite p-tyrosol in rat liver tissues using paracetamol as the internal standard (IS). MATERIALS AND METHODS: Salidroside and p-tyrosol with the IS paracetamol and liver tissues were used as model compounds and biological samples. Samples were processed by protein precipitation (PP) with methanol, the supernatant was dried under nitrogen and the residue was reconstituted in a mobile phase that consisted of a mixture of acetonitrile and water (1:9, v/v). Salidroside and p-tyrosol were detected in negative mode under multiple reaction monitoring (MRM) by a triple quadrupole tandem mass spectrometer coupled with electrospray ionization. RESULTS: Standard curves were linear over the concentration range of 50-2000 ng/mL with correlation coefficients of 0.995 or better for both salidroside and p-tyrosol. The intra- and inter-day accuracy for salidroside ranged between 104.90 and 112.73% with a precision of 3.51-14.27%. For p-tyrosol, the intra- and inter-day accuracy was between 92.38 and 100.59%, and the precision was 8.54% or less. The stability data showed that no significant degradation occurred under the experimental conditions. The recoveries were 111.44, 108.10, and 102.00% for salidroside at concentrations of 50, 500 and 2000 ng/mL, respectively, and were 105.44, 105.50, and 113.04% for tyrosol at concentrations of 50, 500 and 2000 ng/mL, respectively. The matrix effects were 83.85-92.45% for salidroside and 85.61-92.49% for p-tyrosol at three QC levels. This method was successfully applied to a liver tissue distribution study of salidroside and its metabolite p-tyrosol in rats. DISCUSSION AND CONCLUSION: This newly established method is validated as simple, reliable and accurate. It can be used as a valid analytical method for the intrinsic quality control of biological matrices, especially tissue samples.

[Testing of germination rate of hybrid rice seeds based on near-infrared reflectance spectroscopy].

Germination rate of rice seeds was measured according to technical stipulation of germination testing for agricultural crop seeds at present. There existed many faults for this technical stipulation such as long experimental period, more costing and higher professional requirement. A rapid and non-invasive method was put forward to measure the germination rate of hybrid rice seeds based on near-infrared reflectance spectroscopy. Two varieties of hybrid rice seeds were aged artificially at temperature 45 degrees C and humidity 100% condition for 0, 24, 48, 72, 96, 120 and 144 h. Spectral data of 280 samples for 2 varieties of hybrid rice seeds with different aging time were acquired individually by near-infrared spectra analyzer. Spectral data of 280 samples for 2 varieties of hybrid rice seeds were randomly divided into calibration set (168 samples) and prediction set (112 samples). Gormination rate of rice seed with different aging time was tested. Regression model was established by using partial least squares (PLS). The effect of the different spectral bands on the accuracy of models was analyzed and the effect of the different spectral preprocessing methods on the accuracy of models was also compared. Optimal model was achieved under the whole bands and by using standardization and orthogonal signal correction (OSC) preprocessing algorithms with CM2000 software for spectral data of 2 varieties of hybrid rice seeds, the coefficient of determination of the calibration set (Rc) and that of the prediction set (Rp) were 0.965 and 0.931 individually, standard error of calibration set (SEC) and that of prediction set (SEP) were 1.929 and 2.899 respectively. Relative error between tested value and predicted value for prediction set of rice seeds is below 4.2%. The experimental results show that it is feasible that rice germination rate is detected rapidly and nondestructively by using the near-infrared spectroscopy analysis technology.

Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma.

Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides an aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.

A 3D QSAR study of betulinic acid derivatives as anti-tumor agents using topomer CoMFA: model building studies and experimental verification.

Betulinic acid (BA) is a natural product that exerts its cytotoxicity against various malignant carcinomas without side effects by triggering the mitochondrial pathway to apoptosis. Betulin (BE), the 28-hydroxyl analog of BA, is present in large amounts (up to 30% dry weight) in the outer bark of birch trees, and shares the same pentacyclic triterpenoid core as BA, yet exhibits no significant cytotoxicity. Topomer CoMFA studies were performed on 37 BA and BE derivatives and their in vitro anti-cancer activity results (reported as IC50 values) against HT29 human colon cancer cells in the present study. All derivatives share a common pentacyclic triterpenoid core and the molecules were split into three pieces by cutting at the C-3 and C-28 sites with a consideration toward structural diversity. The analysis gave a leave-one-out cross-validation q² value of 0.722 and a non-cross-validation r² value of 0.974, which suggested that the model has good predictive ability (q² > 0.2). The contour maps illustrated that bulky and electron-donating groups would be favorable for activity at the C-28 site, and a moderately bulky and electron-withdrawing group near the C-3 site would improve this activity. BE derivatives were designed and synthesized according to the modeling result, whereby bulky electronegative groups (maleyl, phthalyl, and hexahydrophthalyl groups) were directly introduced at the C-28 position of BE. The in vitro cytotoxicity values of the given analogs against HT29 cells were consistent with the predicted values, proving that the present topomer CoMFA model is successful and that it could potentially guide the synthesis of new betulinic acid derivatives with high anti-cancer activity. The IC50 values of these three new compounds were also assayed in five other tumor cell lines. 28-O-hexahydrophthalyl BE exhibited the greatest anti-cancer activities and its IC50 values were lower than those of BA in all cell lines, excluding DU145 cells.

Related physicochemical properties to microstructure of hard and soft wheat grains with different kernel thickness and specific density.

Physicochemical properties of wheat grains with largest kernel thickness always was lowest than the other sections, examination of microstructure of wheat grains can help us understand this phenomena. Two varieties of wheat, soft white winter wheat Yangmai 11 and hard white winter wheat Zhengmai 9023, were fractionated into five sections by kernel thickness. Then the fractionated wheat grains in 2.7-3.0 mm section were separated into three fractions by kernel specific density sequentially. Microstructure of the fractured surface were evaluated at different scale level to two varieties wheat with different kernel thickness and specific density by using environmental scanning electron microscopy. Compactness and size of endosperm cell tended to decrease with decreasing wheat kernel thickness and specific density. Protein matrix tended to increase with decreasing wheat kernel thickness and specific density. Size of starch granules and proportion for different type starch granules also varied with different wheat kernel thickness and specific density. Those microstructure properties of the fractured surface, formation of endosperm cells, protein matrix and starch granules were close related to rheological properties and pasting properties of wheat grains.

A multimodal fusion enabled ensemble approach for human activity recognition in smart homes.

How to deal with multi-modality data from different types of devices is a challenging issue for accurate recognition of human activities in a smart environment. In this paper, we propose a multimodal fusion enabled ensemble approach. Firstly, useful features collected from Bluetooth beacons, binary sensors, and smart floor are extracted and presented by fuzzy logic based-method with variable-size temporal windows. Secondly, a group of support vector machine classifiers are used to perform the classification task. Finally, a weighted ensemble method is used to obtain the final prediction. Especially, by applying the geometric framework, we are able to obtain the optimal weights for the ensemble. The proposed approach is evaluated on the UJAmI dataset. The experimental results demonstrate the efficacy and robustness of the proposed method.

UHRF1/DNMT1-MZF1 axis-modulated intragenic site-specific CpGI methylation confers divergent expression and opposing functions of PRSS3 isoforms in lung cancer.

As confusion mounts over RNA isoforms involved in phenotypic plasticity, aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity (ITH). Protease serine 3 (PRSS3), possessing four splice variants (PRSS3-SVs; PRSS3-V1-V4), is an indispensable trypsin that shows paradoxical effects on cancer development. Here, we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer, exhibiting opposing functions and clinical outcomes, namely, oncogenic PRSS3-V1 and PRSS3-V2 versus tumor-suppressive PRSS3-V3, by targeting different downstream genes. We identified an intragenic CpG island (iCpGI) in PRSS3. Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1 (MZF1) to regulate PRSS3 transcription. The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2'-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression. Epigenetic silencing of PRSS3-V3 via iCpGI methylation (iCpGIm) in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease. Thus, UHRF1/DNMT1-MZF1 axis-modulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs, conferring nongenetic functional ITH, with implications for early detection of lung cancer and targeted therapies.

Trans-Lesion Synthesis and Mismatch Repair Pathway Crosstalk Defines Chemoresistance and Hypermutation Mechanisms in Glioblastoma.

Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides a new aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define novel molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.

Trans-Lesion Synthesis and Mismatch Repair Pathway Crosstalk Defines Chemoresistance and Hypermutation Mechanisms in Glioblastoma.

Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides a new aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define novel molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.

Safety of vaginal delivery in women with placental chorioangiomas diagnosed by prenatal ultrasound: A retrospective cohort study.

This study aimed to examine the maternal and neonatal outcomes in different mode of delivery in pregnant women with placental chorioangiomas, in order to determine the safety of vaginal delivery. We conducted a retrospective study of 54 women with placental chorioangioma diagnosed by prenatal ultrasound and subsequently proven histologically, excluding those who underwent cesarean section for obstetric indications. The mode of delivery was divided into a vaginal delivery group (23 women) and a cesarean section group (31 women). The indication of cesarean section group was only for placental chorioangioma, no other obstetric indications. The maternal characteristics, pregnancy outcomes and the color doppler imaging characteristics of placental chorioangioma of the 2 groups were compared, and the clinical characteristics of women in the vaginal delivery group were described in detail. The incidence of placental chorioangioma was nearly 0.43‰ in our study. There was no significant difference in the maternal characteristics and pregnancy outcomes between the 2 groups. 82.6% (19/23) of the women successfully delivered vaginally and 4 failed who turned to cesarean section in the vaginal delivery group; among them, 17 women had giant chorioangiomas (>4 cm in diameter). The direct cause of vaginal delivery failure was fetal distress, persistent occiput posterior fetal position and cephalopelvic disproportion. Pregnant women with placental chorioangiomas and no other obstetric indications for cesarean section may attempt a vaginal delivery, even with giant chorioangiomas. If there are risk factors of vaginal delivery failure, the progress of labor needs to be closely monitored.

UBE3A deletion enhances the efficiency of immunotherapy in non-small-cell lung cancer.

Immunotherapy significantly improves the prognosis of advanced lung cancer. It has become an important treatment option for advanced lung cancer. However, there remain many limitations in clinical treatment, and only a small portion of patients can benefit from immunotherapy. Our study aimed to identify markers that can precisely forecast the efficacy of immunotherapy in patients. We analyzed a non-small-cell lung cancer (NSCLC) immune checkpoint inhibitor (ICI) cohort (n=240). We used this discovery cohort to identify CNVs in genes associated with immunotherapy. We further analyzed immune biomarkers and immune infiltration in The Cancer Genome Atlas (TCGA)-NSCLC cohort and the Gene Expression Omnibus (GEO) cohorts. By analyzing an ICI dataset from MSKCC, we found that progression-free survival (PFS) was improved after UBE3A deletion (UBE3A-del). The analysis results showed that UBE3A-del had higher immunocyte infiltration levels and higher expression levels of immune checkpoint biomarkers and affected the enrichment levels of immune signaling pathways. Our results suggest that UBE3A-del can be used as a predictive biomarker of NSCLC to screen for NSCLC patients who may benefit from ICI therapy. Abbreviations: NSCLC: Non-small cell lung cancer; CNV: Copy number variation; ICIs: Immune checkpoint inhibitors; TCGA: The cancer genome atlas; GEO: Gene expression omnibus; GSEA: Gene set enrichment; PFS: Progression-free survival; OS: Overall survival; TMB: Tumor mutational burden; CTLA-4: Cytotoxic T lymphocyte antigen 4; PD-(L)1: Programmed cell death (ligand) 1; MSI: Microsatellite instability; dMMR: DNA mismatch repair; SCNAs: Somatic copy number alterations; TME: Tumor microenvironment; MSK-IMPACT: The Memorial Sloan Kettering-Integrated Mutation Profilng of Actionable; Cancer Targets; FDA: Food and Drug Administration; WES: Whole-exome sequencing; SNP: Single Nucleotide Polymorphisms; FDR: False discovery rate; DCR: Disease control rate; DDR: DNA damage response and repair; MDSCs: Myeloid-derived suppressor cells; FAO: Fatty acid oxidation.

Pharmacological inhibition of Rac1 attenuates myocardial abnormalities in tail-suspended mice.

Microgravity conditions cause myocardial abnormalities with limited therapeutic approaches. We reported that NADPH oxidase-derived reactive oxygen species contribute to microgravity-induced myocardial abnormalities. This study investigated whether pharmacological inhibition of Rac1 protected the heart during microgravity. Simulated microgravity was induced by tail-suspension in mice. Tail-suspension for 28 days increased Rac1 activity in hearts, reduced heart weight and cross-sectional areas of cardiomyocytes, indicative of myocardial atrophy, and myocardial dysfunction. Administration of NSC23766, a selective inhibitor of Rac1, or atorvastatin reported to inhibit Rac1 activation, attenuated myocardial atrophy and preserved myocardial function in tail-suspended mice. These protective effects of Rac1 inhibition were associated with inhibition of NADPH oxidase activation and a reduction of oxidative stress. Our finding may inform a future clinical trial using atorvastatin to prevent myocardial abnormalities under microgravity conditions.

Rapid, accurate, and novel diagnostic technique for respiratory pathogens: Clinical application of loop-mediated isothermal amplification assay in older patients with pneumonia, a multicenter prospective observational study.

Background: Loop-mediated isothermal amplification (LAMP) is a novel nucleic acid amplification method using only one type of enzyme that can amplify DNA with high specificity, efficiency and rapidity under isothermal conditions. Chips for Complicated Infection Detection (CCID) is based on LAMP. This study translate CCID into clinical application and evaluate its diagnostic value for pneumonia. Methods: Eighty one older patients with pneumonia were prospectively enrolled from January 1 to July 23, 2021, and 57 sputum/airway secretion and 35 bronchoalveolar lavage fluid samples were collected and analyzed by CCID and conventional microbiological tests (CMTs). Samples were collected, transported, monitored, and managed by a multidisciplinary team using a sample management information system. Results: CCID turnaround time was 50 min, and the detection limit was 500 copies/reaction. The percentage of positive samples was significantly higher using CCID than CMTs, especially for Klebsiella pneumoniae (odds ratio [OR], 9.0; 95% confidence interval [CI], 1.1-70.5; p < 0.05), Enterococcus faecalis (OR, ∞; p < 0.01), Stenotrophomonas maltophilia (OR, ∞; p < 0.01), fungi (OR, 26.0; 95% CI, 3.6-190.0; p < 0.01), and viruses (CCID only; p < 0.01). In addition, the percentage of positive results was significantly higher using CCID than CMTs in patients who used antibiotics for more than 3 days (91.9% vs. 64.9%; p < 0.01). Analyzing clinical impact, 55 cases (59.8%) benefited from CCID. Conclusion: CCID allows the rapid and accurate detection of pneumonia in older patients. Moreover, this technique is less affected by previous antibiotic treatment and can improve patient care.