Using a new artificial intelligence-aided method to assess body composition CT segmentation in colorectal cancer patients.

INTRODUCTION: This study aimed to evaluate the accuracy of our own artificial intelligence (AI)-generated model to assess automated segmentation and quantification of body composition-derived computed tomography (CT) slices from the lumber (L3) region in colorectal cancer (CRC) patients. METHODS: A total of 541 axial CT slices at the L3 vertebra were retrospectively collected from 319 patients with CRC diagnosed during 2012-2019 at a single Australian tertiary institution, Western Health in Melbourne. A two-dimensional U-Net convolutional network was trained on 338 slices to segment muscle, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Manual reading of these same slices of muscle, VAT and SAT was created to serve as ground truth data. The Dice similarity coefficient was used to assess the U-Net-based segmentation performance on both a validation dataset (68 slices) and a test dataset (203 slices). The measurement of cross-sectional area and Hounsfield unit (HU) density of muscle, VAT and SAT were compared between two methods. RESULTS: The segmentation for muscle, VAT and SAT demonstrated excellent performance for both the validation (Dice similarity coefficients >0.98, respectively) and test (Dice similarity coefficients >0.97, respectively) datasets. There was a strong positive correlation between manual and AI segmentation measurements of body composition for both datasets (Spearman's correlation coefficients: 0.944-0.999, P < 0.001). CONCLUSIONS: Compared to the gold standard, this fully automated segmentation system exhibited a high accuracy for assessing segmentation and quantification of abdominal muscle and adipose tissues of CT slices at the L3 in CRC patients.

A case report of pediatric biliary botryoid rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children, and botryoid rhabdomyosarcoma (BRMS) represents a subtype of RMS. BRMS primarily occurs in infants, young children, and adolescent females, with a predilection for mucosa-lined hollow organs such as the bladder, vagina, bile duct, and so on. Its occurrence in the biliary tract is extremely rare. Due to the high malignancy and rapid metastasis of biliary botryoid rhabdomyosarcoma, early diagnosis and treatment are crucial for improving prognosis.

A Transvaginal Ultrasound-Based Deep Learning Model for the Noninvasive Diagnosis of Myometrial Invasion in Patients with Endometrial Cancer: Comparison with Radiologists.

RATIONALE AND OBJECTIVES: This study aimed to determine the feasibility of using the deep learning (DL) method to determine the degree (whether myometrial invasion [MI] >50%) of MI in patients with endometrial cancer (EC) based on ultrasound (US) images. MATERIALS AND METHODS: From September 2017 to April 2023, 1289 US images of 604 patients with EC who underwent surgical resection at center 1, center 2 or center 3 were obtained and divided into a training set and an internal validation set. Ninety-five patients from center 4 and center 5 were randomly selected as the external testing set according to the same criteria as those for the primary cohort. This study evaluated three DL models trained on the training set and tested them on the validation and testing sets. The models' performance was analyzed based on accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC), and the performance of the models was subsequently compared with that of 15 radiologists. RESULTS: In the final clinical diagnosis of MI in patients with EC, EfficientNet-B6 showed the best performance in the testing set in terms of area under the curve (AUC) [0.814, 95% CI (0.746-0.882]; accuracy [0.802, 95% CI (0.733-0.855]; sensitivity [0.623]; specificity [0.879]; positive likelihood ratio (PLR) [6.750]; and negative likelihood ratio (NLR) [0.389]. The diagnostic efficacy of EfficientNet-B6 was significantly better than that of the 15 radiologists, with an average diagnostic accuracy of 0.681, average AUC of 0.678, AUC of the best performance of 0.739, accuracy of 0.716, sensitivity of 0.806, specificity 0.672, PLR2.457, and NLR 0.289. CONCLUSION: Based on the preoperative US images of patients with EC, the DL model can accurately determine the degree of endometrial MI; the performance of this model is significantly better than that of radiologists, and it can effectively assist in clinical treatment decisions.

p38 MAPK involvement in the thermal stress response occurs via HSP27 and caspase3 in the large yellow croaker (Larimichthys crocea).

The p38 mitogen-activated protein kinase (p38 MAPK) is a multifunctional molecule that is involved in cellular response to various stressful stimuli. In the present study, the full-length cDNA sequence of p38 MAPK (Lcp38 MAPK) was identified from the large yellow croaker Larimichthys crocea, which encoded a polypeptide of 361 amino acid residues. The predicted Lcp38 MAPK protein contained a highly conserved Thr-Gly-Tyr (TGY) motif, a glutamate and aspartate (ED) site, a substrate binding site (Ala-Thr-Arg-Trp < ATRW>), and a serine/threonine kinase catalytic (S_TKc) domain characteristic of the MAPK family. The constitutive expression of Lcp38 MAPK was detected in most of the tissues examined with the strongest expression in intestine. Subcellular localization in LCK cells (kidney cell line from a L. crocea) revealed that Lcp38 MAPK existed in both the cytoplasm and cell nucleus. The expression of Lcp38 MAPK after temperature stress was tested in LCK cells. The results indicated that Lcp38 MAPK transcripts were significantly upregulated under both cold (10 °C) and heat stress (35 °C) (P < 0.05). Furthermore, the phosphorylation levels of p38 MAPK as well the transcriptional levels of heat shock protein 27 (HSP27) and caspase3 in LCK cells were significantly induced under thermal exposure (P < 0.05). However, the cold- and heat induced HSP27 and caspase3 expression was significantly suppressed by SB203580, a specific inhibitor of p38-MAPK (P < 0.05). These findings indicated that Lcp38 MAPK might be involved in the cellular stress response via HSP27 and caspase3 in large yellow croaker.

A novel ZIF-8@IL-MXene/poly (N-isopropylacrylamide) nanocomposite hydrogel toward multifunctional adsorption.

Phenols, dyes, and metal ions present in industrial wastewater can adversely affect the environment and leach biological carcinogens. Given that the current research focuses only on the removal of one or two of those categories. Herein, this work reports a novel ZIF-8@IL-MXene/Poly(N-isopropylacrylamide) (NIPAM) nanocomposite hydrogel that can efficiently and conveniently absorb and separate multiple pollutants from industrial wastewater. Ionic liquid (IL) was grafted onto MXene surfaces using a one-step method, and then incorporated into NIPAM monomer solutions to obtain the IL-MXene/PNIPAM composite hydrogel via in-situ polymerization. ZIF-8@IL-MXene/PNIPAM nanocomposite hydrogels were obtained by in-situ growth of ZIF-8 on the pore walls of composite hydrogels. As-prepared nanocomposite hydrogel showed excellent mechanical properties and can withstand ten repeated compressions without any damage, the specific surface area increased by 100 times, and the maximum adsorption capacities for p-nitrophenol (4-NP), crystal violet (CV), and copper ion (Cu2+) were 198.40, 325.03, and 285.65 mg g-1, respectively, at room temperature. The VPTTs of all hydrogels ranged from 33 to 35 °C, so the desorption process can be achieved in deionized water at 35-40 °C, and its adsorption capacities after five adsorption-desorption cycles decreased to 79%, 91%, and 29% for 4-NP, CV, and Cu2+, respectively. The adsorption data fitting results follow pseudo-second-order kinetics and Freundlich models, which is based on multiple interactions between the functional groups contained in hydrogels and adsorbent molecules. The hydrogel is the first to realize the high-efficiency adsorption of phenols, dyes and metal ions in industrial wastewater simultaneously, and the preparation process of hydrogels is environmentally friendly. Also, giving hydrogel multifunctional adsorption is beneficial to promote the development of multifunctional adsorption materials.

Cross-sectional network analysis of plasma proteins/metabolites correlated with pathogenesis and therapeutic response in acute promyelocytic leukemia.

The treatment of PML/RARA+ acute promyelocytic leukemia (APL) with all-trans-retinoic acid and arsenic trioxide (ATRA/ATO) has been recognized as a model for translational medicine research. Though an altered microenvironment is a general cancer hallmark, how APL blasts shape their plasma composition is poorly understood. Here, we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters, proteomes, and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy. Our study revealed the two prominent features of the APL plasma, suggesting a possible involvement of APL blasts in modulating plasma composition. One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts, and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA. Furthermore, results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage, which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins. Overall, our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.

The effect of early oral nutritional supplements on improving nutritional outcomes and radiation-induced oral mucositis for nasopharyngeal carcinoma patients undergoing concurrent chemoradiotherapy.

BACKGROUND: To explore the value of early oral nutritional supplements (ONS) in patients with nasopharyngeal carcinoma (NPC) treated with concurrent chemoradiotherapy (CCRT). METHODS: Patients with newly diagnosed II-IVA stage NPC were analyzed and divided into Early and Routine ONS groups according to whether they received early ONS at the beginning of CCRT. Changes in nutritional indicators, incidence of treatment-related toxicity, radiation interruption, and completion of CCRT were compared. RESULTS: In total, 161 patients with NPC were analyzed, including 72 in the Early ONS group and 89 in the Routine ONS group. Multivariate analysis showed that early ONS was an independent protective factor for concurrent chemotherapy ≥2 cycles, and a protective factor against ≥grade 3 radiation-induced oral mucositis (RIOM) and weight loss >5%. In stage III-IVA patients, early ONS was beneficial in decreasing the risk of severe malnutrition. CONCLUSIONS: Early ONS can improve nutritional outcomes, reduce RIOM, and enhance treatment adherence.

Prediction of Prognosis, Immunotherapy and Chemotherapy with an Immune-Related Risk Score Model for Endometrial Cancer.

Endometrial cancer (EC) is the most common gynecologic cancer. The overall survival remains unsatisfying due to the lack of effective treatment screening approaches. Immunotherapy as a promising therapy has been applied for EC treatment, but still fails in many cases. Therefore, there is a strong need to optimize the screening approach for clinical treatment. In this study, we employed co-expression network (GCN) analysis to mine immune-related GCN modules and key genes and further constructed an immune-related risk score model (IRSM). The IRSM was proved effective as an independent predictor of poor prognosis. The roles of IRSM-related genes in EC were confirmed by IHC. The molecular basis, tumor immune microenvironment and clinical characteristics of the IRSM were revealed. Moreover, the IRSM effectiveness was associated with immunotherapy and chemotherapy. Patients in the low-risk group were more sensitive to immunotherapy and chemotherapy than those in the high-risk group. Interestingly, the patients responding to immunotherapy were also more sensitive to chemotherapy. Overall, we developed an IRSM which could be used to predict the prognosis, immunotherapy response and chemotherapy sensitivity of EC patients. Our analysis not only improves the treatment of EC but also offers targets for personalized therapeutic interventions.

Allele-specific gene-editing approach for vision loss restoration in RHO-associated retinitis pigmentosa.

Mutant RHO is the most frequent genetic cause of autosomal dominant retinitis pigmentosa (adRP). Here, we developed an allele-specific gene-editing therapeutic drug to selectively target the human T17M RHO mutant allele while leaving the wild-type RHO allele intact for the first time. We identified a Staphylococcus aureus Cas9 (SaCas9) guide RNA that was highly active and specific to the human T17M RHO allele. In vitro experiments using HEK293T cells and patient-specific induced pluripotent stem cells (iPSCs) demonstrated active nuclease activity and high specificity. Subretinal delivery of a single adeno-associated virus serotype 2/8 packaging SaCas9 and single guide RNA (sgRNA) to the retinas of the RHO humanized mice showed that this therapeutic drug targeted the mutant allele selectively, thereby downregulating the mutant RHO mRNA expression. Administration of this therapeutic drug resulted in a long-term (up to 11 months after treatment) improvement of retinal function and preservation of photoreceptors in the heterozygous mutant humanized mice. Our study demonstrated a dose-dependent therapeutic effect in vivo. Unwanted off-target effects were not observed at the whole-genome sequencing level. Our study provides strong support for the further development of this effective therapeutic drug to treat RHO-T17M-associated adRP, also offers a generalizable framework for developing gene-editing medicine. Furthermore, our success in restoring the vision loss in the suffering RHO humanized mice verifies the feasibility of allele-specific CRISPR/Cas9-based medicines for other autosomal dominant inherited retinal dystrophies.

Can sarcopenia predict survival in locally advanced rectal cancer patients?

BACKGROUND: There is mounting evidence that suggests sarcopenia can be used to predict survival outcomes in patients with colon cancer. However, the effect on locally advanced rectal cancer (LARC) is less clear. We sought to determine the association between sarcopenia on Overall Survival and Recurrence-free Survival (OS and RFS) in patients with LARC undergoing multimodal treatment. METHODS: A retrospective study was undertaken of all pre-treatment stage 2-3 rectal cancer patients who underwent neo-adjuvant treatment and surgery with curative intent between January 2010 and September 2016 at Western Health. Sarcopenia was measured on pre-treatment staging scans at the third lumbar vertebrae and defined using cohort-derived, sex-specific thresholds. Primary outcomes were OS and RFS. RESULTS: A total of 132 patients with LARC were analysed. Sarcopenia: Hazard ratio (HR) 3.71; 95% CI, 1.28-10.75, P = 0.016 was independently associated with worse Overall Survival following multivariate analysis. There was no significant relationship between sarcopenia and RFS: Time ratio (TR) 1.67; 95% CI 0.52-5.34, P = 0.386. CONCLUSION: Sarcopenia was found to be an independent risk factor for worse overall survival, but not recurrence free survival, in patients with locally advanced rectal cancer undergoing neo-adjuvant chemo-radiotherapy and surgery with curative intent.

Isolated aberrant right subclavian artery: an underlying clue for genetic anomalies.

OBJECTIVE: Aberrant right subclavian artery (ARSA) is known to be associated with specific chromosomal abnormalities. However, there is no agreement regarding clinical decisions related to isolated ARSA. This study evaluated the association between ARSA and genetic abnormalities to provide evidence for prenatal consultation and the postpartum management of isolated ARSA. METHODS: This single-center cross-sectional study involved fetuses diagnosed with ARSA between January 2014 and May 2021. A range of data was recorded for each patient, including screening ultrasound, fetal echocardiograms, genetic results, postnatal information, and follow-up records. RESULTS: ARSA was detected in 151 fetuses, of which 136 were considered isolated cases. The remaining 9.9% (15/151) of cases had cardiac and/or extracardiac abnormalities or soft markers. Data from karyotype analysis and chromosomal microarray analysis (CMA) were available for 56 and 33 (out of 56) fetuses, respectively. Genetic abnormalities were detected in 10.7% of fetuses (6/56). Of these, 4.4% (2/45) and 36.4% (4/11) were associated with isolated and non-isolated ARSA, respectively, with a significant difference between these two groups regarding the frequency of genetic abnormality (p = 0.011). The analysis detected Klinefelter Syndrome (47, XXY) and 16p11.2 microdeletion in two isolated cases. One case each of trisomy 21 and 22q11.2 deletion, and another case of 47, XXY, were detected in fetuses with cardiac anomalies. Partial 5q deletion was found in a fetus with extracardiac malformations. In total, 141 of the fetuses survived after birth; termination of pregnancy was performed for 10 fetuses; only two fetuses had mild symptoms of dysphagia. CONCLUSION: ARSA may be an underlying ultrasonic clue for genetic anomalies even in isolated ARSA. Fetuses with isolated ARSA cannot be ruled out for invasive antenatal diagnosis.

Comparison of CT derived body composition at the thoracic T4 and T12 with lumbar L3 vertebral levels and their utility in patients with rectal cancer.

BACKGROUND: Computed tomography (CT) derived body composition measurements of sarcopenia are an emerging form of prognostication in many disease processes. Although the L3 vertebral level is commonly used to measure skeletal muscle mass, other studies have suggested the utilisation of other segments. This study was performed to assess the variation and reproducibility of skeletal muscle mass at vertebral levels T4, T12 and L3 in pre-operative rectal cancer patients. If thoracic measurements were equivalent to those at L3, it will allow for body composition comparisons in a larger range of cancers where lumbar CT images are not routinely measured. RESEARCH METHODS: Patients with stage I - III rectal cancer, undergoing curative resection from 2010 - 2014, were assessed. CT based quantification of skeletal muscle was used to determine skeletal muscle cross sectional area (CSA) and skeletal muscle index (SMI). Systematic differences between the measurements at L3 with T4 and T12 vertebral levels were evaluated by percentile rank differences to assess distribution of differences and ordinary least product regression (OLP) to detect and distinguish fixed and proportional bias. RESULTS: Eighty eligible adult patients were included. Distribution of differences between T12 SMI and L3 SMI were more marked than differences between T4 SMI and L3 SMI. There was no fix or proportional bias with T4 SMI, but proportional bias was detected with T12 SMI measurements. T4 CSA duplicate measurements had higher test-retest reliability: coefficient of repeatability was 34.10 cm2 for T4 CSA vs 76.00 cm2 for T12 CSA. Annotation time (minutes) with L3 as reference, the median difference was 0.85 for T4 measurements and -0.03 for T12 measurements. Thirty-seven patients (46%) had evidence of sarcopenia at the L3 vertebral level, with males exhibiting higher rates of sarcopenia. However, there was no association between sarcopenia and post-operative complications, recurrence or hospital LOS (length of stay) in patients undergoing curative resection. CONCLUSIONS: Quantifying skeletal muscle mass at the T4 vertebral level is comparable to measures achieved at L3 in patients with rectal cancer, notwithstanding annotation time for T4 measurements are longer.

Three-dimensional porous manganese oxide/nickel/carbon microspheres as high-performance electromagnetic wave absorbers with superb photothermal property.

Regulating electromagnetic parameters and thus improving impedance matching characteristics by multi-component design is regarded as a prospective approach to obtain highly efficient electromagnetic wave absorption materials. Whereas, it is still challenging to fabricate microwave absorbers with strong absorption capacity and durability in harsh conditions. Based on the above considerations, three-dimensional porous multi-functional manganese oxide/nickel/carbon microspheres had been designed and prepared through a combined approach of facile solvothermal reactions and subsequent carbonization processes. The textural characteristic examinations demonstrated that, numerous manganese oxide and Ni nanoparticles of 15-20 nm in diameter were well dispersed in the carbon-based microspheres of approximately 0.8-1 µm in size. Microwave absorption property evaluation indicated that the minimum reflection loss reached up to -53.6 dB at 9.5 GHz, and effective absorption bandwidth of 3.7 GHz was achieved at matching thickness of merely 2.0 mm. The electromagnetic wave attenuation mechanisms analysis displayed that excellent impedance matching and various dissipation pathways, including magnetic loss, interfacial and dipole polarization relaxation synergistically contributed to the high microwave absorption performances of the porous composites. Radar cross-sectional simulation and photothermal measurements verified that the materials were supposed to have promising foregrounds in complicated circumstances.

Neuregulin-1/ErbB4 upregulates acetylcholine receptors via Akt/mTOR/p70S6K: a study in a rat model of obstetric brachial plexus palsy and in vitro.

In obstetric brachial plexus palsy (OBPP), the operative time window for nerve reconstruction of the intrinsic muscles of the hand (IMH) is much shorter than that of biceps. The reason is that the atrophy of IMH becomes irreversible more quickly than that of biceps. A previous study confirmed that the motor endplates of denervated intrinsic muscles of the forepaw (IMF) were destabilized, while those of denervated biceps remained intact. However, the specific molecular mechanism of regulating the self-repair of motor endplates is still unknown. In this study, we use a rat model of OBPP with right C5-C6 rupture plus C7-C8-T1 avulsion and left side as a control. Bilateral IMF and biceps are harvested at 5 weeks postinjury to assess relative protein and mRNA expression. We also use L6 skeletal myoblasts to verify the effects of signaling pathways regulating acetylcholine receptor (AChR) protein synthesis in vitro. The results show that in the OBPP rat model, the protein and mRNA expression levels of NRG-1/ErbB4 and phosphorylation of Akt/mTOR/p70S6K are lower in denervated IMF than in denervated biceps. In L6 myoblasts stimulated with NRG-1, overexpression and knockdown of ErbB4 lead to upregulation and downregulation of AChR subunit protein synthesis and Akt/mTOR/p70S6K phosphorylation, respectively. Inhibition of mTOR abolishes protein synthesis of AChR subunits elevated by NRG-1/ErbB4. Our findings suggest that in the OBPP rat model, lower expression of AChR subunits in the motor endplates of denervated IMF is associated with downregulation of NRG-1/ErbB4 and phosphorylation of Akt/mTOR/p70S6K. NRG-1/ErbB4 can promote protein synthesis of the AChR subunits in L6 myoblasts via phosphorylation of Akt/mTOR/p70S6K.

[Mitochondrial calcium uniporter knockdown in hippocampal neurons improved the learning and memory dysfunction of Alzheimer's disease mice].

Alzheimer's disease (AD) is a neurodegenerative disorder, which seriously affects health of the elderly, and is still irreversible up to now. Recent studies have indicated that mitochondrial dysfunction is a direct reason to promote the development of AD. Mitochondrial calcium uniporter (MCU), located in the inner membrane of mitochondria, is a key channel of mitochondrial Ca2+ uptake. Abnormal MCU expression results in imbalance of mitochondrial calcium homeostasis, ultimately leading to mitochondrial dysfunction. The purpose of this study was to determine the effects of MCU knockdown on AD hippocampal neurons and learning and memory function of AD model mice. Lentivirus and adeno-associated virus were used as vectors to transfect shRNA into hippocampal neurons (HT22 cells) and hippocampi of amyloid precursor protein (APP)/presenilin 1 (PS1)/tau AD transgenic mice, respectively, in order to interfere with MCU expression. The cellular activity of HT22 cells was detected by MTS method, and the changes of learning and memory dysfunction in APP/PS1/tau AD transgenic mice were tested by Y maze and Morris water maze. The results showed that MCU knockdown reversed the cellular activity of HT22 cells decreased by amyloid beta protein 1-42 (Aß1-42) or okadaic acid (OA). Knockdown of MCU in hippocampal neurons improved spontaneous alternation (spatial working memory), decreased escape latency, and increased time in target quadrant and number of platform crossing (spatial reference memory) of the APP/PS1/tau mice. This study suggests that MCU knockdown in hippocampal neurons has anti-AD effect, and it is expected to be a new strategy for prevention and treatment of AD.

Fabrication of PEBA/HZIF-8 Pervaporation Membranes for High Efficiency Phenol Recovery.

Phenol and its chemical derivatives serve as essential chemical materials are indispensable for the synthesis of many kinds of polymers. However, they are highly toxic, carcinogenic, difficult to be degraded biologically, and often found in aqueous effluents. Recovery of hazardous phenol from wastewater remains a daunting challenge. Herein, we prepared a hybrid membrane containing polyether block amide (PEBA) matrix and HZIF-8 fillers. To improve the compatibility between ZIF-8 and PEBA, ZIF-8 was modified by using polystyrene (PS) as a template to prepare porous HZIF-8. ZIF-8, composed of zinc nodes linked by the imidazole ring skeleton, is a kind of inorganic material with high hydrothermal stability, ordered pores, and hydrophobic microporous surfaces, which has a wide range of applications in membrane separation. The separation performance of the PEBA/HZIF-8 based membranes for phenol/water is improved due to the presence of PS on the surface of HZIF-8 and the imidazole ring skeleton in ZIF-8, which enhance the π-π interaction between HZIF-8 and phenol molecules. The effects of HZIF-8 content, feed phenol concentration, and feed temperature on the pervaporation performance of PEBA/HZIF-8 membranes were further investigated. The results showed that the pervaporation performance of the PEBA/HZIF-8-10 membrane was promising with a separation factor of 80.89 and permeate flux of 247.70 g/m2·h under the feed phenol concentration of 0.2 wt % at 80 °C. In addition, the PEBA/HZIF-8-10 membrane presented excellent stability, which has great prospect for practical application in phenol recovery from waste water.

A new quantitative method for pseudouridine and uridine in human serum and its clinical application in acute myeloid leukemia.

Pseudouridine, a C-C glycosidic isomer of uridine, is derived from uridine via isomerization, and pseudouridylation is the most common post-transcriptional modification. Our previous study shows pseudouridine may serve an important role in acute myeloid leukemia (AML). The clinical value of pseudouridine and uridine is hampered by the lack of a quantitative methods with high sensitivity, specificity, and stability. Here, we established a supercritical fluid chromatography-tandem triple quadrupole mass spectrometry (SFC-TQ-MS)-based method to quantitate serum pseudouridine and uridine simultaneously. The procedure involves protein precipitation of sample, extraction with solid phase extraction (SPE) plate, 5-min SFC separation by applying gradient elution on a Acquity UPC2 Torus DIOL column, and analysis by TQ-MS using well-characterized calibration standards. After validation, the method was used to measure pseudouridine and uridine concentrations in 143 serum samples from healthy controls (HCs) and AML patients to evaluate their prognostic potential. The successfully validated assay had a linear range of 5-5000 ng/mL, accuracies between 97 % and 102 %, and intra- and inter-assay imprecision <10 %. Compared to HCs, pseudouridine was raised significantly, while uridine was curtailed severely in patients with AML. With a median concentration of 671.4 ng/mL as the prognostic cut-off value, high level pseudouridine independently predicted poor survival of AML patients. Quantification of serum pseudouridine and uridine by SFC-TQ-MS provides an analytically sensitive and reproducible method for clinical diagnosis, and high concentration of pseudouridine is an independent prognostic factor for patients with AML.

Theacrine ameliorates experimental liver fibrosis in rats by lowering cholesterol storage via activation of the Sirtuin 3-farnesoid X receptor signaling pathway.

Formulations against liver fibrosis (LF) mitigate the progression of hepatitis to cirrhosis. However, notable toxicity of the currently available anti-LF drugs limits their long-term use. In the study, we aimed to investigate the anti-LF effects of theacrine, a purine alkaloid without obvious toxicity, on high-fat diet-, alcohol-, and carbon tetrachloride-induced LF in rats. The results indicated that 10 and 20 mg/kg of theacrine ameliorated hepatic fibrosis, steatosis, and inflammation in LF rats. Mechanistically, theacrine reduced hepatic stellate cell (HSC)-related α-smooth muscle actin expression, and decreased cholesterol accumulation, followed by decreased expression of transforming growth factor-ß1, interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α. In addition, theacrine upregulated the phosphorylation of AMP-activated protein kinase, accompanied by decreased expression of ß-catenin and stearoyl-CoA desaturase 1, and increased the expression of sirtuin 3 (SIRT3). Further investigation revealed that the theacrine-mediated decrease in cholesterol was independent of cholesterol synthesis or low-density lipoprotein (LDL) uptake in hyperlipidemia mice. However, theacrine activated farnesoid X receptor (FXR), a ß-catenin conjugated protein, accompanied with decreased expression of cholesterol 7α-hydroxylase and sterol 12α-hydroxylase. In conclusion, theacrine alleviated experimental LF in rats by lowering cholesterol storage and decreasing cholesterol-related HSC activation. A plausible mechanism of theacrine on cholesterol metabolism may involve activation of SIRT3-FXR signaling pathway followed by decreased intestinal cholesterol absorption.

Fetal growth restriction impairs hippocampal neurogenesis and cognition via Tet1 in offspring.

Fetal growth restriction (FGR) increases the risk for impaired cognitive function later in life. However, the precise mechanisms remain elusive. Using dexamethasone-induced FGR and protein restriction-influenced FGR mouse models, we observe learning and memory deficits in adult FGR offspring. FGR induces decreased hippocampal neurogenesis from the early post-natal period to adulthood by reducing the proliferation of neural stem cells (NSCs). We further find a persistent decrease of Tet1 expression in hippocampal NSCs of FGR mice. Mechanistically, Tet1 downregulation results in hypermethylation of the Dll3 and Notch1 promoters and inhibition of Notch signaling, leading to reduced NSC proliferation. Overexpression of Tet1 activates Notch signaling, offsets the decline in neurogenesis, and enhances learning and memory abilities in FGR offspring. Our data indicate that a long-term decrease in Tet1/Notch signaling in hippocampal NSCs contributes to impaired neurogenesis following FGR and could serve as potential targets for the intervention of FGR-related cognitive disorders.

Effect of Microstructure on the Dimensional Stability of Extruded Pure Aluminum.

High-performance extruded aluminum alloys with complex textures suffer significant dimension variation under environmental temperature fluctuations, dramatically decreasing the precision of navigation systems. This research mainly focuses on the effect of the texture of extruded pure aluminum on its dimensional stability after various annealing processes. The result reveals that a significant increment in the area fraction of recrystallized grains with <100> orientation and a decrement in the area fraction of grains with <111> orientation were found with increasing annealing temperature. Moreover, with the annealing temperature increasing from 150 °C to 400 °C, the residual plastic strain after twelve thermal cycles with a temperature range of 120 °C was changed from -1.6 × 10-5 to -4.5 × 10-5. The large amount of equiaxed grains with <100> orientation was formed in the microstructure of the extruded pure aluminum and the average grain size was decreased during thermal cycling. The area fraction of grain with <100> crystallographic orientation of the sample annealed at 400 °C after thermal cycling was 30.9% higher than annealed at 350 °C (23.7%) or at 150 °C (18.7%). It is attributed to the increase in the proportion of recrystallization grains with <100> direction as the annealing temperature increases, provided more nucleation sites for the formation of fine equiaxed grains with <100> orientation. The main orientation of the texture was rotated from parallel to <111> to parallel to <100> after thermal cycling. The change in the orientation of grains contributed to a change in interplanar spacing, which explains the change in the dimension along the extrusion direction during thermal cycling.