Melatonin suppresses TLR4-mediated RSV infection in the central nervous cells by inhibiting NLRP3 inflammasome formation and autophagy.

Respiratory syncytial virus (RSV) infects neuronal cells in the central nervous system (CNS), resulting in neurological symptoms. In the present study, we intended to explore the mechanism of RSV infection-induced neuroinflammatory injury from the perspective of the immune response and sought to identify effective protective measures against the injury. The findings showed that toll-like receptor 4 (TLR4) was activated after RSV infection in human neuronal SY5Y cells. Furthermore, TLR4 activation induced autophagy and apoptosis in neuronal cells, promoted the formation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, and increased the secretion of downstream inflammatory cytokines such as interleukin-1ß (IL-1ß), interleukin-18 (IL-18) and tumour necrosis factor-α (TNF-α). Interestingly, blockade of TLR4 or treatment with exogenous melatonin significantly suppressed TLR4 activation as well as TLR4-mediated apoptosis, autophagy and immune responses. Therefore, we infer that melatonin may act on the TLR4 to ameliorate RSV-induced neuronal injury, which provides a new therapeutic target for RSV infection.

The associations between prenatal phthalate exposure and childhood glycolipid metabolism and blood pressure: An updated systematic review and a pilot meta-analysis of prospective cohort studies.

This is the first pilot meta-analysis on the association of prenatal phthalate exposure with childhood cardiometabolic risks. A systematic literature search was performed in MEDLINE, Web of Science and CNKI (Chinese National Knowledge Infrastructure) until June 5, 2023. A total of seven studies with 5746 children (2646 girls and 3100 boys) were finally included. Four, three and two studies investigated the effects of maternal phthalate exposure on childhood blood pressure (BP), blood lipids and blood glucose profiles, respectively. The pilot meta-analysis suggested that di-2-ethylhexyl phthalate (DEHP) metabolite exposure was associated with a decrease in childhood z-systolic BP (SBP, ß = -0.169, 95% CI = -0.338-0.001). Furthermore, the pooled results showed negative relationships of prenatal ∑DEHP exposure with z-SBP (ß = -0.109, 95% CI = -0.163 to -0.055) and z-diastolic BP (DBP, ß = -0.126, 95% CI = -0.182 to -0.069) in girls. In addition, MEP exposure was associated with z-SBP in girls (ß = -0.227, 95% CI = -0.387 to -0.066). The pooled result showed a positive relationship between prenatal ∑DEHP exposure and triglycerides (ß = 0.103, 95% CI = 0.028-0.178). The overall results revealed that exposure to ∑DEHP throughout gestation was associated with a decrease in insulin (ß = -0.074, 95% CI = -0.144 to -0.004) and glucose (ß = -0.129, 95% CI = -0.199 to -0.058) in boys. Interestingly, there was an inverse relationship of prenatal mono- 3 -carboxypropyl phthalate (MCPP) exposure with glucose in pubertal boys (ß = -3.749, 95% CIs = -6.758 to -0.741) but not found in postpubertal children. In conclusion, prenatal phthalate exposure interfered with cardiovascular risk in children with gender-specific differences and was influenced by puberty. Overall, prenatal ∑DEHP was negatively associated with systolic blood pressure in girls and with insulin and glucose in boys but increased the level of triglycerides.

Absolute Quantification of Acylcarnitines Using Integrated Tmt-PP Derivatization-Based LC-MS/MS and Quantitative Analysis of Multi-Components by a Single Marker Strategy.

Acylcarnitines (ACs) play important roles in the fatty acid ß-oxidation and are considered as diagnostic markers for many diseases. Accurate determination of ACs remains challenging due to their low abundance, high structure diversity, and limited availability of standard compounds. In this study, microwave-assisted Tmt-PP (p-[3,5-(dimethylamino)-2,4,6-triazine] benzene-1-sulfonyl piperazine) derivatization was utilized to facilitate the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) determination of ACs. The result indicated that Tmt-PP labeling enables the prediction of the retention time and MS response of ACs and enhances their MS response up to 4 times. The introduction of the microwave during the derivatization procedure greatly improved the reaction efficiency, demonstrated by the shortened reaction time from 90 to 1 min. Furthermore, we applied a strategy named quantitative analysis of multi-components by a single marker (QAMS) for the assay of 26 ACs with only 5 AC standards, solving the standard availability issue to a large extent. The established workflow was applied to discover dysregulated ACs in xenograft colon cancer mice, and the quantification results were highly comparable with traditional methods where there were the corresponding standards for each AC. Our study demonstrated that chemical derivatization-based LC-MS/MS integrated with the QAMS strategy is robust for the identification and quantification of ACs and has great potential in targeted metabolomics study.

Restoring mitochondrial function and normalizing ROS-JNK/MAPK pathway exert key roles in glutamine ameliorating bisphenol A-induced intestinal injury.

Bisphenol A (BPA) is toxic to the reproductive and nervous system, even carcinogenetic in humans and animals. However, few studies focused on effects of BPA on the intestinal tract. Here, we detected BPA-induced injuries on intestinal mucosa and explored a reliable approach to counteract BPA effects. C57BL/6J mice were gavage BPA or BPA accompanied with ingestion of 4% (w/w) of glutamine for 4-wks. In vitro, IEC-6 cells were treated with 0.4 mmol/L BPA for 6 hours mimicking acute injury and 0.2 mmol/L BPA for 12 hours followed with or without the inclusion of 4 mmol/L glutamine for 12 hours to determine cell renewal, mitochondrial function and ROS-JNK/MAPK pathway upon moderate BPA exposure. As results, BPA exposure caused severe intestinal injury, and disturbed intestinal epithelial cell proliferation and apoptosis, accompanied with mitochondrial malfunction and activated JNK/MAPK pathway as well. Notably, glutathione metabolism was implicated in BPA-induce injury. Glutamine could well rescue cell renewal and mitochondrial function from BPA exposure-induced injuries. In conclusion, we demonstrated impaired effect of BPA exposure on intestinal functions, which could be well counteracted by glutamine partly via restoring mitochondrial function and normalizing ROS-JNK/MAPK pathway. Thereby, we provided a novel application of glutamine to rescue intestinal injury.

Dynamic membrane proteome of adipogenic and myogenic precursors in skeletal muscle highlights EPHA2 may promote myogenic differentiation through ERK signaling.

The balance of myogenic and adipogenic differentiation is crucial for skeletal muscle homeostasis. Given the vital role of membrane proteins (MBPs) in cell signal perception, membrane proteomics was conducted to delineate mechanisms regulating differentiation of adipogenic and myogenic precursors in skeletal muscle. Adipogenic and myogenic precursors with divergent differentiation potential were isolated from the longissimus dorsi muscle of neonatal pigs by the preplate method. A total of 85 differentially expressed MBPs ( P < 0.05 and fold change ≥1.2 or ≤0.83) between 2 precursors were detected via isobaric tags for relative and absolute quantitation (iTRAQ) assay, including 67 up-regulated and 18 down-regulated in myogenic precursors. Functional enrichment analysis uncovered that myogenic and adipogenic precursors showed significant differences in cytoskeleton organization, syncytium formation, environmental information processing, and organismal systems. Furthermore, key MBPs in regulating cell differentiation were also characterized, including ITGB3, ITGAV, ITPR3, and EPHA2. Noteworthily, EPHA2 was required for myogenic differentiation, and it may promote myogenic differentiation through ERK signaling. Collectively, our study provided an insight into the distinct MBP profile between myogenic and adipogenic precursors in skeletal muscle and served as a solid basis for supporting the role of MBPs in regulating differentiation.-Zhang, X., Wang, L., Qiu, K., Xu, D., Yin, J. Dynamic membrane proteome of adipogenic and myogenic precursors in skeletal muscle highlights EPHA2 may promote myogenic differentiation through ERK signaling.

Protein Expression Landscape Defines the Differentiation Potential Specificity of Adipogenic and Myogenic Precursors in the Skeletal Muscle.

The balance of adipogenic and myogenic differentiation of skeletal muscle-derived mesenchymal stem cells is particularly important in muscle development and intramuscular fat deposition. This study aimed to explore the differential regulation between adipogenic and myogenic precursors by comparative analysis of their global proteome expression profile. Adipogenic and myogenic precursors isolated from neonatal porcine longissimus dorsi muscle by the preplate method were verified for their unique and distinct differentiation potential under myogenic or adipogenic induction. A total of 433 differentially expressed proteins (DEP) ( P < 0.05 and FC > 1.20 or <0.83) between adipogenic and myogenic precursors were detected via a tandem mass tag (TMT)-coupled LC-MS/MS approach, including 339 up-regulated and 94 down-regulated proteins in myogenic precursors compared with adipogenic precursors. On the basis of functional annotation and enrichment analysis of 433 DEP, adipogenic and myogenic precursors showed significantly different metabolic pattern of energy substances and differential regulations of gene expression, cell structure and development, ion homeostasis, and cell motility and migration. Three pathways including PPAR signaling pathway, phosphatidylinositol signaling system, and autophagy signaling pathway, which was differentially regulated between adipogenic and myogenic precursors, was also discovered to play crucial roles in cell differentiation. In conclusion, these differentiated regulation patterns between the two cell subsets of mesenchymal precursors together defines their differentiation potential specificity.

[Clinical features and hospital costs of neonatal sepsis caused by bacteria and fungi: a comparative analysis].

OBJECTIVE: To study the clinical features and hospital costs of neonatal sepsis caused by Gram-positive (G(+)) bacteria, Gram-negative (G(-)) bacteria, and fungi. METHODS: The clinical data of 236 neonates with sepsis were analyzed retrospectively. Among these neonates, 110 had sepsis caused by G(+) bacteria, 68 had sepsis caused by G(-) bacteria, and 58 had sepsis caused by fungi. RESULTS: Full-term infants accounted for 62% and 38%, respectively, in the G(+) bacteria and G(-) bacteria groups, and preterm infants accounted for 86% in the fungi group. The neonates in the fungi group had significantly lower gestational ages and birth weights than those in the G(+) and G(-) bacteria groups (P<0.05). Compared with the G(+) bacteria group, the G(-) bacteria and fungi groups had significantly higher rates of multiple births (P<0.0125). Compared with the G(+) bacteria and fungi groups, the rates of premature rupture of membranes >18 hours, grade III amniotic fluid contamination, and early-onset sepsis in the G(-) bacteria group were significantly higher (P<0.0125). Compared with the G(-) bacteria and fungi groups, the G(+) bacteria group showed significantly higher rates of abnormal body temperature, omphalitis or herpes as the symptom suggesting the onset of such disease (P<0.0125). The fungi group had significantly higher incidence rates of apnea and low platelet count than the G(+) and G(-) bacteria groups (P<0.0125). The comparison of length of hospital stay and total hospital costs between any two groups showed that the fungi group had a significantly longer hospital stay and significantly higher total hospital costs than the G(+) and G(-) bacteria groups (P<0.05). CONCLUSIONS: Sepsis caused by G(+) bacteria mainly occurs in full-term infants, and most cases of sepsis caused by G(-) bacteria belong to the early-onset type. Sepsis caused by fungi is more common in preterm infants and low birth weight infants, and has high incidence rates of apnea and low platelet count, as well as a longer hospital stay and higher hospital costs than sepsis caused by bacteria.

Synthesis and inclusion study of a novel γ-cyclodextrin derivative as a potential thermo-sensitive carrier for doxorubicin.

A novel γ-cyclodextrin (γ-CD) based carrier for molecular encapsulation of cancer chemotherapeutic agent doxorubicin (DOX) was synthesized and fully characterized by various analytical approaches. The γ-CD derivative, with a ß-naphthyl alanine residue attached in its primary face, exhibits potent binding capacity with DOX. The encapsulation efficiency was assessed under various temperatures and pHs and it was demonstrated that the carrier-DOX inclusion complex is highly stable under a wide range of acidic conditions (pH 1.0-7.0); however, the encapsulated drug is slowly released under hyperthermic conditions (up to 50°C). Cell culture studies showed that the complexation of DOX with the carrier protected the drug from being uptaken by the cells and also greatly reduced its toxicity. Thermo-triggered DOX release was validated and the increase in cellular uptake was observed in in-vitro experiments. We concluded that this novel γ-CD derivative is able to effectively encapsulate DOX and the inclusion is responsive to temperature change, hence renders it a potential encapsulating agent for DOX delivery in combination with hyperthermia treatments.

Advancing necrotizing enterocolitis prediction through iterative monitoring.

Background: Necrotizing enterocolitis (NEC) is a severe inflammatory intestinal disease in preterm infants, marked by heightened morbidity and mortality. Timely prediction of NEC is significant in the management of critical neonates. However, it is difficult to predict NEC accurately because of the multi-factorial pathogenesis. This study aimed to develop a prediction model through repeated measurement data to further improve the accuracy of prediction in NEC. Methods: We retrospectively collected clinical data of premature infants admitted to the Neonatology Department of the First Affiliated Hospital of Anhui Medical University from January 2016 to December 2023. The infants were categorized into the NEC group (Bell's stage ≥ II) (n=150) and the non-NEC group (n=150). The clinical baseline data of the NEC and non-NEC groups were matched. Laboratory examination indicators were collected on the 1st day, the 7th day after birth, and the day of NEC onset. Univariate and multivariate logistic regression analyses were conducted to identify independent factors influencing NEC. A nomogram was constructed based on these factors to predict NEC. The concordance index and calibration plot were used to assess the efficiency of the nomogram in the training and validation cohorts. Results: This study demonstrated that antenatal steroids, antenatal antibiotics, probiotics treatment before NEC, anion gap (AG, day 7), and mean corpuscular volume (MCV, day 7) were independent risk factors which combined to accurately predict NEC. A nomogram of NEC was created utilizing these five predictors. With an area under the receiver operator characteristic (ROC) curve of 0.835 [95% confidence interval (CI): 0.785-0.884]. Concordance index for the training and validation groups were 0.835 and 0.848, respectively. As the calibration plots indicate, the predicted probability of NEC is highly consistent with the actual observation. Conclusions: The risk estimation nomogram for NEC offers clinical value by guiding early prediction, targeted prevention, and early intervention strategies for NEC.

Construction of an immunosensor based on Cys/Au@TiO2 modification for the detection of liver cancer marker PIVKA-II.

An ultrasensitive immunosensor of Cys/Au@TiO2 based on disposable screen-printed electrodes (SPE) for PIVKA-II detection for hepatocellular carcinoma (HCC) diagnosis was developed by utilizing Cystine (Cys) and nanocomposite Au@TiO2. Firstly, HAuCl4 underwent a reduction reaction with NaBH4, then Au nanoparticles were coated onto TiO2 nanoparticles. Followed, Cys/Au@TiO2 was formed through self-assembly of cysteine to allow the monoclonal antibody of abnormal thrombospondin to bound to the amino group on the surface of the composite by covalent bonding. The mechanism is to determine the changes in the current of the sensor caused by the specific binding of the abnormal prothrombin monoclonal antibody adsorbed by the complex with its antigen. The Cys/Au@TiO2 immunosensor was fully characterized by various analytical approaches and it showed a wide linear testing range of 1-10000 pg mL-1 (R2 = 0.991) and the limit of detection down to 0.77 pg ml-1, with highly sensitivity and specificity. The results showed that the developed immunosensor platform can effectively detect trace amounts of PIVKA-II protein and has potent clinical application for HCC diagnosis.

Enhancing antibacterial properties of titanium implants through a novel Ag-TiO2-OTS nanocomposite coating: a comprehensive study on resist-killing-disintegrate approach.

Titanium (Ti) implants are widely used in orthopedic and dental applications due to their excellent biocompatibility and mechanical properties. However, bacterial adhesion and subsequent biofilm formation on implant surfaces pose a significant risk of postoperative infections and complications. Conventional surface modifications often lack long-lasting antibacterial efficacy, necessitating the development of novel coatings with enhanced antimicrobial properties. This study aims to develop a novel Ag-TiO2-OTS (Silver-Titanium dioxide-Octadecyltrichlorosilane, ATO) nanocomposite coating, through a chemical plating method. By employing a 'resist-killing-disintegrate' approach, the coating is designed to inhibit bacterial adhesion effectively, and facilitate pollutant removal with lasting effects. Characterization of the coatings was performed using spectroscopy, electron microscopy, and contact angle analysis. Antibacterial efficacy, quantitatively evaluated against E. coli and S. aureus over 168 h, showed a significant reduction in bacterial adhesion by 76.6% and 66.5% respectively, and bacterial removal rates were up to 83.8% and 73.3% in comparison to uncoated Ti-base material. Additionally, antibacterial assays indicated that the ratio of the Lifshitz-van der Waals apolar component to electron donor surface energy components significantly influences bacterial adhesion and removal, underscoring a tunable parameter for optimizing antibacterial surfaces. Biocompatibility assessments with the L929 cell line revealed that the ATO coatings exhibited excellent biocompatibility, with minimal cytotoxicity and no significant impact on cell proliferation or apoptosis. The ATO coatings provided a multi-functionality surface that not only resists bacterial colonization but also possesses self-cleaning capabilities, thereby marking a substantial advancement in the development of antibacterial coatings for medical implants.

Causal relationships of neonatal jaundice, direct bilirubin and indirect bilirubin with autism spectrum disorder: A two-sample Mendelian randomization analysis.

Background: Multiple systematic reviews and meta-analyses have examined the association between neonatal jaundice and autism spectrum disorder (ASD) risk, but their results have been inconsistent. This may be because the included observational studies could not adjust for all potential confounders. Mendelian randomization study can overcome this drawback and explore the causal relationship between the both. Methods: We used the data of neonatal jaundice, direct bilirubin (DBIL), indirect bilirubin (IBIL), and ASD collected by genome-wide association study (GWAS) to evaluate the effects of neonatal jaundice, DBIL and IBIL on ASD by using a two-sample Mendelian randomized (MR). The inverse variance-weighted method (IVW) was the main method of MR analysis in this study. Weighted median method, MR-Egger regression and mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test were used for sensitivity analysis. Results: There was no evidence of an effect of neonatal jaundice (OR, 1.002, 95% CI, 0.977-1.027), DBIL (OR, 0.970, 95% CI, 0.884-1.064) and IBIL (OR, 1.074, 95% CI, 0.882-1.308) on ASD risk by IVW test. In the weighted median method, MR-Egger regression and leave-one-out analysis, the results were robust and no heterogeneity or pleiotropy was observed. Conclusions: We found that neonatal jaundice, DBIL and IBIL were not associated with ASD in this study. However, this paper did not explore the effect of severity and duration of jaundice on ASD in different ethnic populations, which may require further research.

Neonatal sequential organ failure assessment score within 72†h after delivery reliably predicts bronchopulmonary dysplasia in very preterm infants.

Background: The neonatal sequential organ failure assessment (nSOFA) score is an operational definition of organ dysfunction employed to predict sepsis-associated mortality. However, the relationship between the nSOFA score and bronchopulmonary dysplasia (BPD) has not been investigated clearly. This study evaluates whether the nSOFA score within 72 h after delivery could be used to predict the occurrence of BPD in very preterm infants. Methods: In this retrospective, single-center cohort study, preterm infants born between 2019 and 2021 were investigated, the nSOFA score was calculated from medical records after admission to the neonatal intensive care unit (NICU) within 72 h after delivery, and the peak value was used for calculation. A logistic regression model was used to evaluate the relationship between the nSOFA score and BPD. Propensity score matching and subgroup analysis were performed to verify the reliability of the results. Results: Of 238 infants meeting the inclusion criteria, 93 infants (39.1%) were diagnosed with BPD. The receiver operating characteristic curve of the nSOFA score in predicting BPD was 0.790 [95% confidence interval (CI): 0.731-0.849]. The logistic regression model showed that an increment of one in the nSOFA score was related to a 2.09-fold increase in the odds of BPD (95% CI: 1.57-2.76) and 6.36-fold increase when the nSOFA score was higher than 1.5 (95% CI: 2.73-14.79). Conclusions: The nSOFA score within 72 h after delivery is independently related to BPD and can be used to identify high-risk infants and implement early interventions.

A study on the enrichment mechanism of three nitrophenol isomers in environmental water samples by charge transfer supramolecular-mediated hollow fiber liquid-phase microextraction.

To explore the mechanism of extraction and enrichment of three nitrophenol isomers by charge-transfer supramolecular synergistic three-phase microextraction system, a charge transfer supramolecular-mediated hollow fiber liquid-phase microextraction (CTSM-HF-LPME) combined with high-performance liquid chromatography-ultraviolet detector (HPLC-UV) method was established for the determination of real environmental water samples. In this study, the three nitrophenols (NPs) formed charge-transfer supramolecules with electron-rich hollow fibers, which promoted the transport of NPs in the three-phase extraction system and greatly increased the EFs of NPs. The relationships between the EFs of NPs and their solubility, pKa, apparent partition coefficient, equilibrium constant, and structural property parameters were investigated and discussed. At the same time, most of factors affecting the EFs of NPs were investigated and optimized, such as the type of extraction solvent, pH value of sample phase and acceptor phase, extraction time, and stirring speed. Under optimal conditions, the EFs of o-nitrophenol, m-nitrophenol, and p-nitrophenol were 163, 145, and 87, respectively. With good linearity in the range of 5 × 10-7 ~ 1 µg/mL, and the limit of detection of 0.1 pg/mL, the relative standard deviations of the method precision were lower than 7.4%, and the average recoveries were between 98.6 and 106.4%. This method had good selectivity and sensitivity, satisfactory precision, and accuracy and had been successfully applied to the trace detection of real water samples.

Synthesis and in-vitro study of a novel ligustrazine diselenide as a potential chemotherapy drug for lung adenocarcinoma.

A novel ligustrazine diselenide, 1,2-bis ((3,5,6-trimethylpyrazin-2-yl) methyl) diselenide (Se2), for potential treatment on adenocarcinoma of lung cancer was successfully synthesized and fully characterized by various analytical approaches. Cytotoxic, antiproliferative and apoptosis-triggering mechanism of Se2 compound have been investigated through human lung adenocarcinoma (LUAD) cell line A549. The study found that Se2 significantly inhibit the proliferation of A549 cells in a dose-dependent manner. Flow cytometry showed that Se2 induced cell arrest and apoptosis in S and G2/M phase, and the apoptotic effect of Se2 were associated with the increase of caspase 3 and PARP-1 level approved by western blot assay. Further mechanism study results suggested that Se2 suppressed the migration,invasion and colony formation of A549 cells, significantly inhibited the PI3K/Akt/m-TOR signaling pathway. The study indicated that Se2 is a bioactive substance that can induce apoptosis of A549 cells in-vitro, and it is a potent candidate drug for LUAD.

Lack of adipocyte IP3R1 reduces diet-induced obesity and greatly improves whole-body glucose homeostasis.

The normal function of skeletal muscle and adipose tissue ensures whole-body glucose homeostasis. Ca2+ release channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) plays a vital role in regulating diet-induced obesity and disorders, but its functions in peripheral tissue regulating glucose homeostasis remain unexplored. In this study, mice with Ip3r1 specific knockout in skeletal muscle or adipocytes were used for investigating the mediatory role of IP3R1 on whole-body glucose homeostasis under normal or high-fat diet. We reported that IP3R1 expression levels were increased in the white adipose tissue and skeletal muscle of diet-induced obese mice. Ip3r1 knockout in skeletal muscle improved glucose tolerance and insulin sensitivity of mice on a normal chow diet, but worsened insulin resistance in diet-induced obese mice. These changes were associated with the reduced muscle weight and compromised Akt signaling activation. Importantly, Ip3r1 deletion in adipocytes protected mice from diet-induced obesity and glucose intolerance, mainly due to the enhanced lipolysis and AMPK signaling pathway in the visceral fat. In conclusion, our study demonstrates that IP3R1 in skeletal muscle and adipocytes exerts divergent effects on systemic glucose homeostasis, and characterizes adipocyte IP3R1 as a promising target for treating obesity and type 2 diabetes.

Single-Cell RNA-Sequencing Provides Insight into Skeletal Muscle Evolution during the Selection of Muscle Characteristics.

Skeletal muscle comprises a large, heterogeneous assortment of cell populations that interact to maintain muscle homeostasis, but little is known about the mechanism that controls myogenic development in response to artificial selection. Different pig (Sus scrofa) breeds exhibit distinct muscle phenotypes resulting from domestication and selective breeding. Using unbiased single-cell transcriptomic sequencing analysis (scRNA-seq), the impact of artificial selection on cell profiles is investigated in neonatal skeletal muscle of pigs. This work provides panoramic muscle-resident cell profiles and identifies novel and breed-specific cells, mapping them on pseudotime trajectories. Artificial selection has elicited significant changes in muscle-resident cell profiles, while conserving signs of generational environmental challenges. These results suggest that fibro-adipogenic progenitors serve as a cellular interaction hub and that specific transcription factors identified here may serve as candidate target regulons for the pursuit of a specific muscle phenotype. Furthermore, a cross-species comparison of humans, mice, and pigs illustrates the conservation and divergence of mammalian muscle ontology. The findings of this study reveal shifts in cellular heterogeneity, novel cell subpopulations, and their interactions that may greatly facilitate the understanding of the mechanism underlying divergent muscle phenotypes arising from artificial selection.

Ultrasound activated nano-encapsulated targeted drug delivery and tumour cell poration.

INTRODUCTION: Recently, ultrasonic drug release has been a focus of many research groups for stimuli responsive drug release. It has been demonstrated that a focused ultrasound (FUS) beam rapidly increases the temperature at the focused tissue area. One potential mechanism of drug targeting is to utilize the induced heat to release or increase penetration of chemotherapy to cancer cells. The efficiency of targeted drug delivery may increase by using FUS beam in conjugation with nano--encapsulated drug carriers.The aim of this study is to investigate the effect of heat and ultrasound on the cellular uptake and therapeutic efficacy of an anticancer drug using Magnetic Resonance Imaging guided Focused Ultrasound (MRgFUS). MATERIALS AND METHODS: Human KB cells (CCL-17 cells) were seeded into 96-well plates and heat treated at 37-55°C for 2-10 min. Cell viability was determined using the colorimetric MTT assay. The cells were also subjected to MRgFUS and the degree of cell viability was determined. These experiments were conducted using an ExAblate 2000 system (InSightec, Haifa, Israel) and a GE 1.5 T MRI system, software release 15. RESULTS: We have observed a significant decrease in human KB cell viability due to heat (>41°C) in the presence of Doxorubicin (DOX), in comparison with DOX at normal culture temperature (37°C). The synergistic effect of heat with DOX may be explained by several mechanisms. One potential mechanism may be increased penetration of DOX to the cells during heating. In addition, we have shown that ultrasound induced cavitation causes cell necrosis. DISCUSSION AND FUTURE WORK: Further investigation is required to optimize the potential of MRgFUS to enhance cellular uptake of therapeutic agents. A novel delivery nano-vehicle developed by CapsuTech will be investigated with MRgFUS for its potential as a stimuli responsive delivery system.

Adherence to Oral Nutritional Supplements in Patients With Gastrointestinal Cancer: A Mixed-Method Study.

BACKGROUND: Oral nutritional supplements (ONS) is a cost-effective nutritional therapy in patients with gastrointestinal cancer. However, information is lacking about adherence to ONS in general clinical settings. Figuring out adherence to ONS and related factors will provide evidence for the improvement of ONS usage practice. OBJECTIVE: The aim of this study was to survey adherence to ONS in gastrointestinal cancer patients with an ONS prescription and the factors associated with it. METHODS: A mixed-method prospective study was conducted. Multivariate analysis and semistructured interviews were performed to identify factors that affected patient adherence to ONS. RESULTS: Of 111 gastrointestinal cancer patients provided with an ONS prescription, the median of adherence to ONS was 50.00% (interquartile range, 28.57%-91.67%). Multivariate analysis indicated that participants with low weight showed higher adherence to ONS than those with normal weight (ß = -2.61, P = .011) or overweight (ß = -3.25, P = .002). Semistructured interviews on 14 participants suggested that factors related to adherence to ONS were needs perception and benefits, clarity of the target daily ONS intake, tolerance to ONS, the impact of disease or treatment, personal preference, and professional support. CONCLUSION: This study reveals poor adherence to ONS in patients with gastrointestinal cancer and factors related to it in current clinical settings. IMPLICATIONS FOR PRACTICE: Our findings could provide evidence for the development of strategies to improve ONS usage practice. It suggests that the practice in ONS should be improved from aspects of nutritional assessment, education, tolerance, and symptom management, as well as follow-up and monitoring of patients.

Cysteine Exerts an Essential Role in Maintaining Intestinal Integrity and Function Independent of Glutathione.

SCOPE: Enteral feeding is a primary source of cysteine for intestinal mucosa given negligible transsulfuration activity in enterocytes and furthermore very few cysteine uptake from arterial blood. This study aims to explore the role of cysteine in maintaining intestinal integrity and function. METHODS AND RESULTS: The intestinal porcine enterocytes (IPEC-J2) are cultured in a cysteine-deprived medium with or without glutathione supplementation upon the inhibitions of glutathione synthesis or degradation. As a result, cysteine deprivation impairs mitochondrial function, suppresses mechanistic target of rapamycin (mTOR) signaling, and activates general control nonderepressible 2 (GCN2) signaling, and might lead to resultant ferroptosis. Glutathione supplementation can restore the impairment through degrading into cysteine, while glutathione synthesis inhibition does not disturb the role of cysteine in keeping the intestinal epithelial cells. Furthermore, piglets are fed with cysteine-deficient, -adequate, and -surplus diet for 28 days as a porcine model. In this study, it is evidenced that intestinal integrity and individual growth benefit from adequate dietary cysteine. CONCLUSION: Adequate dietary cysteine supply is essential for intestinal mucosal integrity, epithelial cell turnover, and amino acid sensing as well as optimal individual growth. Cysteine exerts its role independent of glutathione and glutathione restores the impairment of cysteine-deprivation on intestinal mucosal through degrading into cysteine.