Dexmedetomidine alleviates acute postoperative anxiety in rats by suppressing the NF-ĸB pathway.

Evidence suggests that surgical procedures can effect the central nervous system and lead to changes in mood and behavior, rarely understood about the role of acute inflammation in promoting acute anxiety postoperatively. This study was designed to explore the possible mechanism of dexmedetomidine (DEX, a2-adrenergic receptor agonist) for reducing acute postoperative anxiety, which may be related to the activation of nuclear factor kappa B (NF-κB) and downstream signal pathway in the hippocampus. Experiments were conducted with rat, the elevated plus-maze and open field test were performed to evaluate anxiety-like behavior. Inhibit DEX with Atipamezole (AT, α2-adrenergic receptor antagonist) and inhibit NF-κB with Pyrrolidinedithiocarbamate (PDTC, inhibit phosphorylation of IκB, prevent the activation of NF-κB), the level of interleukin-6 (IL-6), IL-1ß, IL-10 and Tumor necrosis factor-α (TNF-α); the nuclear translocation of NF-κB in the hippocampus and anxiety-like behavior were measured. Rats exhibited anxiety-like behavior at 6h and 12h after surgery. Preoperative administration of DEX significantly alleviated postoperative anxiety-like behavior. DEX premedication inhibited the nuclear translocation of NF-κB alleviate acute postoperative anxiety. These findings are the first to show that acute postoperative anxiety may be related to NF-κB nuclear translocation in the hippocampus in rats, which can be alleviated by DEX premedication.

Kinetic reaction mechanism of lignocellulosic biomass oxidative pyrolysis based on combined kinetics.

The kinetics knowledge of lignocellulosic biomass decomposition is essential to develop efficient thermochemical conversion technology. However, the simplification of reaction mechanisms in existing oxidative pyrolysis studies largely compromises the application of kinetic models. To explore more exact kinetic parameters and reaction mechanism of lignocellulosic biomass oxidative pyrolysis, an updated oxidative pyrolysis kinetic model (seven-step reaction combined kinetics model) coupled with an optimization algorithm is proposed. Based on a series of thermogravimetric experiments in an air atmosphere, the extra oxidative pyrolysis kinetic parameters are obtained by the Shuffled Complex Evolution method. The proposed kinetic model is validated based on the degradation process of each component (hemicellulose, cellulose, and lignin). Furthermore, the obtained kinetic parameters are applied to predict the oxidative pyrolysis behavior, and the predicted mass loss rate is in good agreement with the experimental data. Eventually, according to the key combined kinetics parameters, it is found that the oxidative pyrolysis mechanisms of hemicellulose, cellulose, and lignin correspond to the power law, nucleation & growth, and chemical reaction order, respectively, while the combustion of char corresponds to the reaction order mechanism.

The optimal induction dose of ciprofol combined with low-dose rocuronium in children undergoing daytime adenotonsillectomy.

Adenotonsillectomy is the most common daytime surgery performed on children. Anesthesiologists must select the optimal combination of drugs to ensure effective anesthesia effect and prompt recovery in children. The optimal induction dose of ciprofol in children is unclear. In this study, we aim to investigate the effect of different doses of ciprofol on anesthesia induction in children undergoing daytime adenotonsillectomy and provide a reference for clinical use. 144 children aged 3-12 years, ASA I-II, undergoing daytime adenotonsillectomy, were included in this clinical trial. The children were randomly divided into three groups and given 0.4 mg/kg (C4), 0.6 mg/kg (C6), or 0.8 mg/kg (C8) of ciprofol for anesthesia induction. The primary outcome was intubation conditions. Vital signs and injection pain were also recorded. The rates of unacceptable intubation conditions were 30.6%, 8.7%, and 8.2% in the C4, C6, and C8 groups (P value < 0.0167). The overall incidence of reported injection pain was 3.5%. The heart rate and mean arterial pressure did not differ between the groups at the same time points. We found that combining 0.6 mg/kg of ciprofol with low-dose rocuronium could provide optimal intubation conditions in pediatric daytime adenotonsillectomy patients. This combination resulted in stable circulation and BIS values. This study is registered at the Chinese Clinical Trial Registry (Registration number: ChiCTR2200063144, Date of Registration: 31/08/2022).

Effect of epidural block on surgical conditions during pediatric subumbilical laparoscopic surgery involving a supraglottic airway: a randomized clinical trial.

Background: Few studies have examined the effect of epidural block on surgical conditions during pediatric subumbilical laparoscopic surgery involving a supraglottic airway (SGA). This study investigated the surgical condition scores for such procedures in cases where neuromuscular block, epidural block, or neither was used. Methods: A total of 150 patients aged 3-12 years undergoing laparoscopic orchiopexy with a ProSeal SGA device were randomly allocated to one of three groups: the control group (did not receive neuromuscular block and epidural block), the NMB group [received a neuromuscular block (train-of-four 1-2 twitches) using rocuronium], or the EDB group (received an epidural block using ropivacaine). The primary outcome was the quality of surgical conditions evaluated with the Leiden-Surgical Rating Scale by the blinded surgeon. The secondary outcome measures included intraoperative hemodynamic data (including mean arterial pressure and heart rate), the SGA device removal time, the PACU discharge time, the pain score in the PACU and intraoperative adverse events (including bradycardia, hypotension, peak airway pressure > 20 cmH2O, and poor or extremely poor surgical conditions occurred during the operation). Statistical analysis was performed with one-way analysis of variance, the Kruskal-Wallis test, the chi-square test or Fisher's exact test. Bonferroni corrections for multiple comparisons were made for primary and secondary outcomes. Results: Surgical condition scores were significantly higher in the NMB and EDB groups than in the control group (median difference: 0.8; 95% confidence interval [CI], 0.5-1.0; p < 0.0001; and median difference: 0.7; 95% CI, 0.5-0.8; p < 0.0001, respectively). Blood pressure and heart rate were significantly lower in the EDB group than in the other two groups (p < 0.0001 and p = 0.004). Patients in the EDB group had significantly lower pain scores during PACU than those in the other two groups (p < 0.0001). The sufentanil dose was lower in the EDB group than in the other two groups (p = 0.001). Conclusion: Epidural block can improve surgical conditions during pediatric subumbilical laparoscopic surgery involving a SGA to a degree comparable to that with moderate neuromuscular block.

Effect of neuromuscular block on surgical conditions during laparoscopic surgery in neonates and small infants: A randomised controlled trial.

BACKGROUND: Neuromuscular block (NMB) is routinely used in paediatric and adult anaesthesia to facilitate endotracheal intubation and optimise surgical conditions. However, there are limited data regarding NMB and optimising the conditions for laparoscopic surgery in neonates and small infants. OBJECTIVE: The goal of this study was to determine the effect of NMB on the conditions for laparoscopic surgery in neonates and small infants. DESIGN: A randomised controlled trial. SETTING: Single-centre Children's Hospital, conducted from November 2021 to December 2022. PATIENTS: One hundred and two ASA I-II neonates and small infants aged up to 60 weeks postmenstrual age who were scheduled to undergo an elective laparoscopic Ladd's procedure were included in the study. INTERVENTIONS: Patients were randomised into three groups: no NMB group, shallow NMB group and moderate NMB group. Each group was given different doses of rocuronium to achieve the target depth of NMB. MAIN OUTCOME MEASURES: The primary outcome was the quality of the surgical conditions evaluated with the Leiden-Surgical Rating Scale (L-SRS) by a blinded surgeon. Secondary outcomes included tracheal intubating conditions and adverse events. RESULTS: The percentage of L-SRS scores of 4 or 5 was similar among the three groups at all the assessment times ( P  > 0.05 for each time interval). The distribution of L-SRS scores was also similar among the three groups. There were no significant differences in operating condition scores between the groups at any time interval ( P  > 0.05 for each time interval). The incidence of adverse events during anaesthesia induction was significantly higher in the no NMB group (51.4%) than in the other two groups (13.6% and 14.7%) (adjusted P  = 0.012 and adjusted P  = 0.003). In particular, clinically unacceptable intubation conditions occurred in 12 patients (34.3%) in the no NMB group, significantly more than in the shallow NMB group (6.1%, adjusted P  = 0.012) and moderate NMB group (2.9%, adjusted P  = 0.003). There was no statistically significant difference in the incidence of adverse events in the PACU among the three groups ( P  = 0.103). CONCLUSIONS: The depth of NMB was not associated with superior surgical conditions during laparoscopic surgery, but it was associated with a reduction in adverse events during induction and maintenance of anaesthesia in neonates and small infants. TRIAL REGISTRATION: Registered at www.chictr.org.cn (ChiCTR2100052296).

Activation of the Akt Attenuates Ropivacaine-Induced Myelination Impairment in Spinal Cord and Sensory Dysfunction in Neonatal Rats.

Prolonged exposure to local anesthetics (LAs) or intrathecal administration of high doses of LAs can cause spinal cord damage. Intraspinal administration of LAs is increasingly being used in children and neonates. Therefore, it is important to study LA-related spinal cord damage and the underlying mechanism in developmental models. First, neonatal Sprague-Dawley rats received three intrathecal injections of 0.5% ropivacaine, 1% ropivacaine, 2% ropivacaine or saline (90-min interval) on postnatal day 7. Electron microscopy, luxol fast blue staining and behavioral tests were performed to evaluate the spinal neurotoxicity caused by ropivacaine at different concentrations. Western blot analysis and immunostaining was performed to detect the expression changes of p-Akt, Akt, myelin gene regulatory factor (MYRF) and myelin basic protein (MBP) in the spinal cord treated with different concentrations of ropivacaine. Our results showed that 1% or 2% ropivacaine impaired myelination in the spinal cord and induced sensory dysfunction, but 0.5% ropivacaine did not. Moreover, 1% or 2% ropivacaine decreased the expression of p-Akt, MYRF and MBP in the spinal cord. Then, in order to further explore the role of these proteins in this model, the Akt-specific activator (SC79) was intraperitoneally injected 30 min before 2% ropivacaine treatment. Interestingly, SC79-mediated activation of Akt partly rescued ropivacaine-induced myelination impairments and sensory dysfunction. Overall, the results showed that ropivacaine caused spinal neurotoxicity in a dose-dependent manner in neonatal rats and that activation of the Akt partly rescued ropivacaine-induced these changes. These data provide insight into the neurotoxicity to the developing spinal cord caused by LAs.

FEDformer-Based Paddy Quality Assessment Model Affected by Toxin Change in Different Storage Environments.

The storage environment can significantly impact paddy quality, which is vital to human health. Changes in storage can cause growth of fungi that affects grain quality. This study analyzed grain storage monitoring data from over 20 regions and found that five factors are essential in predicting quality changes during storage. The study combined these factors with the FEDformer (Frequency Enhanced Decomposed Transformer for Long-term Series Forecasting) model and k-medoids algorithm to construct a paddy quality change prediction model and a grading evaluation model, which showed the highest accuracy and lowest error in predicting quality changes during paddy storage. The results emphasize the need for monitoring and controlling the storage environment to preserve grain quality and ensure food safety.

A Model for Predicting and Grading the Quality of Grain Storage Processes Affected by Microorganisms under Different Environments.

Changes in storage environments have a significant impact on grain quality. Accurate prediction of any quality changes during grain storage in different environments is very important for human health. In this paper, we selected wheat and corn, which are among the three major staple grains, as the target grains whose storage monitoring data cover more than 20 regions, and constructed a grain storage process quality change prediction model, which includes a FEDformer-based grain storage process quality change prediction model and a K-means++-based grain storage process quality change grading evaluation model. We select six factors affecting grain quality as input to achieve effective prediction of grain quality. Then, evaluation indexes were defined in this study, and a grading evaluation model of grain storage process quality was constructed using clustering model with the index prediction results and current values. The experimental results showed that the grain storage process quality change prediction model had the highest prediction accuracy and the lowest prediction error compared with other models.

An Entity Relationship Extraction Model Based on BERT-BLSTM-CRF for Food Safety Domain.

Dealing with food safety issues in time through online public opinion incidents can reduce the impact of incidents and protect human health effectively. Therefore, by the smart technology of extracting the entity relationship of public opinion events in the food field, the knowledge graph of the food safety field is constructed to discover the relationship between food safety issues. To solve the problem of multi-entity relationships in food safety incident sentences for few-shot learning, this paper adopts the pipeline-type extraction method. Entity relationship is extracted from Bidirectional Encoder Representation from Transformers (BERTs) joined Bidirectional Long Short-Term Memory (BLSTM), namely, the BERT-BLSTM network model. Based on the entity relationship types extracted from the BERT-BLSTM model and the introduction of Chinese character features, an entity pair extraction model based on the BERT-BLSTM-conditional random field (CRF) is established. In this paper, several common deep neural network models are compared with the BERT-BLSTM-CRF model with a food public opinion events dataset. Experimental results show that the precision of the entity relationship extraction model based on BERT-BLSTM-CRF is 3.29%∼23.25% higher than that of other models in the food public opinion events dataset, which verifies the validity and rationality of the model proposed in this paper.

A Delay-Cell-Controlled VCO Design for Unipolar Single-Gate Enhancement-Mode TFT Technologies.

This work outperforms the previous literatures by proposing a delay-cell-controlled voltage control oscillator (VCO) design for common unipolar, single-gate, and enhancement-mode thin-film transistor (TFT) technologies. A design example with InZnO TFTs is simulated to verify the proposed design. The design example has a 500 µW power consumption, 0.7 mm2 area, 3.8 kHz-8 kHz output frequency range, 600 Hz/V tuning sensitivity, and 4% maximum linear error. This design may have the potential to be used for flexible, low cost, and moderate speed sensor readout interfaces.

The effect of dexmedetomidine premedication on postoperative systemic inflammatory response in children undergoing hernia repair surgery: A randomized controlled trial.

BACKGROUND: Surgery results in systemic inflammation, which can affect the central nervous system, leading to changes in mood, emotion, and behavior. Our previous study has shown that compared to midazolam, dexmedetomidine premedication effectively decreased children's postoperative anxiety. AIM: To investigate whether dexmedetomidine infusion before hernia repair alleviates postoperative systemic inflammation in children and whether postoperative anxiety may be associated with postoperative inflammation. METHODS: This prospective double-blind randomized controlled trial was conducted in 120 children scheduled to undergo elective hernia repair. Before anesthesia induction, all children received an intravenous infusion consisted of dexmedetomidine (n = 40; 0.5 µg/g, group D), midazolam (n = 40; 0.08 mg/kg, group M), or normal saline (n = 40; group C). One-way ANOVA with least significant difference multiple comparison test was used for multigroup comparisons of postoperative plasma levels of inflammatory cytokines and m-YPAS scores. Spearman rank correlation tests were used for analyzing m-YPAS scores with postoperative plasma levels of inflammatory cytokines. RESULTS: Plasma levels of tumor necrosis factor-alpha (7.0 ± 1.6 vs. 8.1 ± 1.6, mean difference [95% CI]: 1.19 [0.26-2.11], p = .008) (pg/ml) and of interleukin-6 (1.8 ± 1.2 vs. 3.3 ± 1.6, mean difference [95% CI]: 1.49 [0.74-2.25], p < .001) (pg/ml) and neutrophils-to-lymphocyte ratio (1.0 ± 0.5 vs. 1.5 ± 0.7, mean difference [95% CI]: 0.48 [0.17-0.78], p < .001) were significantly lower in group D than in group C. Furthermore, compared to group M, group D showed significantly lower plasma tumor necrosis factor-alpha levels (7.0 ± 1.6 vs. 7.9 ± 1.9, mean difference [95% CI]: 0.96 [0.04-1.88], p = .04) (pg/ml) and interleukin-6 levels (1.8 ± 1.2 vs. 2.9 ± 1.5, mean difference [95% CI]: 1.06 [0.31-1.81], p = .004) (pg/ml), and neutrophil-to-lymphocyte ratio (1.0 ± 0.5 vs. 1.5 ± 0.6, mean difference [95% CI]: 0.42 [0.11-0.72], p = .004). Anxiety scores at postoperative 2 and 4 h in the three groups positively correlated with plasma levels of proinflammatory cytokines. CONCLUSION: A single preoperative intravenous dexmedetomidine dose in children undergoing same-day surgery reduces postoperative systemic inflammation.

The comparison of dexmedetomidine and midazolam premedication on postoperative anxiety in children for hernia repair surgery: A randomized controlled trial.

BACKGROUND: Perioperative anxiety is common in pediatric patients undergoing surgery. AIMS: The aim of this study was to determine whether an infusion of dexmedetomidine prior to hernia repair in children provides better postoperative anxiety outcomes that a preoperative infusion of midazolam. METHODS: Ninety 6-11-year-old children, who were scheduled to undergo elective hernia repair, were enrolled for this double-blind, randomized controlled trial. Group D (n = 45) received an intravenous infusion of dexmedetomidine (0.5 µg/kg) and Group M (n = 45) received an intravenous infusion of midazolam (0.08 mg/kg) in 20 mL of normal saline for 10 minutes before the induction of anesthesia. Pre- and postoperative scores on the modified Yale Preoperative Anxiety Scale were the main outcomes. Secondary outcomes included systolic blood pressure, diastolic blood pressure, heart rate, and postoperative pain measured on a visual analogue scale and patient satisfaction using a numerical rating scale. RESULTS: Postoperative anxiety in Group D was significantly lower than preoperative anxiety (2 hours postoperatively mean difference [95% CI]: 2.83 [0.87-4.79], P = 0.036, 4 hours postoperatively mean difference [95% CI]: 3.29 [1.39-5.20], P = 0.005). Preoperative and postoperative anxiety in Group M was similar. Anxiety scores in Group D were also significantly lower than anxiety in Group M 2 hours (mean difference [95% CI]: 1.89 [0.52-3.26], P = 0.01) and 4 hours (mean difference [95% CI]: 3.32 [1.98-4.66], P < 0.001) postoperatively. Systolic blood pressure, diastolic blood pressure and heart rate were lower in Group D than in Group M after administration of sedative drugs until children left PACU (SBP mean difference [95% CI]: 13.87 [10.30-17.43], P < 0.001, DBP mean difference [95% CI]: 5.96[3.80-8.11], P < 0.001, HR mean difference [95% CI]: 10.36 [7.58-13.13], P < 0.001). Pain was also significantly lower in Group D than in Group M at 2 hours (median difference [95% CI]: 1 [0.26-1.34], P = 0.004), 4 hours (median difference [95% CI]: 1 [0.31-1.02], P = 0.003), and 1 day (median difference [95% CI]: 0 [0.22-0.76], P = 0.003) postoperatively. Patient satisfaction scores were significantly higher in Group D than in Group M 1 day (median difference [95% CI]: 0 [-0.83 to -0.24], P = 0.006) and somewhat higher 1 week (median difference [95% CI]: 0 [-0.67 to -0.04], P = 0.06) postoperatively. CONCLUSION: Compared with midazolam, a single preoperative intravenous dose of dexmedetomidine appears to provide better postoperative anxiolytic effects for children undergoing same-day surgery.

Necrostatin-1 accelerates time to death in a rat model of cecal ligation and puncture and massively increases hepatocyte caspase-3 cleavage.

Necroptosis, a form of regulated necrosis, has been reported to be involved in numerous pathologies, including sepsis. However, a protective effect of the selective inhibitor of necroptosis, necrostatin-1 (Nec-1), against sepsis remains to be confirmed. Animals (rats and mice) were subjected to cecal ligation and puncture (CLP) to mimic clinical sepsis. Nec-1 or its vehicle (control) was administered 20 min before CLP. Survival time was observed up to 72 h after CLP. Specimens of liver tissue and serum were obtained at 6 h, 12 h, and 18 h. Expression of necroptosis-related proteins [receptor-interacting protein kinase (RIP)1, RIP3, and mixed lineage kinase domain-like (MLKL)] was determined by Western blot analysis. The RIP1/RIP3 interaction and the recruitment of MLKL to RIP3 were also analyzed. Liver function, histopathological changes, serum inflammation cytokines, TUNEL staining, and the expression of apoptosis-related protein, including caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (Bax), was determined. As expected, Nec-1 administration reduced the expression of necroptosis-related proteins and the RIP1/RIP3 interaction, indicating inhibited necroptosis. Surprisingly, Nec-1 treatment exacerbated the liver injury and shortened survival time of septic rats with increased TUNEL-positive cells, cleaved caspase-3 protein content, and Bax/Bcl-2 ratio. Collectively, these findings show that Nec-1 administration inhibited the hepatocyte necroptosis pathway but accelerated apoptosis via the apoptotic pathway in CLP-induced sepsis rat. NEW & NOTEWORTHY The present study demonstrated that a chemical inhibitor necrostatin-1 (Nec-1) or receptor-interacting protein kinase(RIP1) knock down targeted at necroptosis inhibition accelerated liver injury of following sepsis. For fundamental research, these results warrant further investigation of the potential link between Nec-1 administration and the cellular apoptosis following sepsis induced liver injury. For applied research, these results suggest the potential harmful effect of Nec-1 on future sepsis treatment.

SIRT1-mediated HMGB1 deacetylation suppresses sepsis-associated acute kidney injury.

Sepsis is the leading cause of death in the intensive care unit and continues to lack effective treatment. It is widely accepted that high-mobility group box 1 (HMGB1) is a key inflammatory mediator in the pathogenesis of sepsis. Moreover, some studies indicate that the functions of HMGB1 depend on its molecular localization and posttranslational modifications. Our previous study confirms that sirtuin 1, silent information regulator 2-related enzyme 1 (SIRT1), a type III deacetylase, can ameliorate sepsis-associated acute kidney injury (SA-AKI). We explored the effect and mechanism of SIRT1 on HMGB1 using a mouse model of cecal ligation and puncture-induced sepsis and LPS-treated human kidney (HK-2) cell line. We found that HMGB1 is elevated in the serum but is gradually reduced in kidney cells in the later stages of septic mice. The acetylation modification of HMGB1 is a key process before its nucleus-to-cytoplasm translocation and extracellular secretion in kidney cells, accelerating the development of SA-AKI. Moreover, SIRT1 can physically interact with HMGB1 at the deacetylated lysine sites K28, K29, and K30, subsequently suppressing downstream inflammatory signaling. Thus the SIRT1-HMGB1 signaling pathway is a crucial mechanism in the development of SA-AKI and presents a novel experimental perspective for future SA-AKI research.

Salmonella-Mediated Inflammation Eliminates Competitors for Fructose-Asparagine in the Gut.

Salmonella enterica elicits intestinal inflammation to gain access to nutrients. One of these nutrients is fructose-asparagine (F-Asn). The availability of F-Asn to Salmonella during infection is dependent upon Salmonella pathogenicity islands 1 and 2, which in turn are required to provoke inflammation. Here, we determined that F-Asn is present in mouse chow at approximately 400 pmol/mg (dry weight). F-Asn is also present in the intestinal tract of germfree mice at 2,700 pmol/mg (dry weight) and in the intestinal tract of conventional mice at 9 to 28 pmol/mg. These findings suggest that the mouse intestinal microbiota consumes F-Asn. We utilized heavy-labeled precursors of F-Asn to monitor its formation in the intestine, in the presence or absence of inflammation, and none was observed. Finally, we determined that some members of the class Clostridia encode F-Asn utilization pathways and that they are eliminated from highly inflamed Salmonella-infected mice. Collectively, our studies identify the source of F-Asn as the diet and that Salmonella-mediated inflammation is required to eliminate competitors and allow the pathogen nearly exclusive access to this nutrient.

Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in Yarrowia lipolytica.

The yeast Yarrowia lipolytica is a potent accumulator of lipids, and lipogenesis in this organism can be influenced by a variety of factors, such as genetics and environmental conditions. Using a multifactorial study, we elucidated the effects of both genetic and environmental factors on regulation of lipogenesis in Y. lipolytica and identified how two opposite regulatory states both result in lipid accumulation. This study involved comparison of a strain overexpressing diacylglycerol acyltransferase (DGA1) with a control strain grown under either nitrogen or carbon limitation conditions. A strong correlation was observed between the responses on the transcript and protein levels. Combination of DGA1 overexpression with nitrogen limitation resulted in a high level of lipid accumulation accompanied by downregulation of several amino acid biosynthetic pathways, including that of leucine in particular, and these changes were further correlated with a decrease in metabolic fluxes. This downregulation was supported by the measured decrease in the level of 2-isopropylmalate, an intermediate of leucine biosynthesis. Combining the multi-omics data with putative transcription factor binding motifs uncovered a contradictory role for TORC1 in controlling lipid accumulation, likely mediated through 2-isopropylmalate and a Leu3-like transcription factor.IMPORTANCE The ubiquitous metabolism of lipids involves refined regulation, and an enriched understanding of this regulation would have wide implications. Various factors can influence lipid metabolism, including the environment and genetics. We demonstrated, using a multi-omics and multifactorial experimental setup, that multiple factors affect lipid accumulation in the yeast Yarrowia lipolytica Using integrative analysis, we identified novel interactions between nutrient restriction and genetic factors involving regulators that are highly conserved among eukaryotes. Given that lipid metabolism is involved in many diseases but is also vital to the development of microbial cell factories that can provide us with sustainable fuels and oleochemicals, we envision that our report introduces foundational work to further unravel the regulation of lipid accumulation in eukaryal cells.

SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model.

Sepsis often results in damage to multiple organ systems, possibly due to severe mitochondrial dysfunction. Two members of the sirtuin family, SIRT1 and SIRT3, have been implicated in the reversal of mitochondrial damage. The aim of this study was to determine the role of SIRT1/3 in acute kidney injury (AKI) following sepsis in a septic rat model. After drug pretreatment and cecal ligation and puncture (CLP) model reproduction in the rats, we performed survival time evaluation and kidney tissue extraction and renal tubular epithelial cell (RTEC) isolation. We observed reduced SIRT1/3 activity, elevated acetylated SOD2 (ac-SOD2) levels and oxidative stress, and damaged mitochondria in RTECs following sepsis. Treatment with resveratrol (RSV), a chemical SIRT1 activator, effectively restored SIRT1/3 activity, reduced acetylated SOD2 levels, ameliorated oxidative stress and mitochondrial function of RTECs, and prolonged survival time. However, the beneficial effects of RSV were greatly abrogated by Ex527, a selective inhibitor of SIRT1. These results suggest a therapeutic role for SIRT1 in the reversal of AKI in septic rat, which may rely on SIRT3-mediated deacetylation of SOD2. SIRT1/3 activation could therefore be a promising therapeutic strategy to treat sepsis-associated AKI.

Comprehensive Metabolomic, Lipidomic and Microscopic Profiling of Yarrowia lipolytica during Lipid Accumulation Identifies Targets for Increased Lipogenesis.

Yarrowia lipolytica is an oleaginous ascomycete yeast that accumulates large amounts of lipids and has potential as a biofuel producing organism. Despite a growing scientific literature focused on lipid production by Y. lipolytica, there remain significant knowledge gaps regarding the key biological processes involved. We applied a combination of metabolomic and lipidomic profiling approaches as well as microscopic techniques to identify and characterize the key pathways involved in de novo lipid accumulation from glucose in batch cultured, wild-type Y. lipolytica. We found that lipids accumulated rapidly and peaked at 48 hours during the five day experiment, concurrent with a shift in amino acid metabolism. We also report that exhaustion of extracellular sugars coincided with thickening of the cell wall, suggesting that genes involved in cell wall biogenesis may be a useful target for improving the efficiency of lipid producing yeast strains.

Exploring Metabolic Profile Differences between Colorectal Polyp Patients and Controls Using Seemingly Unrelated Regression.

Despite the fact that colorectal cancer (CRC) is one of the most prevalent and deadly cancers in the world, the development of improved and robust biomarkers to enable screening, surveillance, and therapy monitoring of CRC continues to be evasive. In particular, patients with colon polyps are at higher risk of developing colon cancer; however, noninvasive methods to identify these patients suffer from poor performance. In consideration of the challenges involved in identifying metabolite biomarkers in individuals with high risk for colon cancer, we have investigated NMR-based metabolite profiling in combination with numerous demographic parameters to investigate the ability of serum metabolites to differentiate polyp patients from healthy subjects. We also investigated the effect of disease risk on different groups of biologically related metabolites. A powerful statistical approach, seemingly unrelated regression (SUR), was used to model the correlated levels of metabolites in the same biological group. The metabolites were found to be significantly affected by demographic covariates such as gender, BMI, BMI(2), and smoking status. After accounting for the effects of the confounding factors, we then investigated potential of metabolites from serum to differentiate patients with polyps and age matched healthy controls. Our results showed that while only valine was slightly associated, individually, with polyp patients, a number of biologically related groups of metabolites were significantly associated with polyps. These results may explain some of the challenges and promise a novel avenue for future metabolite profiling methodologies.

Metabolomics approach for predicting response to neoadjuvant chemotherapy for breast cancer.

Breast cancer is a clinically heterogeneous disease, which necessitates a variety of treatments and leads to different outcomes. As an example, only some women will benefit from chemotherapy. Identifying patients who will respond to chemotherapy and thereby improve their long-term survival has important implications to treatment protocols and outcomes, while identifying non responders may enable these patients to avail themselves of other investigational approaches or other potentially effective treatments. In this study, serum metabolite profiling was performed to identify potential biomarker candidates that can predict response to neoadjuvant chemotherapy for breast cancer. Metabolic profiles of serum from patients with complete (n = 8), partial (n = 14) and no response (n = 6) to chemotherapy were studied using a combination of nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography-mass spectrometry (LC-MS) and statistical analysis methods. The concentrations of four metabolites, three (threonine, isoleucine, glutamine) from NMR and one (linolenic acid) from LC-MS were significantly different when comparing response to chemotherapy. A prediction model developed by combining NMR and MS derived metabolites correctly identified 80% of the patients whose tumors did not show complete response to chemotherapy. These results show promise for larger studies that could result in more personalized treatment protocols for breast cancer patients.