PE6c greatly enhances prime editing in transgenic rice plants.

Prime editing is a versatile CRISPR/Cas-based precise genome-editing technique for crop breeding. Four new types of prime editors (PEs) named PE6a-d were recently generated using evolved and engineered reverse transcriptase (RT) variants from three different sources. In this study, we tested the editing efficiencies of four PE6 variants and two additional PE6 constructs with double-RT modules in transgenic rice (Oryza sativa) plants. PE6c, with an evolved and engineered RT variant from the yeast Tf1 retrotransposon, yielded the highest prime-editing efficiency. The average fold change in the editing efficiency of PE6c compared with PEmax exceeded 3.5 across 18 agronomically important target sites from 15 genes. We also demonstrated the feasibility of using two RT modules to improve prime-editing efficiency. Our results suggest that PE6c or its derivatives would be an excellent choice for prime editing in monocot plants. In addition, our findings have laid a foundation for prime-editing-based breeding of rice varieties with enhanced agronomically important traits.

Pipeline for Planning and Execution of Transcranial Ultrasound Neuromodulation Experiments in Humans.

Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation technique capable of manipulating both cortical and subcortical structures with high precision. Conducting experiments involving humans necessitates careful planning of acoustic and thermal simulations. This planning is essential to adjust for bone interference with the ultrasound beam's shape and trajectory and to ensure TUS parameters meet safety requirements. T1- and T2-weighted, along with zero-time echo (ZTE) magnetic resonance imaging (MRI) scans with 1 mm isotropic resolution, are acquired (alternatively computed tomography x-ray (CT) scans) for skull reconstruction and simulations. Target and trajectory mapping are performed using a neuronavigational platform. SimNIBS is used for the initial segmentation of the skull, skin, and brain tissues. Simulation of TUS is carried over with the BabelBrain tool, which uses the ZTE scan to produce synthetic CT images of the skull to be converted into acoustic properties. We use a phased array ultrasound transducer with electrical steering capabilities. Z-steering is adjusted to ensure that the target depth is reached. Other transducer configurations are also supported in the planning tool. Thermal simulations are run to ensure temperature and mechanical index requirements are within the acoustic guidelines for TUS in human subjects as recommended by the FDA. During TUS delivery sessions, a mechanical arm assists in the movement of the transducer to the required location using a frameless stereotactic localization system.

Broadband nonlinear conversion and random quasi-phase-matching in transparent glass composite.

With the development of laser technology, nonlinear optics plays a crucial role in frequency conversion. However, the generation of second harmonics in nonlinear optical crystals is generally subject to rigorous phase-matching conditions that hinder the performance of broadband tunability. It is believed that introducing disorders in nonlinear optical materials is helpful to overcome this obstacle. In this work, we have prepared a nonlinear microcrystal-doped glass (NMG) composite material, allowing for tunable and polarization-independent nonlinear conversion from visible to near-infrared. The linear dependence of SHG intensity versus sample thickness indicated the facilitation of random quasi-phase matching by using the NMG. Our results provide a more stable and promising platform for disordered nonlinear photonic materials and suggest the possibility of more efficient nonlinear conversions using the NMG composite glass fibers in future.

LncRNA CCRR maintains Ca2+ homeostasis against myocardial infarction through the FTO-SERCA2a pathway.

Cardiac conduction regulatory RNA (CCRR) has been documented as an antiarrhythmic lncRNA in our earlier investigation. This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca2+ homeostasis in myocardial infarction (MI). Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca2+ homeostasis and reduced the heightened methylation level of SERCA2a following MI. These effects were also observed in CCRR over-expressing transgenic mice. A conserved sequence domain of CCRR mimicked the protective function observed with the full length. Furthermore, silencing CCRR in healthy mice led to intracellular Ca2+ overloading of cardiomyocytes. CCRR increased SERCA2a protein stability by upregulating FTO expression. The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation (RIP) analysis and RNA pulldown experiments. Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI. This study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO, thereby reducing the m6A RNA methylation level of SERCA2a, ultimately preserving calcium homeostasis for myocardial contractile function in MI. Therefore, CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.

A Review of Dynamic Mechanical Behavior and the Constitutive Models of Aluminum Matrix Composites.

Aluminum matrix composites (AMMCs) have demonstrated substantial potential in the realm of armor protection due to their favorable properties, including low density, high specific stiffness, and high specific strength. These composites are widely employed as structural components and frequently encounter high strain rate loading conditions, including explosions and penetrations during service. And it is crucial to note that under dynamic conditions, these composites exhibit distinct mechanical properties and failure mechanisms compared to static conditions. Therefore, a thorough investigation into the dynamic mechanical behavior of aluminum matrix composites and precise constitutive equations are imperative to advance their application in armor protection. This review aims to explore the mechanical properties, strengthening the mechanism and deformation damage mechanism of AMMCs under high strain rate. To facilitate a comprehensive understanding, various constitutive equations are explored, including phenomenological constitutive equations, those with physical significance, and those based on artificial neural networks. This article provides a critical review of the reported work in this field, aiming to analyze the main challenges and future development directions of aluminum matrix composites in the field of protection.

Improved accuracy and efficiency of primary care fall risk screening of older adults using a machine learning approach.

BACKGROUND: While many falls are preventable, they remain a leading cause of injury and death in older adults. Primary care clinics largely rely on screening questionnaires to identify people at risk of falls. Limitations of standard fall risk screening questionnaires include suboptimal accuracy, missing data, and non-standard formats, which hinder early identification of risk and prevention of fall injury. We used machine learning methods to develop and evaluate electronic health record (EHR)-based tools to identify older adults at risk of fall-related injuries in a primary care population and compared this approach to standard fall screening questionnaires. METHODS: Using patient-level clinical data from an integrated healthcare system consisting of 16-member institutions, we conducted a case-control study to develop and evaluate prediction models for fall-related injuries in older adults. Questionnaire-derived prediction with three questions from a commonly used fall risk screening tool was evaluated. We then developed four temporal machine learning models using routinely available longitudinal EHR data to predict the future risk of fall injury. We also developed a fall injury-prevention clinical decision support (CDS) implementation prototype to link preventative interventions to patient-specific fall injury risk factors. RESULTS: Questionnaire-based risk screening achieved area under the receiver operating characteristic curve (AUC) up to 0.59 with 23% to 33% similarity for each pair of three fall injury screening questions. EHR-based machine learning risk screening showed significantly improved performance (best AUROC = 0.76), with similar prediction performance between 6-month and one-year prediction models. CONCLUSIONS: The current method of questionnaire-based fall risk screening of older adults is suboptimal with redundant items, inadequate precision, and no linkage to prevention. A machine learning fall injury prediction method can accurately predict risk with superior sensitivity while freeing up clinical time for initiating personalized fall prevention interventions. The developed algorithm and data science pipeline can impact routine primary care fall prevention practice.

LncRNA CCRR Attenuates Postmyocardial Infarction Inflammatory Response by Inhibiting the TLR Signalling Pathway.

BACKGROUND: Timely and proper suppression of inflammation can effectively reduce myocardial injury and promote the postmyocardial infarction (post-MI) wound-healing process. We have previously found that cardiac conduction regulatory RNA (CCRR), a long noncoding RNA (lncRNA) transcribed by the gene located on chromosome 9, with abundant expression in the heart, elicits antiarrhythmic effects in heart failure, and this is a continuing study on the role of CCRR in MI. METHODS: CCRR was overexpressed in CCRR transgenic mice or after injection of adeno-associated virus-9 (AAV-9). MI surgery was performed, and cardiac function was assessed in vivo by echocardiography, followed by histologic analyses. Western blot analysis and qRT-PCR were performed to investigate the effects of CCRR on macrophages, cardiomyocytes, and cardiomyocytes cocultured with macrophages. Through microarray analysis and RNA-binding protein immunoprecipitation (RIP) and other related techniques were also employed to study the effects of CCRR on Toll-like receptor (TLR)2 and TLR4. RESULTS: We found that CCRR level was significantly decreased with increases in proinflammatory cytokines and activation of the TLR signalling pathway in the heart of the 3-day MI mice. CCRR overexpression downregulated TLR2 and TLR4 in MI and effectively inhibited the inflammatory responses in primary cardiomyocytes and macrophages cultured under hypoxic conditions. Downregulation of CCRR induced excessive inflammatory responses by activating the TLR signalling pathway. CCRR acted by suppressing TLR2 and TLR4 to inhibit the secretion of proinflammatory factors to reduce infarct size, thereby improving cardiac function. CONCLUSIONS: CCRR protected cardiomyocytes against MI injury by suppressing inflammatory response through targeting the TLR signalling pathway.

An overview of systematic reviews of acupuncture for neurodegenerative disease.

BACKGROUND: Acupuncture has been widely used in the treatment of neurodegenerative diseases and a large number of systematic reviews (SRs) have been published, but the results are controversial. Therefore, it is necessary to comprehensively summarize and objectively evaluate the clinical evidence of acupuncture for neurodegenerative diseases. OBJECTIVE: To evaluate the SRs that assess the efficacy and safety of acupuncture for neurodegenerative diseases. This overview is intended to provide evidence for clinical decision making by healthcare providers and policymakers and to provide evidence for clinical decision making by healthcare providers and policymakers and to provide recommendations for researchers to conduct high quality SRs and clinical studies. METHODS: We searched four Chinese databases (SinoMed, CNKI, Wanfang and VIP) and four international databases (Cochrane Library, Embase, PubMed and Web of Science) for SRs of acupuncture for neurodegenerative diseases. The search period ran from the beginning of the database to March 5, 2023. Literature screening and data extraction were performed independently by two individuals. Methodological quality, risk of bias and associated evidence levels were assessed for all SRs using AMSTER 2, ROBIS and GRADE tools. In addition, the RCT overlap between SRs was calculated by corrected coverage area (CCA). We also conducted quantitative synthesis or descriptive analysis of the relevant data. RESULTS: Finally, we identified 53 SRs (three were qualitative descriptions and fifty were meta-analyses). Under AMSTAR 2, only one SR was rated as moderate quality, six SRs as low quality and 46 SRs as very low quality. According to ROBIS, 33 SRs were rated as a high risk of bias and 20 as a low risk of bias. Cognitive functions in neurodegenerative diseases, activities of daily living and the motor and non-motor outcomes associated with PD were included to summary description. The pooled results show that acupuncture combined with conventional treatment may have an overall advantage over conventional treatment, but the quality of evidence is low. Specific adverse reactions/events were reported in 20 SRs. Common needle-related adverse events included pain, dizziness, bleeding, or subcutaneous hematoma. No severe adverse events were reported in any SRs. CONCLUSION: Evidence suggests that acupuncture is generally effective and relatively safe for cognitive function and activities of daily living in neurodegenerative diseases. In addition, acupuncture may have some benefits in improving motor and non-motor symptoms in patients with PD. However, high-quality RCTs and SRs are still needed to further clarify the efficacy and safety of acupuncture in treating neurodegenerative diseases.

Diversity recovery and probiotic shift of gastric microbiota in functional dyspepsia patients after Helicobacter pylori eradication therapy.

The effects of Helicobacter pylori eradication on gastric mucosa-colonizing microbes in patients with functional dyspepsia (FD) remain unclear. Here, we explored microbial variation induced by H. pylori infection and eradication treatment in FD patients. Gastric microbial abundance and diversity were significantly reduced in the H. pylori-infected FD patients. Eradication treatment increased alpha and beta diversity of gastric mucosa-colonizing microbes, and promoted the expansion of several probiotic microbes, such as Leuconostoc mesenteroides, which exhibited a matched antagonistic performance against H. pylori. Significant variation was observed in gastric mucosa-colonizing microbes between H. pylori-positive and H. pylori-negative FD patients. Eradication treatment induced microbial diversity recovery and may provide sufficient nutrition and space for probiotic microbes, such as Leuconostoc mesenteroides.

Biaxial ultrasound driving technique for small animal blood-brain barrier opening.

Biaxial driving can more efficiently convert electrical power to forward acoustic power in piezoelectric materials, and the interaction between the orthogonal electric fields can produce a combination of extensional and shear deformations as a function of the phase difference between them to allow dynamic steering of the beam with a single-element. In this study, we demonstrate for the first time the application of a single-element biaxially driven ring transducerin vivofor blood-brain barrier opening in mice, and compare it to that achieved with a conventional single-element highly focused (F# = 0.7) spherical transducer operating at a similar frequency. Transcranial focused ultrasound (0.45 MPa, 10 ms pulse length, 1 Hz repetition frequency, 30 s duration) was applied bilaterally to mice with a 40µl/kg bolus of DefinityTMmicrobubbles, employing either a single-element biaxial ring (1.482 MHz, 10 mm inner diameter, 13.75 mm outer diameter) or spherical (1.5 MHz, 35 mm diameter, F# = 0.7; RK50, FUS Instruments) transducer on each side. Follow-up MRI scans (T1 pre- and post- 0.2 mmol/kg Gd injection, T2) were acquired to assess blood-brain barrier opening volume and potential damage. Compared to blood-brain barrier opening achieved with a conventional single-element spherical focused transducer, the opening volume achieved with a single-element biaxial ring transducer was 35% smaller (p= 0.002) with a device of a ring diameter of 40% the aperture size. Axial refocusing was further demonstrated with the single-element biaxial ring transducer, yielding a 1.63 mm deeper, five-fold larger opening volume (p= 0.048) relative to its small-focus mode. The biaxial ring transducer achieved a more localized opening compared to the spherical focused transducer under the same parameters, and further enabled dynamic axial refocusing with a single-element transducer with a smaller fabrication footprint.

TEAS, DHEA, CoQ10, and GH for poor ovarian response undergoing IVF-ET: a systematic review and network meta-analysis.

BACKGROUND: Assisted reproductive technology (ART) has brought good news to infertile patients, but how to improve the pregnancy outcome of poor ovarian response (POR) patients is still a serious challenge and the scientific evidence of some adjuvant therapies remains controversial. AIM: Based on previous evidence, the purpose of this systematic review and network meta-analysis was to evaluate the effects of DHEA, CoQ10, GH and TEAS on pregnancy outcomes in POR patients undergoing in vitro fertilization and embryo transplantation (IVF-ET). In addition, we aimed to determine the current optimal adjuvant treatment strategies for POR. METHODS: PubMed, Embase, The Cochrane Library and four databases in China (CNKI, Wanfang, VIP, SinoMed) were systematically searched up to July 30, 2022, with no restrictions on language. We included randomized controlled trials (RCTs) of adjuvant treatment strategies (DHEA, CoQ10, GH and TEAS) before IVF-ET to improve pregnancy outcomes in POR patients, while the control group received a controlled ovarian stimulation (COS) regimen only. This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The surface under the cumulative ranking curve (SUCRA) was used to provide a pooled measure of cumulative ranking for each outcome. RESULTS: Sixteen RCTs (2323 women) with POR defined using the Bologna criteria were included in the network meta-analysis. Compared with the control group, CoQ10 (OR 2.22, 95% CI: 1.05 to 4.71) and DHEA (OR 1.92, 95% CI: 1.16 to 3.16) had obvious advantages in improving the clinical pregnancy rate. CoQ10 was the best in improving the live birth rate (OR 2.36, 95% CI: 1.07 to 5.38). DHEA increased the embryo implantation rate (OR 2.80, 95%CI: 1.41 to 5.57) and the high-quality embryo rate (OR 2.01, 95% CI: 1.07 to 3.78) and number of oocytes retrieved (WMD 1.63, 95% CI: 0.34 to 2.92) showed a greater advantage, with GH in second place. Several adjuvant treatment strategies had no significant effect on reducing the cycle canceling rate compared with the control group. TEAS was the least effective of the four adjuvant treatments in most pooled results, but the overall effect appeared to be better than that of the control group. CONCLUSION: Compared with COS regimen, the adjuvant use of CoQ10, DHEA and GH before IVF may have a better clinical effect on the pregnancy outcome of POR patients. TEAS needs careful consideration in improving the clinical pregnancy rate. Future large-scale RCTs with direct comparisons are needed to validate or update this conclusion. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022304723.

Research trends in complementary and alternative treatments for insomnia over the past decade: A bibliometrics analysis.

Insomnia is the most common sleep disorder, with persistent insomnia being associated with greater risk and leading to a range of functional consequences that place a heavy burden on patients and healthcare systems. A weight of evidence has shown that complementary and alternative medicine (CAM) seems to have a positive effect on improving sleep. However, the research trends of CAM intervention for insomnia have not been studied systematically through bibliometrics. We searched the relevant literature over the past decade in the Web of Science Core Collection database on September 20, 2022 and used CiteSpace and gCLUTO to visually analyze and cluster countries, institutions, authors, journals and keywords. Through screening, 1655 papers were included. In the past decade, the number of articles published in this field shown an annual trend of growth, with explosive growth in 2020. The USA has the largest number of publications, the University of Hong Kong is the leading institution in this field, and the most cited journal is Sleep. Mental condition and quality of life in patients with insomnia, insomnia related to cancer, effect of mindfulness meditation, yoga and aromatherapy on insomnia and the psychiatric symptoms resulting from the COVID-19 pandemic are at the forefront of this field. In this study, bibliometrics and visualization analysis were performed on related studies on CAM intervention for insomnia. This will be the focus and development direction of insomnia treatment in the future to formulate structured treatment plans for traditional Chinese medicine-related CAM, validate large-scale clinical trials, solve cancer comorbidity insomnia and related psychiatric symptoms and deal with mental health-related insomnia after public health outbreaks.

Higher harmonics dynamic focalization in single-element ring transducers using biaxial driving.

Biaxial driving is a new driving technique that allows the steering of the ultrasound field generated by a single-element piezoceramic transducer. Because of their natural axisymmetric geometry, ultrasound generation with ring transducers can take advantage of the biaxial driving to change the focus of the beam generated by this type of transducer using only two driving signals. In this study, we applied the biaxial driving technique into a single-element PZT ring transducer operating at 500 kHz to produce a change in size and position of the focal spot while using the 1st (482 kHz), 3rd (1.362 MHz) and 5th (2.62 MHz) harmonic excitation. The transducer had a thickness of 2.85 mm, an inner diameter of 9.75 mm and a ring width of 2.0 mm, and two pairs of electrodes as required for biaxial driving. Simulation and experimental results showed that both the focal area and the distance at which the focal area centre was located changed as a function of the phase and power difference between the two driving signals. Experimental results showed that the focal area could be reduced from 31.6 mm2 (conventional driving) to 3.4 mm2 (89 % reduction) when using the first harmonic excitation. For the third harmonic, the focal area could be reduced from 4.0 mm2 (conventional driving) to 3.3 mm2 (17.5 % reduction). For the fifth harmonic, the focal area could be reduced from 1.7 mm2 (conventional driving) to 1 mm2 (41.7 % reduction). Results also demonstrated the centre of the focus could be displaced between 3.0 mm and 9.3 mm from the surface of the transducer when using the first harmonic, between 7.3 mm and 8.4 mm at the third harmonic, and between 4.9 mm and 8.2 mm at the fifth harmonic. The reduction in the focus area, as well as the possibility to displace the focus dynamically will be advantageous for preclinical applications of focused ultrasound, especially on drug delivery and neuromodulation studies in small rodents.

Transcriptomic and physiological analyses reveal changes in secondary metabolite and endogenous hormone in ginger (Zingiber officinale Rosc.) in response to postharvest chilling stress.

Storing postharvest ginger at low temperatures can extend its shelf life, but can also lead to chilling injury, loss of flavor, and excessive water loss. To investigate the effects of chilling stress on ginger quality, morphological, physiological, and transcriptomic changes were examined after storage at 26 °C, 10 °C, and 2 °C for 24 h. Compared to 26 °C and 10 °C, storage at 2 °C significantly increased the concentrations of lignin, soluble sugar, flavonoids, and phenolics, as well as the accumulation of H2O2, O2-, and thiobarbituric acid reactive substances (TBARS). Additionally, chilling stress inhibited the levels of indoleacetic acid, while enhancing gibberellin, abscisic acid, and jasmonic acid, which may have increased postharvest ginger's adaptation to chilling. Storage at 10 °C decreased lignin concentration and oxidative damage, and induced less fluctuant changes in enzymes and hormones than storage at 2 °C. RNA-seq revealed that the number of differentially expressed genes (DEGs) increased with decreasing temperature. Functional enrichment analysis of the 523 DEGs that exhibited similar expression patterns between all treatments indicated that they were primarily enriched in phytohormone signaling, biosynthesis of secondary metabolites, and cold-associated MAPK signaling pathways. Key enzymes related to 6-gingerol and curcumin biosynthesis were downregulated at 2 °C, suggesting that cold storage may negatively impact ginger quality. Additionally, 2 °C activated the MKK4/5-MPK3/6-related protein kinase pathway, indicating that chilling may increase the risk of ginger pathogenesis.

Investigating the impact of skull vibrations on motor responses to focused ultrasound neuromodulation in small rodents and methods to mitigate them.

Objective. Focused ultrasound (FUS) neuromodulation non-invasively alters brain activity, likely via acoustic radiation force with dynamics of the pulse repetition frequency (PRF). PRF impacts neuromodulation as well as indirect auditory activation, a confound linked to skull vibrations. This study aimed to minimize these vibrations, by adjusting and randomizing PRF, and determine their impact on FUS-induced motor activity. We hypothesized that: the skull would vibrate most at a specific PRF; randomizing PRF would reduce skull vibrations without affecting motor responses; and FUS would yield motor activity while actuator-induced skull vibrations would not.Approach. Three objectives were studied in parallel using C57Bl/6 mice (n= number of mice used per objective). First, skull vibration amplitude, measured as a percentage of maximum amplitude per treatment, was recorded via contact microphone over a range of PRFs to assess the PRF-dependency of skull vibrations (n= 19). Vibrations were then compared between random and fixed PRFs (n= 15). Lastly, motor responses were compared between fixed 1.5 kHz PRF FUS, random PRF FUS, air-puff stimulation, sham stimulation, and vibration induction via piezoelectric actuator (n= 30).Main Results.The study found amplitude peaked at 1.51 kHz (88.1 ± 11.5%), significantly higher than at 0.54 kHz (75.5 ± 15.1%;p= 0.0149). Random PRF reduced amplitude by 4.2% (p= 0.0181). Motor response rates to actuator-induced skull vibrations at the PRF (5.73 ± 6.96%) and its third harmonic (22.9 ± 22.7%) were not significantly different than sham (14.1 ± 11.6%), but lower than FUS (70.2 ± 16.3%;p< 0.0001).Significance. Based on these results, PRF near 0.5 kHz may best avoid skull vibrations, while random PRF could be utilized to slightly reduce vibration amplitude. The results also suggested that skull vibrations likely do not significantly impact motor responses to FUS neuromodulation.

Resveratrol Regulates Glucose and Lipid Metabolism in Diabetic Rats by Inhibition of PDK1/AKT Phosphorylation and HIF-1α Expression.

Purpose: To explore the underlying mechanism of the anti-diabetic effect of resveratrol (RSV) on regulating glycolipid metabolism in diabetic rats induced by streptozotocin (STZ) and a high-fat diet (HFD). Methods: Male Wistar rats were randomized into three groups. Two groups were fed a high-fat diet and intraperitoneally injected with STZ (35 mg/kg), with one group also treated with RSV (30 mg/kg/d), and the third, control group was fed a normal diet. After 12 weeks, blood lipid levels and fasting blood glucose (FBG) were assessed. Histopathological changes were evaluated by hematoxylin-eosin (HE) staining and periodic acid-Schiff (PAS) staining. The protein expression of hypoxia-inducible factor 1α (HIF-1α) was assessed by Western blotting and immunofluorescence, and the proteins level of 3-phosphoinositide-dependent protein kinase 1 (PDK1), phosphorylated-PDK1 (p-PDK1), phosphorylated-protein kinase B (p-AKT), glucose transporter 1 (GLUT1) and low-density lipoprotein receptor (LDLR) in the liver were analyzed by Western blotting. The mRNA levels of Hif-1α, Glut1 and Ldlr in the liver were determined by RT-qPCR. Results: RSV treatment significantly reduced liver/body weight ratio (L/W, P < 0.05), FBG (P < 0.01) and serum concentrations of total cholesterol (TC, P < 0.05), triglycerides (TG, P < 0.01) and low-density lipoprotein-cholesterol (LDL-C, P < 0.05) in diabetic rats. RSV also improved diabetic symptoms, attenuated liver steatosis and increased liver glycogen accumulation. RSV treatment significantly downregulated the proteins expression of p-PDK1 and p-AKT (P < 0.01) and the levels of HIF-1α (P < 0.05) and GLUT1 (P < 0.01), while significantly upregulating the level of LDLR (P < 0.05). Conclusion: RSV was effective in improving glycolipid metabolism in diabetic rats, probably by inhibiting the PDK1/AKT/HIF-1α pathway and regulation of its downstream target levels. These findings may provide new insight into the mechanism of action of RSV in the treatment of diabetes.

Inhibitory Effect of Resveratrol on LPS-induced Glomerular Mesangial Cells Proliferation and TGF-ß1 Expression via Sphingosine Kinase 1 Pathway.

OBJECTIVE: To elucidate the renoprotective effect of resveratrol (RSV) on sphingosine kinase 1 (SphK1) signaling pathway and expression of its downstream molecules including activator protein 1 (AP-1) and transformation growth factor-ß1 (TGF-ß1) in lipopolysaccharide (LPS)-induced glomerular mesangial cells (GMCs). METHODS: The rat GMCs line (HBZY-1) were cultured and randomly divided into 5 groups, including control, LPS (100 ng/mL), and 5, 10, 20 µmol/L RSV-treated groups. In addition, SphK1 inhibitor (SK-II) was used as positive control. GMCs were pretreated with RSV for 2 h and treated with LPS for another 24 h. GMCs proliferation was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The proteins expression of SphK1, p-c-Jun and TGF-ß1 in GMCs were detected by Western blot, and DNA-binding activity of AP-1 was performed by electrophoretic mobility shift assay (EMSA). The binding activity between RSV and SphK1 protein was detected by AutoDock Vina and visualized by Discovery Studio 2016. RESULTS: LPS could obviously stimulate GMCs proliferation, elevate SphK1, p-c-Jun and TGF-ß1 expression levels and increase the DNA-binding activity of AP-1 (P<0.05 or P<0.01), whereas these effects were significantly blocked by RSV pretreatment. It was also suggested that the effect of RSV was similar to SK-II (P>0.05). Moreover, RSV exhibited good binding affinity towards SphK1, with docking scores of -8.1 kcal/moL and formed hydrogen bonds with ASP-178 and LEU-268 in SphK1. CONCLUSION: RSV inhibited LPS-induced GMCs proliferation and TGF-ß1 expression, which may be independent of its hypoglycemic effect on preventing the development of mesangial cell fibrosis and closely related to the direct inhibition of SphK1 pathway.

Corrigendum: Diversity recovery and probiotic shift of gastric microbiota in functional dyspepsia patients after Helicobacter pylori eradication therapy.

[This corrects the article DOI: 10.3389/fmicb.2023.1288920.].

Considerations in the reliability and fairness audits of predictive models for advance care planning.

Multiple reporting guidelines for artificial intelligence (AI) models in healthcare recommend that models be audited for reliability and fairness. However, there is a gap of operational guidance for performing reliability and fairness audits in practice. Following guideline recommendations, we conducted a reliability audit of two models based on model performance and calibration as well as a fairness audit based on summary statistics, subgroup performance and subgroup calibration. We assessed the Epic End-of-Life (EOL) Index model and an internally developed Stanford Hospital Medicine (HM) Advance Care Planning (ACP) model in 3 practice settings: Primary Care, Inpatient Oncology and Hospital Medicine, using clinicians' answers to the surprise question ("Would you be surprised if [patient X] passed away in [Y years]?") as a surrogate outcome. For performance, the models had positive predictive value (PPV) at or above 0.76 in all settings. In Hospital Medicine and Inpatient Oncology, the Stanford HM ACP model had higher sensitivity (0.69, 0.89 respectively) than the EOL model (0.20, 0.27), and better calibration (O/E 1.5, 1.7) than the EOL model (O/E 2.5, 3.0). The Epic EOL model flagged fewer patients (11%, 21% respectively) than the Stanford HM ACP model (38%, 75%). There were no differences in performance and calibration by sex. Both models had lower sensitivity in Hispanic/Latino male patients with Race listed as "Other." 10 clinicians were surveyed after a presentation summarizing the audit. 10/10 reported that summary statistics, overall performance, and subgroup performance would affect their decision to use the model to guide care; 9/10 said the same for overall and subgroup calibration. The most commonly identified barriers for routinely conducting such reliability and fairness audits were poor demographic data quality and lack of data access. This audit required 115 person-hours across 8-10 months. Our recommendations for performing reliability and fairness audits include verifying data validity, analyzing model performance on intersectional subgroups, and collecting clinician-patient linkages as necessary for label generation by clinicians. Those responsible for AI models should require such audits before model deployment and mediate between model auditors and impacted stakeholders.