Oral arsenic administration to humanizedUDP-glucuronosyltransferase1 neonatal mice induces UGT1A1 through a dependence on Nrf2 and PXR.

Inorganic arsenic (iAs) is an environmental toxicant that can lead to severe health consequences, which can be exacerbated if exposure occurs early in development. Here, we evaluated the impact of oral iAs treatment on UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and bilirubin metabolism in humanized UGT1 (hUGT1) mice. We found that oral administration of iAs to neonatal hUGT1 mice that display severe neonatal hyperbilirubinemia leads to induction of intestinal UGT1A1 and a reduction in total serum bilirubin values. Oral iAs administration accelerates neonatal intestinal maturation, an event that is directly associated with UGT1A1 induction. As a reactive oxygen species producer, oral iAs treatment activated the Keap-Nrf2 pathway in the intestinal tract and liver. When Nrf2-deficient hUGT1 mice (hUGT1/Nrf2-/-) were treated with iAs, it was shown that activated Nrf2 contributed significantly toward intestinal maturation and UGT1A1 induction. However, hepatic UGT1A1 was not induced upon iAs exposure. We previously demonstrated that the nuclear receptor PXR represses liver UGT1A1 in neonatal hUGT1 mice. When PXR was deleted in hUGT1 mice (hUGT1/Pxr-/-), derepression of UGT1A1 was evident in both liver and intestinal tissue in neonates. Furthermore, when neonatal hUGT1/Pxr-/- mice were treated with iAs, UGT1A1 was superinduced in both tissues, confirming PXR release derepressed key regulatory elements on the gene that could be activated by iAs exposure. With iAs capable of generating reactive oxygen species in both liver and intestinal tissue, we conclude that PXR deficiency in neonatal hUGT1/Pxr-/- mice allows greater access of activated transcriptional modifiers such as Nrf2 leading to superinduction of UGT1A1.

The Accuracy of Evaluation of the Requirements of the Standards IEC 61000-3-2(12) with the Application of the Wideband Current Transducer.

The aim of this paper is to determine the conversion accuracy of the Danisense DC200IF (Danisense A/S, Taastrup, Denmark) wideband current transducer for its possible application to test electromagnetic compatibility requirements of the standards IEC 61000-3-2 and IEC 61000-3-12 with the digital power meter Yokogawa WT5000 (Yokogawa Electric Corporation, Tokyo, Japan). To obtain this goal for distorted current of main frequency equal to 50 Hz and in the frequencies range of higher harmonics from 100 Hz to 2500 Hz its amplitude error and phase shift are evaluated. Moreover, the measurable level of higher harmonics with the rated accuracy of the used precision power analyzer is also investigated. Finally, the measuring system is applied to determine the RMS values of current harmonics produced by the audio power amplifier in order to assess its compliance with the standard IEC 61000-3-12.

Metrology for Indoor Radon Measurements and Requirements for Different Types of Devices.

Indoor radon measurements have been conducted in many countries worldwide for several decades. However, to date, there is a lack of a globally harmonized measurement standard. Furthermore, measurement protocols in the US (short-term tests for 2-7 days) and European Union countries (long-term tests for at least 2 months) differ significantly, and their metrological support is underdeveloped, as clear mathematical algorithms (criteria) and QA/QC procedures considering fundamental ISO/IEC concepts such as "measurement uncertainty" and "conformity assessment" are still absent. In this context, for many years, the authors have been advancing and refining the theory of metrological support for standardizing indoor radon measurements based on a rational criterion for conformity assessment within the ISO/IEC concepts. The rational criterion takes into account the main uncertainties arising from temporal variations in indoor radon and instrumental errors, enabling the utilization of both short- and long-term measurements while ensuring specified reliability in decision making (typically no less than 95%). The paper presents improved mathematical algorithms for determining both temporal and instrumental uncertainties. Additionally, within the framework of the rational criterion, unified metrological requirements are formulated for various methods and devices employed in indoor radon measurements.

Enhancing Cybersecurity in Distributed Microgrids: A Review of Communication Protocols and Standards.

The effective operation of distributed energy sources relies significantly on the communication systems employed in microgrids. This article explores the fundamental communication requirements, structures, and protocols necessary to establish a secure connection in microgrids. This article examines the present difficulties facing, and progress in, smart microgrid communication technologies, including wired and wireless networks. Furthermore, it evaluates the incorporation of diverse security methods. This article showcases a case study that illustrates the implementation of a distributed cyber-security communication system in a microgrid setting. The study concludes by emphasizing the ongoing research endeavors and suggesting potential future research paths in the field of microgrid communications.

l-Theanine delays d-galactose-induced senescence by regulating the cell cycle and inhibiting apoptosis in rat intestinal cells.

BACKGROUND: Intestinal senescence is associated with several aging-related diseases. l-Theanine (LTA) has demonstrated strong potential as an antioxidant and antisenescence agent. This study investigated the regulatory effect of LTA on cellular senescence using an in vitro model of d-galactose (D-Gal)-induced senescence in the rat epithelial cell line, intestinal epithelioid cell-6 (IEC-6). RESULTS: Treatment of IEC-6 cells with 40 mg/mL D-Gal for 48 h resulted in the successful development of the senescent cell model. Compared with D-Gal alone, both LTA preventive and delayed intervention increased cell viability and the ratio of JC-1 monomers to aggregates, increased the antioxidant capacity, and decreased the advanced glycation end product (AGE) levels and the overall number of senescent cells. Preventive and delayed intervention with 1000 µM LTA alleviated the D-Gal-induced cell cycle arrest by regulating p38, p53, CDK4, and CDK6 expression at the mRNA and protein levels, and further induced CycD1 proteins. Moreover, LTA preventive intervention reduced apoptosis to a greater degree than delayed intervention by upregulating the expression of the receptors of AGEs, Bax, Bcl-2, and NF-κB at the mRNA and protein levels. CONCLUSION: Our findings indicate that LTA intervention could attenuate senescence in IEC-6 cells by regulating the cell cycle and inhibiting apoptosis. © 2023 Society of Chemical Industry.

Microbiology proficiency testing in fish and fishery products: detection of Listeria monocytogenes and Salmonella spp.

This paper presents the results of two proficiency testing (PT) rounds conducted by the Export Inspection Agency (EIA) Chennai laboratory in 2021 for food testing laboratories in India. The PT program was designed in accordance with ISO/TS 22117, a standard for proficiency testing in food microbiology, and targeted Listeria monocytogenes and Salmonella spp as the organisms of focus. The samples were found to be stable and recoverable during the analysis, and all PT sample packages were delivered to participant laboratories in good condition. The participant laboratories reported high sensitivity rates of 100% for PT round 061021 M and 96.49% for PT round 050721 M. The accuracy rate in PT round 061021 M was 91.89% and 92.10% in case of PT round 050721 M. However, there were some false positive and false negative results reported by some participant laboratories in both PT rounds, which may have been caused by operational errors or inconsistencies in analysis. During the PT round 061021 M, out of a total of 38 participant laboratories, five laboratories reported false positive results and one laboratory reported a false negative result. Similarly, during the PT round 050721 M, six laboratories reported false positive results which resulted in their results being deemed unsatisfactory.

Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids.

We examined the impact of statins on protein kinase D (PKD) activation by G protein-coupled receptor (GPCR) agonists. Treatment of intestinal IEC-18 cells with cerivastatin inhibited PKD autophosphorylation at Ser916 induced by angiotensin II (ANG II) or vasopressin in a dose-dependent manner with half-maximal inhibition at 0.2 µM. Cerivastatin treatment inhibited PKD activation stimulated by these agonists for different times (5-60 min) and blunted HDAC5 phosphorylation, a substrate of PKD. Other lipophilic statins, including simvastatin, atorvastatin, and fluvastatin also prevented PKD activation in a dose-dependent manner. Using IEC-18 cell lines expressing PKD1 tagged with EGFP (enhanced green fluorescent protein), cerivastatin or simvastatin blocked GPCR-mediated PKD1-EGFP translocation to the plasma membrane and its subsequent nuclear accumulation. Similar results were obtained in IEC-18 cells expressing PKD3-EGFP. Mechanistically, statins inhibited agonist-dependent PKD activation rather than acting directly on PKD catalytic activity since exposure to cerivastatin or simvastatin did not impair PKD autophosphorylation or PKD1-EGFP membrane translocation in response to phorbol dibutyrate, which bypasses GPCRs and directly stimulates PKC and PKD. Furthermore, cerivastatin did not inhibit recombinant PKD activity determined via an in vitro kinase assay. Using enteroids generated from intestinal crypt-derived epithelial cells from PKD1 transgenic mice as a model of intestinal regeneration, we show that statins oppose PKD1-mediated increase in enteroid area, complexity (number of crypt-like buds), and DNA synthesis. Our results revealed a previously unappreciated inhibitory effect of statins on receptor-mediated PKD activation and in opposing the growth-promoting effects of PKD1 on intestinal epithelial cells.

Technical and health governance aspects of the External Quality Assessment Scheme for the SARS-CoV-2 molecular tests: institutional experience performed in all clinical laboratories of a Regional Health Service.

OBJECTIVES: Since December 2019, the worldwide public health has been threatened by a severe acute respiratory syndrome caused by Coronavirus-2. From the beginning, a turning point has been the identification of new cases of infection, in order to minimize the virus spreading among the population. For this reason, it was necessary introducing a panel of tests able to identify positive cases, which became crucial for all countries. METHODS: As a Regional Reference Centre, the CRQ Laboratory (Regional Laboratory for the Quality Control) developed and conducted an External Quality Assessment (EQA) panel of assay, so as to evaluate the quality of real-time reverse transcription polymerase chain reaction (PCR), which were used by 62 Sicilian laboratories, previously authorized to issue certificates for the COVID-19 diagnosis, on behalf of the Public Health Service. RESULTS: The qualitative performance test was based on pooled samples with different viral loads of SARS-CoV-2 or human Coronavirus OC43. 75% of the participating laboratories tested all core samples correctly, while the remaining 25% interpreted incorrectly the EQA exercise samples matching negatively the standards required. CONCLUSIONS: Subsequent inspection visits confirmed the issue of incorrect positive and negative certifications for COVID-19 by private and public laboratories, despite the possession of the authorization requirements currently provided for by current regulations, with a significant impact on the SSR.

Family planning service availability and readiness assessment of primary health care facilities in Delta State, Nigeria: a mixed methods survey.

BACKGROUND: The availability of contraceptives, family planning guidelines, and Information, Education, and Communication (IEC) materials can increase access to family planning services. This study assessed the availability of commodities and readiness of primary health care (PHC) facilities in Delta State to offer family planning services. METHODS: A cross-sectional design with an explanatory mixed-method approach was used i.e., the authors first collected the quantitative data, and after preliminary analysis of quantitative information, the qualitative approach was utilised to gather data on the perspectives of 32 PHC facility managers and 6 reproductive health supervisors on factors affecting family planning service availability and readiness. RESULTS: Twenty-one (65.6%) of the PHC facilities surveyed offered at least five modern methods of family planning. Stock-outs of emergency contraceptives, implants, intra-uterine contraceptive device (IUCD), oral contraceptive pills (OCP), condoms, and injectables were observed in 31 (96.9%), 17 (53.1%), 13 (40.6%), 4 (12.5%), 2 (6.3%), and 1 (3.1%) of the facilities respectively. Eleven (34.4%) and 8 (25.0%) of the facilities had IEC materials and family planning guidelines, and contraceptive commodity checklists respectively. Seventeen (53.1%) of the facilities did not have complete records of family planning activities. CONCLUSION: This study shows that a significant proportion of PHC facilities had stock-outs of contraceptive commodities, no complete records of contraceptive activities, no IEC materials and no family planning checklists. Continuous training of health providers and increased government commitment can help to improve contraceptive services.

Schisandra B, a representative lignan from Schisandra chinensis, improves cisplatin-induced toxicity: An in vitro study.

Schisandrin B (Scheme B) is the most abundant and active lignan monomer isolated from Schisandra chinensis. At present, most reports focus on its cardioprotective and hepatoprotective effects, however, the related reports on gastrointestinal protective effects are still limited. The study aims to evaluate the protective effect of Scheme B on cisplatin-induced rat intestinal crypt epithelial (IEC-6) cell injury and the possible molecular mechanisms. The results showed that Scheme B at 2.5, 5 and 10 µM could inhibit dose-dependently the reduction of cell activity induced by cisplatin exposure at 1 µM, decrease the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) to alleviate oxidative stress injury in IEC-6 cell lines. Meanwhile, Scheme B could relieve cisplatin-induced apoptosis by regulating PI3K/AKT and the downstream caspase signaling pathway. The results from flow cytometry analysis and mitochondrial membrane potential (MMP) staining also demonstrated the anti-apoptosis effect of Scheme B. Furthermore, Scheme B was found to reduce the inflammation associated with cell damage by evaluating the protein expressions of the nuclear factor-kappa B (NF-κB) signaling pathway. Importantly, Wnt/ß-catenin, as a functional signaling pathway that drives intestinal self-recovery, was also in part regulated by Scheme B. In conclusion, Scheme B might alleviate cisplatin-induced IEC-6 cell damage by inhibiting oxidative stress, apoptosis, inflammation, and repairing intestinal barrier function. The present research provides a strong evidence that Scheme B may be a useful modulator in cisplatin-induced intestinal toxicity.

New Synthetic Partial Discharge Calibrator for Qualification of Partial Discharge Analyzers for Insulation Diagnosis of HVDC and HVAC Grids.

A synthetic partial discharge (PD) calibrator has been developed to qualify PD analyzers used for insulation diagnosis of HVAC and HVDC grids including cable systems, AIS, GIS, GIL, power transformers, and HVDC converters. PD analyzers that use high-frequency current transformers (HFCT) can be qualified by means of the metrological and diagnosis tests arranged in this calibrator. This synthetic PD calibrator can reproduce PD pulse trains of the same sequence as actual representative defects (cavity, surface, floating potential, corona, SF6 protrusion, SF6 jumping particles, bubbles in oil, etc.) acquired in HV equipment in service or by means of measurements made in HV laboratory test cells. The diagnostic capabilities and PD measurement errors of the PD analyzers using HFCT sensors can be determined. A new time parameter, "PD Time", associated with any arbitrary PD current pulse i(t) is introduced for calibration purposes. It is defined as the equivalent width of a rectangular PD pulse with the same charge value and amplitude as the actual PD current pulse. The synthetic PD calibrator consists of a pulse generator that operates on a current loop matched to 50 Ω impedance to avoid unwanted reflections. The injected current is measured by a reference measurement system built into the PD calibrator that uses two HFCT sensors to ensure that the current signal is the same at the input and output of the calibration cage where the HFCT of the PD analyzer is being calibrated. Signal reconstruction of the HFCT output signal to achieve the input signal is achieved by applying state variable theory using the transfer impedance of the HFCT sensor in the frequency domain.

Constrained Dynamic Matrix Control under International Electrotechnical Commission Standard 61499 and the Open Platform Communications Unified Architecture.

This paper focuses on the implementation of a constrained Dynamic Matrix Control (DMC) approach within the level processes of the FESTO™ MPS-PA Compact Workstation plant in the context of the Industrial Internet of Things (IIoT) paradigm. The goal is to develop an industrial control application with decentralized logic that optimizes the operation of the plant while adhering to specific constraints. The implementation is carried out using the IEC-61499 standard and the OPC-UA protocol, enabling seamless communication between devices and systems. The authors utilize the 4diac-IDE and 4diac-FORTE as the development and runtime environments, respectively, to enable the execution of the control application on low-cost devices. The Beagle Bone Black (BBB) card is used for data acquisition and actuator control. Three types of constraints are considered: control increment (Δu(k)), output (ym(k)), and control (u(k)) constraints, to prevent unnecessary stress on the actuator and avoid damage to the plant. The QP algorithm is employed to optimize the objective function and address these constraints effectively. By integrating advanced control strategies into industrial processes in the IIoT paradigm and implementing them on low-cost devices, this paper demonstrates the feasibility and effectiveness of improving system performance, resource utilization, and overall productivity while considering system limitations and constraints.

Performance Analysis of Routable GOOSE Security Algorithm for Substation Communication through Public Internet Network.

Traditional unidirectional power systems that produce large-scale electricity and supply it using an ultra-high voltage power grid are changing globally to increase efficiency. Current substations' protection relays rely only on internal substation data, where they are located, to detect changes. However, to more accurately detect changes in the system, various data from several external substations, including micro-grids, are required. As such, communication technology regarding data acquisition has become an essential function for next-generation substations. Data aggregators that use the GOOSE protocol to collect data inside substations in real-time have been developed, but data acquisition from external substations is challenging in terms of cost and security, so only internal substation data are used. This paper proposes the acquisition of data from external substations by applying security to R-GOOSE, defined in the IEC 61850 standard, over a public internet network. This paper also develops a data aggregator based on R-GOOSE, showing data acquisition results.

Fast and Reliable Sending of Generic Object Oriented Substation Event Frames between Remote Locations over Loss-Prone Networks.

WAMPAC (Wide Area Monitoring Protection and Control) applications are becoming crucial for granting a stable operation of the electricity transmission grid. These systems use a set of sensors distributed between different electrical substations to gather real-time measurements from the field. These sensors are called Phasor Measurement Units (PMUs). Using the gathered data, different monitoring, protection, and control algorithms are run in a Phasor Data Concentrator (PDC) located in a central location. These algorithms close the loop via the generation of remedial commands, which are sent back to the field level with stringent delay, security, and reliability requirements. GOOSE (Generic Object Oriented Substation Events) protocol, defined by IEC 61850 (IEC stands for International Electrotechnical Commission), is used for that aim and also considers the option of sending these commands over IP networks (this option is called Routed-GOOSE). The present article proposes two alternatives for the tunneling of GOOSE frames over IP. Both options allow the decoupling of the transmission and the security aspects, thus increasing flexibility and allowing for easier deployment. The first option, called VX-GOOSE, is a combination of standard protocols, allowing the sending of these frames over UDP/IP tunnels. The tests that have been carried out demonstrate that, under certain network conditions, the transmission of GOOSE frames over UDP may fail, and in some extreme cases, even a whole burst of GOOSEs could be lost. This may have very bad consequences for a distributed electrical system. It should be noted that this limitation affects both VX-GOOSE and Routed-GOOSE. To overcome these limitations, the second option, called Simplemux blast mode, includes a novel mechanism that provides delivery guarantees and a reduced delay, with the counterpart of a certain degree of redundancy. As shown in the experiments, the incurred delays can be significantly reduced when remote locations are connected via unreliable networks, whereas the bandwidth increase caused by redundancy can be kept at reasonable levels. Finally, it should be remarked that although GOOSE is a relevant example use case, this approach can be applied in other fields where flows require very low delay and delivery guarantees.

A Standardized Protocol for Assuring the Validity of Proteomics Results from Liquid Chromatography-High-Resolution Mass Spectrometry.

Significant advances in the technological development of mass spectrometry in the field of proteomics and the generation of extremely large amounts of data require a very critical approach to assure the validity of results. Commonly used procedures involved liquid chromatography followed by high-resolution mass spectrometry measurements. Proteomics analysis is used in many fields including the investigation of the metabolism of biologically active substances in organisms. Thus, there is a need to care about the validity of the obtained results. In this work, we proposed a standardized protocol for proteomic analysis using liquid chromatography-high-resolution mass spectrometry, which covers all of these analytical steps to ensure the validity of the results. For this purpose, we explored the requirements of the ISO/IEC 17025:2017 standard as a reference document for quality control in biochemistry research-based mass spectrometry.

Quality of COVID-19 information, education and communication materials in India: A content analysis.

Objective: This study examined the characteristics and quality of publicly available COVID-19 information education and communication (IEC) materials in India between March and December 2020. Design: An explanatory sequential mixed-method design was employed to examine the characteristics and quality of 265 purposefully selected IEC materials. Setting: The IEC materials analysed were those published between March and December 2020 on the Ministry of Health and Family Welfare website, Government of India. Methods: A checklist was utilised to examine the quality and characteristics of the materials. Thereafter, qualitative analysis provided insights into the contents of the materials with specific focus on the 'COVID-19 continuum of care'. Results: The majority (73.96%, n = 196) of the selected materials were directed towards the general public and had a focus on prevention (67.55 %, n = 179). Despite COVID-19-associated stigma, only 56 (21.13%) of the materials addressed this issue. However, most (95.47%, n = 253) of the materials adhered to quality standards for contents, readability and aesthetics. This qualitative analysis focused on the contents of selected IEC materials using the concept of 'continuum of care'. The analysis identified three important themes: prevention to early diagnosis and treatment; mitigation of stigma and discrimination surrounding COVID-19; and addressing the infodemic caused by COVID-19. Conclusion: The quality of materials was mostly satisfactory and appropriate to the emergent requirements. Strengthening audience engagement and attractiveness of the materials might enhance readability and actionability. A bottom-up approach to the development of future IEC materials, involving the community might widen the coverage of vulnerable populations in future crisis events.

Machine learning for mHealth apps quality evaluation: An approach based on user feedback analysis.

Mobile apps for healthcare (mHealth apps for short) have been increasingly adapted to help users manage their health or to get healthcare services. User feedback analysis is a pertinent method that can be used to improve the quality of mHealth apps. The objective of this paper is to use supervised machine learning algorithms to evaluate the quality of mHealth apps according to the ISO/IEC 25010 quality model based on user feedback. For this purpose, a total of 1682 user reviews have been collected from 86 mHealth apps provided by Google Play Store. Those reviews have been classified initially into the ISO/IEC 25010 eight quality characteristics, and further into Negative, Positive, and Neutral opinions. This analysis has been performed using machine learning and natural language processing techniques. The best performances were provided by the Stochastic Gradient Descent (SGD) classifier with an accuracy of 82.00% in classifying user reviews according to the ISO/IEC 25010 quality characteristics. Moreover, Support Vector Machine (SVM) classified the collected user reviews into Negative, Positive, and Neutral with an accuracy of 90.50%. Finally, for each quality characteristic, we classified the collected reviews according to the sentiment polarity. The best performance results were obtained for the Usability, Security, and Compatibility quality characteristics using SGD classifier with an accuracy equal to 98.00%, 97.50%, and 96.00%, respectively. The results of this paper will be effective to assist developers in improving the quality of mHealth apps.

Molecular Assessment of Staphylococcus Aureus Strains in STAT3 Hyper-IgE Syndrome Patients.

Hyper-IgE syndromes (HIES) are a group of inborn errors of immunity (IEI) caused by monogenic defects such as in the gene STAT3 (STAT3-HIES). Patients suffering from HIES show an increased susceptibility to Staphylococcus aureus (S. aureus) including skin abscesses and pulmonary infections. To assess if the underlying immune defect of STAT3-HIES patients influences the resistance patterns, pathogenicity factors or strain types of S. aureus. We characterized eleven S. aureus strains isolated from STAT3-HIES patients (n = 4) by whole genome sequencing (WGS) to determine presence of resistance and virulence genes. Additionally, we used multi-locus sequence typing (MLST) and protein A (spa) typing to classify these isolates. Bacterial isolates collected from this cohort of STAT3-HIES patients were identified as common spa types in Germany. Only one of the isolates was classified as methicillin-resistant S. aureus (MRSA). For one STAT3 patient WGS illustrated that infection and colonization occurred with different S. aureus isolates rather than one particular clone. The identified S. aureus carriage profile on a molecular level suggests that S. aureus strain type in STAT3-HIES patients is determined by local epidemiology rather than the underlying immune defect highlighting the importance of microbiological assessment prior to antibiotic treatment.

Circular RNA CircHIPK3 Promotes Homeostasis of the Intestinal Epithelium by Reducing MicroRNA 29b Function.

BACKGROUND & AIMS: Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that form covalently closed circles. Although circRNAs influence many biological processes, little is known about their role in intestinal epithelium homeostasis. We surveyed circRNAs required to maintain intestinal epithelial integrity and identified circular homeodomain-interacting protein kinase 3 (circHIPK3) as a major regulator of intestinal epithelial repair after acute injury. METHODS: Intestinal mucosal tissues were collected from mice exposed to cecal ligation and puncture for 48 hours and patients with inflammatory bowel diseases and sepsis. We isolated primary enterocytes from the small intestine of mice and derived intestinal organoids. The levels of circHIPK3 were silenced in intestinal epithelial cells (IECs) by transfection with small interfering RNAs targeting the circularization junction of circHIPK3 or elevated using a plasmid vector that overexpressed circHIPK3. Intestinal epithelial repair was examined in an in vitro injury model by removing part of the monolayer. The association of circHIPK3 with microRNA 29b (miR-29b) was determined by biotinylated RNA pull-down assays. RESULTS: Genome-wide profile analyses identified ∼300 circRNAs, including circHIPK3, differentially expressed in the intestinal mucosa of mice after cecal ligation and puncture relative to sham mice. Intestinal mucosa from patients with inflammatory bowel diseases and sepsis had reduced levels of circHIPK3. Increasing the levels of circHIPK3 enhanced intestinal epithelium repair after wounding, whereas circHIPK3 silencing repressed epithelial recovery. CircHIPK3 silencing also inhibited growth of IECs and intestinal organoids, and circHIPK3 overexpression promoted intestinal epithelium renewal in mice. Mechanistic studies revealed that circHIPK3 directly bound to miR-29b and inhibited miR-29 activity, thus increasing expression of Rac1, Cdc42, and cyclin B1 in IECs after wounding. CONCLUSIONS: In studies of mice, IECs, and human tissues, our results indicate that circHIPK3 improves repair of the intestinal epithelium at least in part by reducing miR-29b availability.

L-lactate promotes intestinal epithelial cell migration to inhibit colitis.

Lactate, one of the most common primary metabolites of bacteria and human cells, has been shown to play essential roles in the regulation of inflammatory diseases, including inflammatory bowel diseases. However, whether and how host-derived lactate affects intestinal epithelial homeostasis is still not completely understood. Here, we investigated how L-lactate, mainly produced by host cells, regulates intestinal epithelial cell (IEC) migration to promote intestinal wound healing. Using video microscopy and tracking individual cells, we found that L-lactate enhanced IEC migration in direction persistence and speed. Mechanistically, L-lactate promoted IEC mitochondrial ATP production. The mitochondrial ATP synthase inhibitor, oligomycin, significantly decreased IEC persistence and speed, which inhibited cell migration induced by L-lactate. Furthermore, administering mice with L-lactate suppressed colitis induced by dextran sulfate sodium. In conclusion, our study demonstrates that host-derived L-lactate promotes IEC mitochondrial ATP production to drive cell migration, promoting intestinal wound healing to alleviate intestinal inflammation.