Structural basis for intrinsic transcription termination.

Efficient and accurate termination is required for gene transcription in all living organisms1,2. Cellular RNA polymerases in both bacteria and eukaryotes can terminate their transcription through a factor-independent termination pathway3,4-called intrinsic termination transcription in bacteria-in which RNA polymerase recognizes terminator sequences, stops nucleotide addition and releases nascent RNA spontaneously. Here we report a set of single-particle cryo-electron microscopy structures of Escherichia coli transcription intrinsic termination complexes representing key intermediate states of the event. The structures show how RNA polymerase pauses at terminator sequences, how the terminator RNA hairpin folds inside RNA polymerase, and how RNA polymerase rewinds the transcription bubble to release RNA and then DNA. These macromolecular snapshots define a structural mechanism for bacterial intrinsic termination and a pathway for RNA release and DNA collapse that is relevant for factor-independent termination by all RNA polymerases.

Spin current from sub-terahertz-generated antiferromagnetic magnons.

Spin dynamics in antiferromagnets has much shorter timescales than in ferromagnets, offering attractive properties for potential applications in ultrafast devices1-3. However, spin-current generation via antiferromagnetic resonance and simultaneous electrical detection by the inverse spin Hall effect in heavy metals have not yet been explicitly demonstrated4-6. Here we report sub-terahertz spin pumping in heterostructures of a uniaxial antiferromagnetic Cr2O3 crystal and a heavy metal (Pt or Ta in its ß phase). At 0.240 terahertz, the antiferromagnetic resonance in Cr2O3 occurs at about 2.7 tesla, which excites only right-handed magnons. In the spin-canting state, another resonance occurs at 10.5 tesla from the precession of induced magnetic moments. Both resonances generate pure spin currents in the heterostructures, which are detected by the heavy metal as peaks or dips in the open-circuit voltage. The pure-spin-current nature of the electrically detected signals is unambiguously confirmed by the reversal of the voltage polarity observed under two conditions: when switching the detector metal from Pt to Ta, reversing the sign of the spin Hall angle7-9, and when flipping the magnetic-field direction, reversing the magnon chirality4,5. The temperature dependence of the electrical signals at both resonances suggests that the spin current contains both coherent and incoherent magnon contributions, which is further confirmed by measurements of the spin Seebeck effect and is well described by a phenomenological theory. These findings reveal the unique characteristics of magnon excitations in antiferromagnets and their distinctive roles in spin-charge conversion in the high-frequency regime.

Imaging viscous flow of the Dirac fluid in graphene.

The electron-hole plasma in charge-neutral graphene is predicted to realize a quantum critical system in which electrical transport features a universal hydrodynamic description, even at room temperature1,2. This quantum critical 'Dirac fluid' is expected to have a shear viscosity close to a minimum bound3,4, with an interparticle scattering rate saturating1 at the Planckian time, the shortest possible timescale for particles to relax. Although electrical transport measurements at finite carrier density are consistent with hydrodynamic electron flow in graphene5-8, a clear demonstration of viscous flow at the charge-neutrality point remains elusive. Here we directly image viscous Dirac fluid flow in graphene at room temperature by measuring the associated stray magnetic field. Nanoscale magnetic imaging is performed using quantum spin magnetometers realized with nitrogen vacancy centres in diamond. Scanning single-spin and wide-field magnetometry reveal a parabolic Poiseuille profile for electron flow in a high-mobility graphene channel near the charge-neutrality point, establishing the viscous transport of the Dirac fluid. This measurement is in contrast to the conventional uniform flow profile imaged in a metallic conductor and also in a low-mobility graphene channel. Via combined imaging and transport measurements, we obtain viscosity and scattering rates, and observe that these quantities are comparable to the universal values expected at quantum criticality. This finding establishes a nearly ideal electron fluid in charge-neutral, high-mobility graphene at room temperature4. Our results will enable the study of hydrodynamic transport in quantum critical fluids relevant to strongly correlated electrons in high-temperature superconductors9. This work also highlights the capability of quantum spin magnetometers to probe correlated electronic phenomena at the nanoscale.

An SI3-σ arch stabilizes cyanobacteria transcription initiation complex.

Multisubunit RNA polymerases (RNAPs) associate with initiation factors (σ in bacteria) to start transcription. The σ factors are responsible for recognizing and unwinding promoter DNA in all bacterial RNAPs. Here, we report two cryo-EM structures of cyanobacterial transcription initiation complexes at near-atomic resolutions. The structures show that cyanobacterial RNAP forms an "SI3-σ" arch interaction between domain 2 of σA (σ2) and sequence insertion 3 (SI3) in the mobile catalytic domain Trigger Loop (TL). The "SI3-σ" arch facilitates transcription initiation from promoters of different classes through sealing the main cleft and thereby stabilizing the RNAP-promoter DNA open complex. Disruption of the "SI3-σ" arch disturbs cyanobacteria growth and stress response. Our study reports the structure of cyanobacterial RNAP and a unique mechanism for its transcription initiation. Our data suggest functional plasticity of SI3 and provide the foundation for further research into cyanobacterial and chloroplast transcription.

Mapping the intrinsic photocurrent streamlines through micromagnetic heterostructure devices.

Photocurrent in quantum materials is often collected at global contacts far away from the initial photoexcitation. This collection process is highly nonlocal. It involves an intricate spatial pattern of photocurrent flow (streamlines) away from its primary photoexcitation that depends sensitively on the configuration of current collecting contacts as well as the spatial nonuniformity and tensor structure of conductivity. Direct imaging to track photocurrent streamlines is challenging. Here, we demonstrate a microscopy method to image photocurrent streamlines through ultrathin heterostructure devices comprising platinum on yttrium iron garnet (YIG). We accomplish this by combining scanning photovoltage microscopy with a uniform rotating magnetic field. Here, local photocurrent is generated through a photo-Nernst type effect with its direction controlled by the external magnetic field. This enables the mapping of photocurrent streamlines in a variety of geometries that include conventional Hall bar-type devices, but also unconventional wing-shaped devices called electrofoils. In these, we find that photocurrent streamlines display contortion, compression, and expansion behavior depending on the shape and angle of attack of the electrofoil devices, much in the same way as tracers in a wind tunnel map the flow of air around an aerodynamic airfoil. This affords a powerful tool to visualize and characterize charge flow in optoelectronic devices.

Structural insights into the transcription activation mechanism of the global regulator GlnR from actinobacteria.

In actinobacteria, an OmpR/PhoB subfamily protein called GlnR acts as an orphan response regulator and globally coordinates the expression of genes responsible for nitrogen, carbon, and phosphate metabolism in actinobacteria. Although many researchers have attempted to elucidate the mechanisms of GlnR-dependent transcription activation, progress is impeded by lacking of an overall structure of GlnR-dependent transcription activation complex (GlnR-TAC). Here, we report a co-crystal structure of the C-terminal DNA-binding domain of GlnR (GlnR_DBD) in complex with its regulatory cis-element DNA and a cryo-EM structure of GlnR-TAC which comprises Mycobacterium tuberculosis RNA polymerase, GlnR, and a promoter containing four well-characterized conserved GlnR binding sites. These structures illustrate how four GlnR protomers coordinate to engage promoter DNA in a head-to-tail manner, with four N-terminal receiver domains of GlnR (GlnR-RECs) bridging GlnR_DBDs and the RNAP core enzyme. Structural analysis also unravels that GlnR-TAC is stabilized by complex protein-protein interactions between GlnR and the conserved ß flap, σAR4, αCTD, and αNTD domains of RNAP, which are further confirmed by our biochemical assays. Taken together, these results reveal a global transcription activation mechanism for the master regulator GlnR and other OmpR/PhoB subfamily proteins and present a unique mode of bacterial transcription regulation.

NAT10 Is Involved in Cardiac Remodeling Through ac4C-Mediated Transcriptomic Regulation.

BACKGROUND: Heart failure, characterized by cardiac remodeling, is associated with abnormal epigenetic processes and aberrant gene expression. Here, we aimed to elucidate the effects and mechanisms of NAT10 (N-acetyltransferase 10)-mediated N4-acetylcytidine (ac4C) acetylation during cardiac remodeling. METHODS: NAT10 and ac4C expression were detected in both human and mouse subjects with cardiac remodeling through multiple assays. Subsequently, acetylated RNA immunoprecipitation and sequencing, thiol-linked alkylation for the metabolic sequencing of RNA (SLAM-seq), and ribosome sequencing (Ribo-seq) were employed to elucidate the role of ac4C-modified posttranscriptional regulation in cardiac remodeling. Additionally, functional experiments involving the overexpression or knockdown of NAT10 were conducted in mice models challenged with Ang II (angiotensin II) and transverse aortic constriction. RESULTS: NAT10 expression and RNA ac4C levels were increased in in vitro and in vivo cardiac remodeling models, as well as in patients with cardiac hypertrophy. Silencing and inhibiting NAT10 attenuated Ang II-induced cardiomyocyte hypertrophy and cardiofibroblast activation. Next-generation sequencing revealed ac4C changes in both mice and humans with cardiac hypertrophy were associated with changes in global mRNA abundance, stability, and translation efficiency. Mechanistically, NAT10 could enhance the stability and translation efficiency of CD47 and ROCK2 transcripts by upregulating their mRNA ac4C modification, thereby resulting in an increase in their protein expression during cardiac remodeling. Furthermore, the administration of Remodelin, a NAT10 inhibitor, has been shown to prevent cardiac functional impairments in mice subjected to transverse aortic constriction by suppressing cardiac fibrosis, hypertrophy, and inflammatory responses, while also regulating the expression levels of CD47 and ROCK2 (Rho associated coiled-coil containing protein kinase 2). CONCLUSIONS: Therefore, our data suggest that modulating epitranscriptomic processes, such as ac4C acetylation through NAT10, may be a promising therapeutic target against cardiac remodeling.

Enzyme-catalysed [6+4] cycloadditions in the biosynthesis of natural products.

Pericyclic reactions are powerful transformations for the construction of carbon-carbon and carbon-heteroatom bonds in organic synthesis. Their role in biosynthesis is increasingly apparent, and mechanisms by which pericyclases can catalyse reactions are of major interest1. [4+2] cycloadditions (Diels-Alder reactions) have been widely used in organic synthesis2 for the formation of six-membered rings and are now well-established in biosynthesis3-6. [6+4] and other 'higher-order' cycloadditions were predicted7 in 1965, and are now increasingly common in the laboratory despite challenges arising from the generation of a highly strained ten-membered ring system8,9. However, although enzyme-catalysed [6+4] cycloadditions have been proposed10-12, they have not been proven to occur. Here we demonstrate a group of enzymes that catalyse a pericyclic [6+4] cycloaddition, which is a crucial step in the biosynthesis of streptoseomycin-type natural products. This type of pericyclase catalyses [6+4] and [4+2] cycloadditions through a single ambimodal transition state, which is consistent with previous proposals11,12. The [6+4] product is transformed to a less stable [4+2] adduct via a facile Cope rearrangement, and the [4+2] adduct is converted into the natural product enzymatically. Crystal structures of three pericyclases, computational simulations of potential energies and molecular dynamics, and site-directed mutagenesis establish the mechanism of this transformation. This work shows how enzymes are able to catalyse concerted pericyclic reactions involving ambimodal transition states.

Serum GSDMD for Early Diagnosis of Bloodstream Infection and Differentiating Bacterial from Fungal Infections.

BACKGROUND: The role of Gasdermin D (GSDMD) in bloodstream infection (BSI) diagnosis is unknown. METHODS: Serum GSDMD levels were measured in BSI patients. Endothelial cells and PBMCs were isolated, infected with bacteria/fungi, and intracellular/extracellular GSDMD concentrations were measured. An animal model was established to investigate the association between serum GSDMD levels and BSI incidence/progression. RESULTS: ROC curve analysis indicated that GSDMD could be a potential early diagnostic biomarker for BSI (AUC = 0.9885). Combining GSDMD with procalcitonin (PCT) improved the differential diagnosis of Gram-positive and Gram-negative bacteria (AUC = 0.6699, 66.15% specificity), and early diagnosis of Gram-positive bacteria (98.46% sensitivity), while PCT was not significantly elevated. The combined GSDMD and G-test had higher sensitivity (AUC = 0.7174) for differential diagnosis of bacterial and fungal infections, and early detection of fungal infections (98.44% sensitivity). In vitro and in vivo experiments confirmed that GSDMD levels increased significantly within 2 hours, peaked at 16 hours, and exhibited a time-dependent upward trend. CONCLUSIONS: Serum GSDMD, alone or combined with other biomarkers, has potential for early diagnosis and differential diagnosis of BSI caused by various pathogens. This finding offers a new strategy for early detection and treatment of BSI.

Real-Time Monitoring of Tyrosine Hydroxylase Activity with a Ratiometric Fluorescent Probe.

Parkinson's disease (PD) represents the second most widespread neurodegenerative disease, and early monitoring and diagnosis are urgent at present. Tyrosine hydroxylase (TH) is a key enzyme for producing dopamine, the levels of which can serve as an indicator for assessing the severity and progression of PD. This renders the specific detection and visualization of TH a strategically vital way to meet the above demands. However, a fluorescent probe for TH monitoring is still missing. Herein, three rationally designed wash-free ratiometric fluorescent probes were proposed. Among them, TH-1 exhibited ideal photophysical properties and specific dual-channel bioimaging of TH activity in SH-SY5Y nerve cells. Moreover, the probe allowed for in vivo imaging of TH activity in zebrafish brain and living striatal slices of mice. Overall, the ratiometric fluorescent probe TH-1 could serve as a potential tool for real-time monitoring of PD in complex biosystems.

EP300 promotes lung cancer cell proliferation by regulating the oncogenic transcription of Hippo-YAP signaling pathway.

The transcriptional activation function of YAP in cancer development has been widely studied. However, the underlying regulatory mechanisms remain largely unknown. In this study, we found that EP300, one histone acetyltransferase, interacted with YAP and was recruited into the phase separated condensates of YAP. Transcriptomic analysis revealed substantial alterations in gene expression upon EP300 depletion, with downregulated genes associated with cancer progression and Hippo-YAP pathway. Notably, disruption of EP300 inhibited the transcriptional activation of YAP and reduced the binding of H3K27ac on YAP target oncogenes in Hippo pathway. Moreover, depletion of EP300 effectively inhibited YAP-driven tumor growth. Taken together, these results indicate that EP300 contributes to lung cancer progression by promoting the oncogenic transcription of YAP through H3K27ac, which suggests that YAP-EP300 axis may be potential therapeutic targets for lung cancer treatment.

PTPRO inhibits LPS-induced apoptosis in alveolar epithelial cells.

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), represent critical clinical syndromes with multifactorial origins, notably stemming from sepsis within intensive care units (ICUs). Despite their high mortality rates, no selective cure is available beside ventilation support. Apoptosis plays a complex and pivotal role in the pathophysiology of acute lung injury. Excessive apoptosis of alveolar epithelial and microvascular endothelial cells can lead to disruption of lung epithelial barrier integrity, impairing the body's ability to exchange blood and gas. At the same time, apoptosis of damaged or dysfunctional cells, including endothelial and epithelial cells, can help maintain tissue integrity and accelerate recovery from organ pro-inflammatory stress. The balance between pro-survival and pro-apoptotic signals in lung injury determines patient outcomes, making the modulation of apoptosis an area of intense research in the quest for more effective therapies. Here we found that protein tyrosine phosphatase receptor type O (PTPRO), a poorly understood receptor-like protein tyrosine phosphatase, is consistently upregulated in multiple tissue types of mice under septic conditions and in the lung alveolar epithelial cells. PTPRO reduction by its selective short-interfering RNA (siRNA) leads to excessive apoptosis in lung alveolar epithelial cells without affecting cell proliferation. Consistently PTPRO overexpression by a DNA construct attenuates apoptotic signaling induced by LPS. These effects of PTPTO on cellular apoptosis are dependent on an ErbB2/PI3K/Akt/NFκB signaling pathway. Here we revealed a novel regulatory pathway of cellular apoptosis by PTPRO in lung alveolar epithelial cells during sepsis.

Thermal Induced Conversion of CoFe Prussian Blue Analogs Nanocubes Wrapped by Doped Carbon Network Exhibiting Fast and Stable Potassium Ion Storage as Anode.

Prussian blue analogs (PBAs) show great promise as anode materials for potassium-ion batteries (PIBs) due to their high specific capacity. However, PBAs still suffer from the drawbacks of low electronic conductivity and poor structural stability, leading to inadequate rate and cyclic performance. To address these limitations, CoFe PBA nanocubes wrapped with N/S doped carbon network (CoFe PBA@NSC) as anode for PIBs is designed by using thermal-induced in situ conversion strategy. As expected, the structural advantages of nanosized PBA cubes, such as abundant interfaces and large surface area, enable the CoFe PBA@NSC electrode to demonstrate superior rate properties (557 and 131 mAh g-1 at 0.05 and 10 A g-1) and low capacity degradation (0.093% per cycle over 1000 cycles at 0.5 A g-1). Furthermore, several ex situ characterizations revealed the K-ion storage mechanism. Fe+ and Co0 are generated during potassicization, followed by a completely reversible chemical state of iron while some cobalt monomers remained during depotassication. Additionally, the as-built potassium-ion hybrid capacitor based on CoFe PBA@NSC anode exhibits a high energy density of 118 Wh kg-1. This work presents an alternative but promising synthesis route for Prussian blue analogs, which is significant for the advancement of PIBs and other related energy storage devices.

RplI interacts with 5' UTR of exsA to repress its translation and type III secretion system in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an important opportunistic pathogen capable of causing variety of infections in humans. The type III secretion system (T3SS) is a critical virulence determinant of P. aeruginosa in the host infections. Expression of the T3SS is regulated by ExsA, a master regulator that activates the expression of all known T3SS genes. Expression of the exsA gene is controlled at both transcriptional and posttranscriptional levels. Here, we screened a P. aeruginosa transposon (Tn5) insertional mutant library and found rplI, a gene coding for the ribosomal large subunit protein L9, to be a repressor for the T3SS gene expression. Combining real-time quantitative PCR (qPCR), western blotting and lacZ fusion assays, we show that RplI controls the expression of exsA at the posttranscriptional level. Further genetic experiments demonstrated that RplI mediated control of the exsA translation involves 5' untranslated region (5' UTR). A ribosome immunoprecipitation assay and qPCR revealed higher amounts of a 24 nt fragment from exsA mRNA being associated with ribosomes in the ΔrplI mutant. An interaction between RplI and exsA mRNA harboring its 24 nt, but not 12 nt, 5' UTR was confirmed by RNA Gel Mobility Shift and Microscale Thermophoresis assays. Overall, this study identifies the ribosomal large subunit protein L9 as a novel T3SS repressor that inhibits ExsA translation in P. aeruginosa.

2 W, 1.5†µm single-mode fiber methane Raman laser pumped by a Yb-doped fiber amplifier.

We report here, to the best of our knowledge, the first 1.5 µm methane-filled fiber Raman laser pumped by a fiber laser. Based on the narrow-linewidth pulsed Yb-doped fiber laser pump source and a 15 m hollow-core fiber filled with 2.5 bar methane, the maximum power of 2.06 W Stokes wave at 1543 nm is obtained. The output laser has a narrow linewidth of 2.3 GHz, and the pulse repetition frequency can be adjusted flexibly. The output shows excellent near-diffraction-limited beam quality with a M2 factor of ∼1.09. This work proves the advantage of the fiber laser pump source with modest peak power and flexible temporal characteristics in 1.5 µm fiber gas Raman laser emission, providing good guidance for generating pulsed fiber source with narrow linewidth and high beam quality.

Lysine-372-dependent SUMOylation inhibits the enzymatic activity of glutamine synthases.

Glutamine synthetase (GS) is a crucial enzyme involved in de novo synthesis of glutamine and participates in several biological processes, including nitrogen metabolism, nucleotide synthesis, and amino acid synthesis. Post-translational modification makes GS more adaptable to the needs of cells, and acetylation modification of GS at double sites has attracted considerable attention. Despite very intensive research, how SUMOylation affects GS activity at a molecular level remains unclear. Here, we report that previously undiscovered GS SUMOylation which is deficient mutant K372R of GS exhibits more bluntness under glutamine starvation. Mechanistically, glutamine deprivation triggers the GS SUMOylation, and this SUMOylation impaired the protein stability of GS, within a concomitant decrease in enzymatic activity. In addition, we identified SAE1, Ubc9, and PIAS1 as the assembly enzymes of GS SUMOylation respectively. Furthermore, Senp1/2 functions as a SUMO-specific protease to reverse the SUMOylation of GS. This study provides the first evidence that SUMOylation serves as a regulatory mechanism for determining the GS enzymatic activity, contributing to understanding the GS regulation roles in various cellular and pathophysiological processes.

Bisphenol a downregulates GLUT4 expression by activating aryl hydrocarbon receptor to exacerbate polycystic ovary syndrome.

BACKGROUND: Bisphenol A (BPA) levels are high in women with polycystic ovary syndrome (PCOS). The mechanism by which BPA induces abnormal glucose metabolism in PCOS patients is largely unknown. METHODS: Serum and urine samples were collected from women with and without PCOS (control) at the reproductive medicine center with informed consent. Non-PCOS patients who received in vitro fertilization were recruited for collection of ovarian follicular fluid and granular cells. Wild-type C57BL/6 and AhR -/- mice were used to verify the effects of BPA on PCOS. Real-time PCR, western blotting, and ELISA were conducted to analyze the function of BPA. Chip-qPCR verified the role of AhR in GLUT4 transcription. Flow cytometry was performed to determine glucose uptake. RESULTS: A positive correlation was observed between BPA concentration and serum BPA levels in PCOS patients. BPA aggravated the changes in PCOS with abnormal glucose metabolism, impaired fertility, and increased body fat. Mechanistically, we showed that BPA activated AhR and led to decreased glucose transport via GLUT4 downregulation in ovarian granular cells. Therefore, the use of inhibitors or knockout of AhR could effectively rescue BPA-induced metabolic disorders in PCOS mice. CONCLUSIONS: Our results revealed that BPA suppressed GLUT4 expression and induced abnormal glucose metabolism by activating AhR, causing insulin resistance, and is thus a potential contributor to the development of PCOS. Therefore, AhR could be a potential new therapeutic target for PCOS. Video Abstract.

Pregnancy outcomes of fetal reduction in patients with intrauterine haematoma following double embryo transfer.

RESEARCH QUESTION: Is there an association between intrauterine haematoma (IUH) and pregnancy outcomes in patients who undergo fetal reduction after double embryo transfer (DET), and if so, what is the relationship between IUH-related characteristics and pregnancy outcomes? DESIGN: Clinical information and pregnancy outcomes of women who underwent fetal reduction after DET were analysed. Patients with other systematic diseases, ectopic pregnancy or heterotopic pregnancy, monochorionic twin pregnancies and incomplete data were excluded. Stratification of IUH pregnancies was undertaken based on IUH-related characteristics. The main outcome was incidence of fetal demise (<24 weeks), with other adverse pregnancy outcomes considered as secondary outcomes. RESULTS: Thirty-four IUH patients and 136 non-IUH patients who underwent fetal reduction after DET were included based on a 1:4 match for age, cycle type and fertilization method. IUH patients had a higher incidence of early fetal demise (20.6% versus 7.4%, P = 0.048), threatened abortion (48.1% versus 10.3%, P<0.001) and postpartum haemorrhage (PPH; 14.8% versus 4.0%, P = 0.043) compared with non-IUH patients. IUH was an independent risk factor for early fetal demise [adjusted OR (aOR) 3.34, 95% CI 1.14-9.77] and threatened abortion (aOR 8.61, 95% CI 3.28-22.61) after adjusting for potential confounders. IUH pregnancies undergoing fetal reduction that resulted in miscarriage had larger IUH volumes and earlier diagnosis (both P < 0.03). However, IUH characteristics (i.e. volume, changing pattern, presence or absence of cardiac activity) were not associated with threatened abortion or PPH. CONCLUSIONS: Fetal reduction should be performed with caution in IUH pregnancies after DET as the risk of fetal demise is relatively high. Particular attention should be given to IUH patients with early signs of threatened abortion and inevitable fetal demise.

Intraoperative Glucose and Kidney Injury After On-Pump Cardiac Surgery: A Retrospective Cohort Study.

INTRODUCTION: Acute kidney injury (AKI) is a common complication after on-pump cardiac surgery, and previous studies have suggested that blood glucose is associated with postoperative AKI. However, limited evidence is available regarding intraoperative glycemic thresholds in cardiac surgery. The aim of this study was to explore the association between peak intraoperative blood glucose and postoperative AKI, and determine the cut-off values for intraoperative glucose concentration associated with an increased risk of AKI. METHODS: The study was retrospective and single-centered. Adult patients in West China Hospital of Sichuan University who underwent on-pump cardiac surgery (n = 3375) were included. The primary outcome was the incidence of AKI. Multivariable logistic analysis using restricted cubic spline was performed to explore the association between intraoperative blood glucose and postoperative AKI. RESULTS: The incidence of AKI in the study population was 18.0% (607 of 3375). Patients who developed AKI had a significantly higher peak intraoperative glucose during the surgery compared to those without AKI. After adjustment for confounders, the incidence of AKI increased with peak intraoperative blood glucose (adjusted odds ratio, 1.08, 95% confidence interval 1.03, 1.12). Furthermore, it was demonstrated that the possibility of AKI was relatively flat till 127.8 mg/dL (7.1 mmol/L) glucose levels which started to rapidly increase afterward. CONCLUSIONS: Increased intraoperative blood glucose was associated with an increased risk of AKI. Among patients undergoing on-pump cardiac surgery, avoiding a high glucose peak (i.e., below 127.8 mg/dL [7.1 mmol/L]) may reduce the risk of postoperative AKI.

The relationship between innate/adaptive immunity and gastrointestinal cancer : a multi-omics Mendelian randomization study.

BACKGROUND: Innate/adaptive immunity is the key to anti-tumor therapy. However, its causal relationship to Gastrointestinal (GI) cancer remains unclear. METHODS: Immunity genes were extracted from the MSigDB database. The Genome-wide association studies (GWAS) summary data of GI cancer were integrated with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) associated with genes. Summary-data-based Mendelian randomization (SMR) and co-localization analysis were used to reveal causal relationships between genes and GI cancer. Two-sample MR analysis was used for sensitivity analysis. Single cell analysis clarified the enrichment of genes. RESULTS: Three-step SMR analysis showed that a putative mechanism, cg17294865 CpG site regulating HLA-DRA expression was negatively associated with gastric cancer risk. HLA-DRA was significantly differentially expressed in monocyte/macrophage and myeloid cells in gastric cancer. CONCLUSION: This study provides evidence that upregulating the expression level of HLA-DRA can reduce the risk of gastric cancer.