Structural transitions upon guide RNA binding and their importance in Cas12g-mediated RNA cleavage.

Cas12g is an endonuclease belonging to the type V RNA-guided CRISPR-Cas family. It is known for its ability to cleave RNA substrates using a conserved endonuclease active site located in the RuvC domain. In this study, we determined the crystal structure of apo-Cas12g, the cryo-EM structure of the Cas12g-sgRNA binary complex and investigated conformational changes that occur during the transition from the apo state to the Cas12g-sgRNA binary complex. The conserved zinc finger motifs in Cas12g undergo an ordered-to-disordered transition from the apo to the sgRNA-bound state and their mutations negatively impact on target RNA cleavage. Moreover, we identified a lid motif in the RuvC domain that undergoes transformation from a helix to loop to regulate the access to the RuvC active site and subsequent cleavage of the RNA substrate. Overall, our study provides valuable insights into the mechanisms by which Cas12g recognizes sgRNA and the conformational changes it undergoes from sgRNA binding to the activation of the RNase active site, thereby laying a foundation for the potential repurposing of Cas12g as a tool for RNA-editing.

LncRNA RP11-301G19.1 is required for the maintenance of vascular smooth muscle cell contractile phenotype via sponging miR-17-5P/ATOH8 axis.

Long noncoding RNAs (LncRNAs) play essential roles in regulating gene expression in various biological processes. However, the function of lncRNAs in vascular smooth muscle cell (VSMC) transformation remains to be explained. In this work, we discover that a new bone marrow protein (BMP) signaling target, lncRNA RP11-301G19.1, is significantly induced in BMP7-treated VSMCs through lncRNA microarray analysis. Addition of BMP signaling inhibitor LDN-193189 attenuates the expression of ACTA2 and SM-22α, as well as the mRNA level of RP11-301G19.1. Furthermore, lncRNA RP11-301G19.1 is critical to the VSMC differentiation and is directly activated by SMAD1/9. Mechanistically, knocking down of RP11-301G19.1 leads to the decrease of ATOH8, another BMP target, while the forced expression of RP11-301G19.1 reactivates ATOH8. In addition, miR-17-5p, a miRNA negatively regulated by BMP-7, contains predicted binding sites for lncRNA RP11-301G19.1 and ATOH8 3'UTR. Accordingly, overexpression of miR-17-5p decreases the levels of them. Together, our results revealed the role of lncRNA RP11-301G19.1 as a miRNA sponge to upregulate ATOH8 in VSMC phenotype transformation.

Wetting Effect Induced Depletion and Adsorption Layers: Diffuse Interface Perspective.

When a multi-component fluid contacts arigid solid substrate, the van der Waals interaction between fluids and substrate induces a depletion/adsorption layer depending on the intrinsic wettability of the system. In this study, we investigate the depletion/adsorption behaviors of A-B fluid system. We derive analytical expressions for the equilibrium layer thickness and the equilibrium composition distribution near the solid wall, based on the theories of de Gennes and Cahn. Our derivation is verified through phase-field simulations, wherein the substrate wettability, A-B interfacial tension, and temperature are systematically varied. Our findings underscore two pivotal mechanisms governing the equilibrium layer thickness. With an increase in the wall free energy, the substrate wettability dominates the layer formation, aligning with de Gennes' theory. When the interfacial tension increases, or temperature rises, the layer formation is determined by the A-B interactions, obeying Cahn's theory. Additionally, we extend our study to non-equilibrium systems where the initial composition deviates from the binodal line. Notably, macroscopic depletion/adsorption layers form on the substrate, which are significantly thicker than the equilibrium microscopic layers. This macroscopic layer formation is attributed to the interplay of phase separation and Ostwald ripening. We anticipate that the present finding could deepen our knowledge on the depletion/adsorption behaviors of immiscible fluids.

Prospective Evaluation of the Peripheral Perfusion Index in Assessing the Organ Dysfunction and Prognosis of Adult Patients With Sepsis in the ICU.

Background: The peripheral perfusion index (PI) reflects microcirculatory blood flow perfusion and indicates the severity and prognosis of sepsis. Method: The cohort comprised 208 patients admitted to the intensive care unit (ICU) with infection, among which 117 had sepsis. Demographics, medication history, ICU variables, and laboratory indexes were collected. Primary endpoints were in-hospital mortality and 28-day mortality. Secondary endpoints included organ function variables (coagulation function, liver function, renal function, and myocardial injury), lactate concentration, mechanical ventilation time, and length of ICU stay. Univariate and multivariate analyses were conducted to assess the associations between the PI and clinical outcomes. Sensitivity analyses were performed to explore the associations between the PI and organ functions in the sepsis and nonsepsis groups. Result: The PI was negatively associated with in-hospital mortality (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.15 to 0.55), but was not associated with 28-day mortality. The PI was negatively associated with the coagulation markers prothrombin time (PT) (ß -0.36, 95% CI -0.59 to 0.13) and activated partial thromboplastin time (APTT) (ß -1.08, 95% CI -1.86 to 0.31), and the myocardial injury marker cardiac troponin I (cTnI) (ß -2085.48, 95% CI -3892.35 to 278.61) in univariate analysis, and with the PT (ß -0.36, 95% CI -0.60 to 0.13) in multivariate analysis. The PI was negatively associated with the lactate concentration (ß -0.57, 95% CI -0.95 to 0.19), mechanical ventilation time (ß -23.11, 95% CI -36.54 to 9.69), and length of ICU stay (ß -1.28, 95% CI -2.01 to 0.55). Sensitivity analyses showed that the PI was significantly associated with coagulation markers (PT and APTT) and a myocardial injury marker (cTnI) in patients with sepsis, suggesting that the associations between the PI and organ function were stronger in the sepsis group than the nonsepsis group. Conclusion: The PI provides new insights for assessing the disease severity, short-term prognosis, and organ function damage in ICU patients with sepsis, laying a theoretical foundation for future research.

Community screening for dementia among older adults in China: a machine learning-based strategy.

BACKGROUND: Dementia is a leading cause of disability in people older than 65 years worldwide. However, diagnosing dementia in its earliest symptomatic stages remains challenging. This study combined specific questions from the AD8 scale with comprehensive health-related characteristics, and used machine learning (ML) to construct diagnostic models of cognitive impairment (CI). METHODS: The study was based on the Shenzhen Healthy Ageing Research (SHARE) project, and we recruited 823 participants aged 65 years and older, who completed a comprehensive health assessment and cognitive function assessments. Permutation importance was used to select features. Five ML models using BalanceCascade were applied to predict CI: a support vector machine (SVM), multilayer perceptron (MLP), AdaBoost, gradient boosting decision tree (GBDT), and logistic regression (LR). An AD8 score ≥ 2 was used to define CI as a baseline. SHapley Additive exPlanations (SHAP) values were used to interpret the results of ML models. RESULTS: The first and sixth items of AD8, platelets, waist circumference, body mass index, carcinoembryonic antigens, age, serum uric acid, white blood cells, abnormal electrocardiogram, heart rate, and sex were selected as predictive features. Compared to the baseline (AUC = 0.65), the MLP showed the highest performance (AUC: 0.83 ± 0.04), followed by AdaBoost (AUC: 0.80 ± 0.04), SVM (AUC: 0.78 ± 0.04), GBDT (0.76 ± 0.04). Furthermore, the accuracy, sensitivity and specificity of four ML models were higher than the baseline. SHAP summary plots based on MLP showed the most influential feature on model decision for positive CI prediction was female sex, followed by older age and lower waist circumference. CONCLUSIONS: The diagnostic models of CI applying ML, especially the MLP, were substantially more effective than the traditional AD8 scale with a score of ≥ 2 points. Our findings may provide new ideas for community dementia screening and to promote such screening while minimizing medical and health resources.

Echocardiographic features of right ventricle in septic patients with elevated central venous pressure.

BACKGROUND: Elevated central venous pressure (CVP) is deemed as a sign of right ventricular (RV) dysfunction. We aimed to characterize the echocardiographic features of RV in septic patients with elevated CVP, and quantify associations between RV function parameters and 30-day mortality. METHODS: We retrospectively reviewed a cohort of septic patients with CVP ≥ 8 mmHg in a tertiary hospital intensive care unit. General characteristics and echocardiographic parameters including tricuspid annular plane systolic excursion (TAPSE), pulmonary vascular resistance (PVR) as well as prognostic data were collected. Associations between RV function parameters and 30-day mortality were assessed using Cox regression models. RESULTS: Echocardiography was performed in 244 septic patients with CVP ≥ 8 mmHg. Echocardiographic findings revealed that various types of abnormal RV function can occur individually or collectively. Prevalence of RV systolic dysfunction was 46%, prevalence of RV enlargement was 34%, and prevalence of PVR increase was 14%. In addition, we collected haemodynamic consequences and found that prevalence of systemic venous congestion was 16%, prevalence of RV-pulmonary artery decoupling was 34%, and prevalence of low cardiac index (CI) was 23%. The 30-day mortality of the enrolled population was 24.2%. In a Cox regression analysis, TAPSE (HR:0.542, 95% CI:0.302-0.972, p = 0.040) and PVR (HR:1.384, 95% CI:1.007-1.903, p = 0.045) were independently associated with 30-day mortality. CONCLUSIONS: Echocardiographic findings demonstrated a high prevalence of RV-related abnormalities (RV enlargement, RV systolic dysfunction and PVR increase) in septic patients with elevated CVP. Among those echocardiographic parameters, TAPSE and PVR were independently associated with 30-day mortality in these patients.

RfxCas13d-mediated inhibition of Circ1647 alleviates renal fibrosis via PI3K/AKT signaling pathway.

BACKGROUND: Circular RNAs (CircRNAs) have been shown to be involved in the development of chronic kidney disease (CKD). This study aimed to investigate the role of Circ1647 in renal fibrosis, which is a hallmark of CKD. METHODS: In this study, we established a unilateral ureteral obstruction (UUO) model and delivered Circ1647 RfxCas13d knockdown plasmid into renal parenchymal cells via retrograde injection through the ureter followed by electroporation. After that, the pathological changes were determined by Hematoxylin and Eosin. Meanwhile, Immunohistochemistry, qRT-PCR and Western blot were conducted to assess the degree of fibrosis. In addition, overexpressing of Circ1647 in renal tubular epithelial cells (TCMK1) was performed to investigate the underlying mechanisms of Circ1647. RESULTS: Our results displayed that electroporation-mediated knockdown of Circ1647 by RfxCas13d knockdown plasmid significantly inhibited renal fibrosis in UUO mice as evidenced by reduced expression of fibronectin and α-SMA (alpha-smooth muscle actin). Conversely, overexpression of Circ1647 in TCMK1 cells promoted the fibrosis. In terms of mechanism, Circ1647 may mediate the PI3K/AKT Signaling Pathway as demonstrated by the balance of the phosphorylation of PI3K and AKT in vivo and the aggravated phosphorylation of PI3K and AKT in vitro. These observations were corroborated by the effects of the PI3K inhibitor LY294002, which mitigated fibrosis post Circ1647 overexpression. CONCLUSION: Our study suggests that Circ1647 plays a significant role in renal fibrosis by mediating the PI3K/AKT signaling pathway. RfxCas13d-mediated inhibition of Circ1647 may serve as a therapeutic target for renal fibrosis in CKD.

Whole-cell FRET monitoring of transcription factor activities enables functional annotation of signal transduction systems in living bacteria.

Bacteria adapt to their constantly changing environments largely by transcriptional regulation through the activities of various transcription factors (TFs). However, techniques that monitor TF-promoter interactions in situ in living bacteria are lacking. Herein, we developed a whole-cell TF-promoter binding assay based on the intermolecular FRET between an unnatural amino acid, l-(7-hydroxycoumarin-4-yl) ethylglycine, which labels TFs with bright fluorescence through genetic encoding (donor fluorophore) and the live cell nucleic acid stain SYTO 9 (acceptor fluorophore). We show that this new FRET pair monitors the intricate TF-promoter interactions elicited by various types of signal transduction systems, including one-component (CueR) and two-component systems (BasSR and PhoPQ), in bacteria with high specificity and sensitivity. We demonstrate that robust CouA incorporation and FRET occurrence is achieved in all these regulatory systems based on either the crystal structures of TFs or their simulated structures, if 3D structures of the TFs were unavailable. Furthermore, using CueR and PhoPQ systems as models, we demonstrate that the whole-cell FRET assay is applicable for the identification and validation of complex regulatory circuit and novel modulators of regulatory systems of interest. Finally, we show that the FRET system is applicable for single-cell analysis and monitoring TF activities in Escherichia coli colonizing a Caenorhabditis elegans host. In conclusion, we established a tractable and sensitive TF-promoter binding assay, which not only complements currently available approaches for DNA-protein interactions but also provides novel opportunities for functional annotation of bacterial signal transduction systems and studies of the bacteria-host interface.

Effect of wall free energy formulation on the wetting phenomenon: Conservative Allen-Cahn model.

Cahn introduced the concept of wall energy to describe the interaction between two immiscible fluids and a solid wall [J. W. Cahn, J. Chem. Phys. 66, 3667-3672 (1977)]. This quintessential concept has been successfully applied to describe various wetting phenomena of a droplet in contact with a solid surface. The usually formulated wall free energy results in the so-called surface composition that is not equal to the bulk composition. This composition difference leads to a limited range of contact angles which can be achieved by the linear/high-order polynomial wall free energy. To address this issue and to improve the adaptability of the model, we symmetrically discuss the formulation of the wall free energy on the Young's contact angle via Allen-Cahn model. In our model, we modify the calculation of the fluid-solid interfacial tensions according to the Cahn's theory by considering the excess free energy contributed by the distorted composition profile induced by the surface effect. Additionally, we propose a semi-obstacle wall free energy which enforces the surface composition to be the bulk composition within the framework of bulk obstacle potential. By this way, the accuracy of the contact angle close to 0° and 180° is significantly improved in the phase-field simulations. We further reveal that the volume preservation term in the conservative Allen-Cahn model has a more significant impact on the wetting behavior on superhydrophobic surfaces than on hydrophilic surfaces, which is attributed to the curvature effect. Our findings provide alternative insights into wetting behavior on superhydrophilic and superhydrophobic surfaces.

Sociodemographic and lifestyle determinants of multimorbidity among community-dwelling older adults: findings from 346,760 SHARE participants.

BACKGROUND: This study aimed to investigate the prevalence of multimorbidity and its associated factors among the older population in China to propose policy recommendations for the management of chronic diseases in older adults. METHODS: This study was conducted based on the 2021 Shenzhen Healthy Ageing Research (SHARE), and involved analysis of 346,760 participants aged 65 or older. Multimorbidity is defined as the presence of two or more clinically diagnosed or non self-reported chronic diseases among the eight chronic diseases surveyed in an individual. The Logistic analysis was adopted to explore the potential associated factors of multimorbidity. RESULTS: The prevalences of obesity, hypertension, diabetes, anemia, chronic kidney disease, hyperuricemia, dyslipidemia and fatty liver disease were 10.41%, 62.09%, 24.21%, 12.78%, 6.14%, 20.52%, 44.32%, and 33.25%, respectively. The prevalence of multimorbidity was 63.46%. The mean count of chronic diseases per participant was 2.14. Logistic regression indicated that gender, age, marriage status, lifestyle (smoking status, drinking status, and physical activity), and socioeconomic status (household registration, education level, payment method of medical expenses) were the common predictors of multimorbidity for older adults, among which, being women, married, or engaged in physical activity was found to be a relative determinant as a protective factor for multimorbidity after the other covariates were controlled. CONCLUSION: Multimorbidity is prevalent among older adults in Chinese. Guideline development, clinical management,and public intervention should target a group of diseases instead of a single condition.

Tricuspid annular plane systolic excursion/mitral annular plane systolic excursion ratio in critically ill patients: an index of right- and left-ventricular function mismatch and a risk factor for cardiogenic pulmonary edema.

BACKGROUND: This study aimed to explore whether the tricuspid annular systolic excursion (TAPSE)/mitral annular systolic excursion (MAPSE) ratio was associated with the occurrence of cardiogenic pulmonary edema (CPE) in critically ill patients. MATERIALS AND METHODS: This was a prospective observational study conducted in a tertiary hospital. Adult patients admitted to the intensive care unit who were on mechanical ventilation or in need of oxygen therapy were prospectively screened for enrolment. The diagnosis of CPE was determined based on lung ultrasound and echocardiography findings. TAPSE ≥ 17 mm and MAPSE ≥ 11 mm were used as normal references. RESULTS: Among the 290 patients enrolled in this study, 86 had CPE. In the logistic regression analysis, the TASPE/MAPSE ratio was independently associated with the occurrence of CPE (odds ratio 4.855, 95% CI: 2.215-10.641, p < 0.001). The patients' heart function could be categorized into four types: normal TAPSE in combination with normal MAPSE (TAPSE↑/MAPSE↑) (n = 157), abnormal TAPSE in combination with abnormal MAPSE (TAPSE↓/MAPSE↓) (n = 40), abnormal TAPSE in combination with normal MAPSE (TAPSE↓/MAPSE↑) (n = 50) and normal TAPSE in combination with abnormal MAPSE (TAPSE↑/MAPSE↓) (n = 43). The prevalence of CPE in patients with TAPSE↑/MAPSE↓ (86.0%) was significantly higher than that in patients with TAPSE↑/MAPSE↑ (15.3%), TAPSE↓/MAPSE↓ (37.5%), or TAPSE↓/MAPSE↑ (20.0%) (p < 0.001). The ROC analysis showed that the area under the curve for the TAPSE/MAPSE ratio was 0.761 (95% CI: 0.698-0.824, p < 0.001). A TAPSE/MAPSE ratio of 1.7 allowed the identification of patients at risk of CPE with a sensitivity of 62.8%, a specificity of 77.9%, a positive predictive value of 54.7% and a negative predictive value of 83.3%. CONCLUSIONS: The TAPSE/MAPSE ratio can be used to identify critically ill patients at higher risk of CPE.

Renal hemodynamic evaluation protocol based on the pathophysiological mechanism of acute kidney injury: Critical Care UltraSound Guided-A(KI)BCDE.

The multiple etiological characteristics of acute kidney injury (AKI) have brought great challenges to its clinical diagnosis and treatment. Renal injury in critically ill patients always indicates hemodynamic injury. The Critical Care UltraSound Guided (CCUSG)-A(KI)BCDE protocol developed by the Chinese Critical Ultrasound Study Group (CCUSG), respectively, includes A(KI) diagnosis and risk assessment and uses B-mode ultrasound, Color doppler ultrasound, spectral Doppler ultrasound, and contrast Enhanced ultrasound to obtain the hemodynamic characteristics of the kidney so that the pathophysiological mechanism of the occurrence and progression of AKI can be captured and the prognosis of AKI can be predicted combined with other clinical information; therefore, the corresponding intervention and treatment strategies can be formulated to achieve targeted, protocolized, and individualized therapy.

Constructing Interconnected Microporous Structures in Carbon by Homogeneous Activation as a Sustainable Electrode Material for High-Performance Supercapacitors.

Microporous carbon attracts attention as an electrode material for supercapacitors. However, a large number of deep and distorted mesoporous and macroporous structures are usually created by non-uniform etching, resulting in underutilized internal space. Homogeneous activation has been considered by researchers as a necessary condition for the formation of interconnected microporous structures in carbon materials. Herein, a simple strategy of hydrothermal introduction of defects followed by homogeneous activation for the preparation of microporous carbon was developed for the synthesis of electrode materials for high-performance supercapacitors. The optimized sample with defect-enriched microporous structure and large specific surface area has a specific capacity of 315 F g-1 (1 A g-1) in KOH solution, and the assembled symmetric supercapacitor achieves a high energy density of 7.3 Wh kg-1 at a power density of 250 W kg-1. This work is interesting because it not only demonstrates that rational design of electrode materials is important to boost the performance of supercapacitors, but also provides inspiration for the design of efficient supercapacitors in the future.

Self-Appraisal of Clinical Competence in Echocardiography of Chinese Intensivists Post Basic Echocardiography Training.

Objectives To learn the echocardiography skills of intensivists after receiving a basic critical care echocardiography training course, and investigate factors that may influence their performance. Methods We completed a web-based questionnaire that assessed the skills in ultrasound scanning techniques of intensivists who took a training course on basic critical care echocardiography held in 2019 and 2020. Mann-Whitney test was used to analyze the factors which might affect their performance on image acquisition, recognizing clinical syndrome, and measuring the diameter of inferior vena cava, left ventricular ejection fraction and left ventricular outflow tract velocity-time integral.Results We enrolled 554 physicians from 412 intensive care units across China. Among them, 185 (33.4%) reported that they had 10%-30% chance of being misled by critical care echocardiography when making therapeutic decision, and 34 (6.1%) reported that the chance was greater than 30%. Intensivists who performed echocardiography under the guidance of a mentor and finished ultrasound scanning more than 10 times per week reported significant higher scores in image acquisition, clinical syndrome recognition, and quantitative measurement of inferior vena cava diameter, left ventricular ejection fraction and left ventricular outflow tract velocity-time integral than those without mentor and performing echocardiography 10 times or less per week respectively (all P < 0.05).Conclusion The skills in diagnostic medical echocardiography of Chinese intensivists after a basic echocardiographic training course remain low, and further quality assurance training program is clearly warranted.

Discovery of a Novel Specific Inhibitor Targeting Influenza A Virus Nucleoprotein with Pleiotropic Inhibitory Effects on Various Steps of the Viral Life Cycle.

Influenza A viruses (IAVs) continue to pose an imminent threat to humans due to annual influenza epidemic outbreaks and episodic pandemics with high mortality rates. In this context, the suboptimal vaccine coverage and efficacy, coupled with recurrent events of viral resistance against a very limited antiviral portfolio, emphasize an urgent need for new additional prophylactic and therapeutic options, including new antiviral targets and drugs with new mechanisms of action to prevent and treat influenza virus infection. Here, we characterized a novel influenza A virus nucleoprotein (NP) inhibitor, FA-6005, that inhibited a broad spectrum of human pandemic and seasonal influenza A and B viruses in vitro and protects mice against lethal influenza A virus challenge. The small molecule FA-6005 targeted a conserved NP I41 domain and acted as a potentially broad, multimechanistic anti-influenza virus therapeutic since FA-6005 suppressed influenza virus replication and perturbed intracellular trafficking of viral ribonucleoproteins (vRNPs) from early to late stages. Cocrystal structures of the NP/FA-6005 complex reconciled well with concurrent mutational studies. This study provides the first line of direct evidence suggesting that the newly identified NP I41 pocket is an attractive target for drug development that inhibits multiple functions of NP. Our results also highlight FA-6005 as a promising candidate for further development as an antiviral drug for the treatment of IAV infection and provide chemical-level details for inhibitor optimization.IMPORTANCE Current influenza antivirals have limitations with regard to their effectiveness and the potential emergence of resistance. Therefore, there is an urgent need for broad-spectrum inhibitors to address the considerable challenges posed by the rapid evolution of influenza viruses that limit the effectiveness of vaccines and lead to the emergence of antiviral drug resistance. Here, we identified a novel influenza A virus NP antagonist, FA-6005, with broad-spectrum efficacy against influenza viruses, and our study presents a comprehensive study of the mode of action of FA-6005 with the crystal structure of the compound in complex with NP. The influenza virus inhibitor holds promise as an urgently sought-after therapeutic option offering a mechanism of action complementary to existing antiviral drugs for the treatment of influenza virus infection and should further aid in the development of universal therapeutics.

Phase retrieval of two random phase-shifting interferograms using Zernike coefficient extraction network.

This paper proposes a deep learning method for phase retrieval from two interferograms. The proposed method converts phase retrieval into the Zernike coefficient extraction problem, which can achieve Zernike coefficient extraction from two interferograms with random phase shifts. After knowing Zernike coefficients, the phase distribution can be retrieved using Zernike polynomials. The pre-filtering and phase unwrapping process are not required using the proposed method. The simulated data are analyzed, and the root mean square (RMS) of phase error reaches 0.01 λ. The effectiveness of the method is verified by the measured data.

Serum NLRP3: A biomarker for identifying high-risk septic patients.

BACKGROUND: Over-activation of the NLRP3 inflammasome can lead to sepsis. NLRP3 is an essential protein in the classical pathway of pyroptosis. This study assessed the use of serum NLRP3 level as a potential inflammatory biomarker in septic patients. METHODS: Patients were categorized into five groups: healthy controls (n = 30), ICU controls (n = 22), infection (n = 19), septic non-shock (n = 33), and septic shock (n = 83). Serum NLRP3 levels were measured by enzyme-linked immunosorbent assay for all patients upon enrollment. Clinical parameters and laboratory test data (APACHE II, SOFA, and lactate) were also assessed. Moreover, the ability of serum NLRP3 levels to predict sepsis was determined by the area under the curve (AUC) analysis. RESULTS: The NLRP3 levels in the septic shock group was significantly higher (431.89, 386.61-460.21 pg/mL) than that in the healthy control group (23.24, 9.38-49.73 pg/mL), ICU control group (74.82, 62.71-85.93 pg/mL), infection group (114.34, 99.21-122.56 pg/mL), and septic non-shock group (136.99, 128.80-146.98 pg/mL; P＜0.001 for all comparisons). Additionally, the AUC indicated that the ability of serum NLRP3 levels to predict sepsis and septic shock incidences was not lower than that of the SOFA score. Patients with higher NLRP3 serum levels (>147.72 pg/mL) had significantly increased 30-day mortality rate. CONCLUSIONS: NLRP3 is useful for the early identification of high-risk septic patients, particularly septic shock patients. Moreover, elevated NRLP3 levels could result in poor septic prediction outcomes.

Exploration of the lower threshold of iodine intake in Southern Chinese young adults based on 'overflow theory' in an iodine balance study.

BACKGROUND: Appropriate iodine intake for adults is essential to reduce the prevalence of thyroid diseases, but there is little research data on iodine requirement of Chinese population. This study aimed to explore the iodine requirement of young adults to maintain a healthy status based on 'overflow theory'. METHODS: Iodine-balance experiment has been performed in this project. We conducted an 18-day study consisted of a 6-day acclimation period and 3 consecutive experimental stages in 37 Chinese healthy young adults (23 female and 14 male). Each stage was consumed for 4 days. Strictly-controlled low-iodine intake diets were provided for adults in the first period, an egg or 125mL milk was added in the second and third period, respectively. The dietary samples, 24-h urine specimens and faeces of volunteers were collected daily for assessment of iodine intake and excretion in volunteers. RESULTS: Mean values of iodine intake (22.7±3.6, 35.1±3.7, and 52.2±3.8µg/d), excretion (64.7±13.9, 62.3±12.6, and 94.3±14.5µg/d) and iodine balance (-35.2±19.5, -21.0±19.8, and -33.5±26.9µg/d) were significantly different among three periods for male (P<0.001 for all); mean values of iodine intake (16.6±3.1, 29.7±2.7, and 48.0±2.7µg/d), and excretion (47.0±9.9, 55.5±8.1, and 75.7±12.4µg/d) were significantly different among three periods for female (P < 0.001 for all). No significant difference was observed among the 3 periods for female in the iodine balance (-30.5±9.3, -25.9±7.3, and -27.6±12.1µg/d). The linear regression equation of iodine excretion on iodine intake was Y=0.979X+37.04 (male) and Y=0.895X+31.48 (female). Compared with stage 2, iodine excretion increments in stage 3 had exceeded the iodine intake increment for men. The ratio of increment was 1.675 for male when the average iodine intake was 52.2µg/d in stage 3. When the iodine excretion increment equaled to the iodine intake increment, the daily iodine intake of men was 47.0µg. CONCLUSION: We have evaluated the iodine requirement of young adults in southern China based on overflow theory. Our results indicate the lower limit of iodine requirement for Chinese young men is 47.0µg/d. The trial was registered at www.chictr.org.cn as ChiCTR1800014877.

Hepatic vein Doppler in critically ill patients: a reflection of central venous pressure or right ventricular systolic function?

BACKGROUND: To explore whether hepatic vein systolic filling fraction (SFF) is associated with central venous pressure (CVP) and right ventricular (RV) systolic function in critically ill patients. METHODS: Adult patients admitted to ICU with echocardiographic examination were retrospectively enrolled. Echocardiographic parameters including hepatic vein systolic velocity (S) and diastolic phase velocity (D) and haemodynamic information at the time of echo examination were collected. RV systolic dysfunction was defined as tricuspid annular plane systolic excursion (TAPSE) < 16 mm. SFF was calculated as S/(S + D). RESULTS: Two hundred four patients were enrolled in this study among whom 40 patients had a CVP ≤5 mmHg, 110 patients had a CVP 6-9 mmHg and 54 patients had a CVP ≥10 mmHg. The three groups had similar S velocity, D velocity and SFF. No correlation between SFF and CVP was found (r = - 0.046, p = 0.500), but correlation between SFF and TAPSE was noticed (r = 0.468, p < 0.001). The ROC analysis showed that the area under curve (AUC) of SFF for determining CVP ≥10 mmHg was 0.513 (95% CI: 0.420-0.606, p = 0.775), but the AUC of SFF for determining RV systolic dysfunction was 0.759 (95% CI: 0.686-0.833, p < 0.001). CONCLUSION: Hepatic vein systolic filling fraction is associated with RV systolic function in critically ill patients and is not associated with CVP.

Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents.

Emerging drug resistance is generating an urgent need for novel and effective antibiotics. A promising target that has not yet been addressed by approved antibiotics is the bacterial DNA gyrase subunit B (GyrB), and GyrB inhibitors could be effective against drug-resistant bacteria, such as methicillin-resistant S. aureus (MRSA). Here, we used the 4-hydroxy-2-quinolone fragment to search the Specs database of purchasable compounds for potential inhibitors of GyrB and identified AG-690/11765367, or f1, as a novel and potent inhibitor of the target protein (IC50: 1.21 µM). Structural modification was used to further identify two more potent GyrB inhibitors: f4 (IC50: 0.31 µM) and f14 (IC50: 0.28 µM). Additional experiments indicated that compound f1 is more potent than the others in terms of antibacterial activity against MRSA (MICs: 4-8 µg/mL), non-toxic to HUVEC and HepG2 (CC50: approximately 50 µM), and metabolically stable (t1/2: > 372.8 min for plasma; 24.5 min for liver microsomes). In summary, this study showed that the discovered N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides are novel GyrB-targeted antibacterial agents; compound f1 is promising for further development.