Predictive nomogram for 28-day mortality risk in mitral valve disorder patients in the intensive care unit: A comprehensive assessment from the MIMIC-III database.

BACKGROUND: Mitral valve disorder (MVD) stands as the most prevalent valvular heart disease. Presently, a comprehensive clinical index to predict mortality in MVD remains elusive. The aim of our study is to construct and assess a nomogram for predicting the 28-day mortality risk of MVD patients. METHODS: Patients diagnosed with MVD were identified via ICD-9 code from the MIMIC-III database. Independent risk factors were identified utilizing the LASSO method and multivariate logistic regression to construct a nomogram model aimed at predicting the 28-day mortality risk. The nomogram's performance was assessed through various metrics including the area under the curve (AUC), calibration curves, Hosmer-Lemeshow test, integrated discriminant improvement (IDI), net reclassification improvement (NRI), and decision curve analysis (DCA). RESULTS: The study encompassed a total of 2771 patients diagnosed with MVD. Logistic regression analysis identified several independent risk factors: age, anion gap, creatinine, glucose, blood urea nitrogen level (BUN), urine output, systolic blood pressure (SBP), respiratory rate, saturation of peripheral oxygen (SpO2), Glasgow Coma Scale score (GCS), and metastatic cancer. These factors were found to independently influence the 28-day mortality risk among patients with MVD. The calibration curve demonstrated adequate calibration of the nomogram. Furthermore, the nomogram exhibited favorable discrimination in both the training and validation cohorts. The calculations of IDI, NRI, and DCA analyses demonstrate that the nomogram model provides a greater net benefit compared to the Simplified Acute Physiology Score II (SAPSII), Acute Physiology Score III (APSIII), and Sequential Organ Failure Assessment (SOFA) scoring systems. CONCLUSION: This study successfully identified independent risk factors for 28-day mortality in patients with MVD. Additionally, a nomogram model was developed to predict mortality, offering potential assistance in enhancing the prognosis for MVD patients. It's helpful in persuading patients to receive early interventional catheterization treatment, for example, transcatheter mitral valve replacement (TMVR), transcatheter mitral valve implantation (TMVI).

GB12-09, a bispecific antibody targeting IL4Rα and IL31Rα for atopic dermatitis therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by dysregulated immune responses. The key mediators of AD pathogenesis are T helper 2 (TH2) cells and TH2 cytokines. Targeting interleukin 4 (IL4), IL13 or IL31 has become a pivotal focus in both research and clinical treatments for AD. However, the need remains pressing for the development of a more effective and safer therapy, as the current approaches often yield low response rates and adverse effects. In response to this challenge, we have engineered a immunoglobulin G-single-chain fragment variable (scFv) format bispecific antibody (Ab) designed to concurrently target IL4R and IL31R. Our innovative design involved sequence optimization of VL-VH and the introduction of disulfide bond (VH44-VL100) within the IL31Rα Ab scFv region to stabilize the scFv structure. Our bispecific Ab efficiently inhibited the IL4/IL13/IL31 signaling pathways in vitro and reduced serum immunoglobulin E and IL31 levels in vivo. Consequently, this intervention led to improved inflammation profiles and notable amelioration of AD symptoms. This research highlighted a novel approach to AD therapy by employing bispecific Ab targeting IL4Rα and IL31Rα with potent efficacy.

Revealing the Dynamic Lithiation Process of Copper Disulfide by in Situ TEM.

Transition metal oxides, fluorides, and sulfides are extensively studied as candidate electrode materials for lithium-ion batteries driven by the urgency of developing next-generation higher energy density lithium batteries. These conversion-type electrode materials often require nanosized active materials to enable a "smooth" lithiation and de-lithiation process during charge/discharge cycles, determined by their size, structure, and phase. Herein, the structural and chemical changes of Copper Disulfide (CuS2 ) hollow nanoparticles during the lithiation process through an in situ transmission electron microscopy (TEM) method are investigated. The study finds the hollow structure of CuS2 facilitates the quick formation of fluidic Li2 S "drops," accompanied by a de-sulfurization to the Cu7 S4 phase. Meanwhile, the metallic Cu phase emerges as fine nanoparticles and grows into nano-strips, which are embedded in the Li2 S/Cu7 S4 matrix. These complex nanostructured phases and their spatial distribution can lead to a low de-lithiation barrier, enabling fast reaction kinetics.

Temporal and spatial analysis of vegetation cover change in the Yellow River Delta based on Landsat and MODIS time series data.

Based on the Landsat normalized difference vegetation index (NDVI) and the NDVI product of MODIS, this study synthesized two kinds of time-series images. The features were selected according to the characteristics of the time series, and the random forest algorithm was used for classification. Based on the classification results and GIS spatial analysis, the temporal and spatial changes in vegetation cover in the Yellow River Delta from 2000 to 2020 were studied. The results showed that from 2000 to 2020, the vegetation first increased and then decreased, and the dynamic degree of land cover change was generally low. The monthly average minimum NDVI values during the vegetation growth period mostly occurred before 2010, and the maximum values occurred after 2010. From the spatial perspective, the average vegetation area of the Yellow River Delta accounted for 31.54% of the total study area; specifically, the spatial pattern of vegetation distribution was relatively fixed, and the fixed vegetation area accounted for 63.90% of the total vegetation area. The spatial distribution had significant differences, and the vegetation was distributed radially from the center of the Yellow River to the periphery, with significant fragmentation found outside the watershed. The Yellow River had a strong interference with vegetation growth, and the stable vegetation distribution areas were concentrated near the Yellow River. The correlation coefficient between vegetation distribution and the location of the Yellow River was - 0.9964.

Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain.

AIMS: Beyond digestion, bile acids have been recognized as signaling molecules with broad paracrine and endocrine functions by activating plasma membrane receptor (Takeda G protein-coupled receptor 5, TGR5) and the nuclear farnesoid X receptor (FXR). The present study investigated the role of bile acids in alleviating neuropathic pain by activating TGR5 and FXR. METHOD: Neuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. TGR5 or FXR agonist was injected intrathecally. Pain hypersensitivity was measured with Von Frey test. The amount of bile acids was detected using a bile acid assay kit. Western blotting and immunohistochemistry were used to assess molecular changes. RESULTS: We found that bile acids were downregulated, whereas the expression of cytochrome P450 cholesterol 7ahydroxylase (CYP7A1), a rate-limiting enzyme for bile acid synthesis, was upregulated exclusively in microglia in the spinal dorsal horn after SNI. Furthermore, the expression of the bile acid receptors TGR5 and FXR was increased in glial cells and GABAergic neurons in the spinal dorsal horn on day 7 after SNI. Intrathecal injection of either TGR5 or FXR agonist on day 7 after SNI alleviated the established mechanical allodynia in mice, and the effects were blocked by TGR5 or FXR antagonist. Bile acid receptor agonists inhibited the activation of glial cells and ERK pathway in the spinal dorsal horn. All of the above effects of TGR5 or FXR agonists on mechanical allodynia, on the activation of glial cells, and on ERK pathway were abolished by intrathecal injection of the GABAA receptor antagonist bicuculline. CONCLUSION: These results suggest that activation of TGR5 or FXR counteracts mechanical allodynia. The effect was mediated by potentiating function of GABAA receptors, which then inhibited the activation of glial cells and neuronal sensitization in the spinal dorsal horn.

Transcriptomic and Proteomic Analysis of Gardnerella vaginalis Responding to Acidic pH and Hydrogen Peroxide Stress.

Gardnerella vaginalis is the main pathogen that causes bacterial vaginosis. In the healthy vaginal microecological environment of a woman, the lactobacilli produce lactate and hydrogen peroxide to inhibit the growth of pathogens such as G. vaginalis. The lack of lactobacilli results in a high pH and low hydrogen peroxide in the vagina which facilitate G. vaginalis growth, leading to the imbalance of the vaginal microecology. In this study, lactate and hydrogen peroxide were added to a G. vaginalis culture medium to simulate the co-culture of the lactobacilli and G. vaginalis, and then the genes related to the stress response of G. vaginalis were identified using transcriptomics and proteomics. It was indicated that, among all the upregulated genes, most of them encoded transporters associated with the efflux of harmful substances, and the majority of the downregulated genes were related to the biofilm formation and epithelial cell adhesion. This study may help find new drug targets for G. vaginalis for the development of novel therapies for bacterial vaginosis.

DEXMEDETOMIDINE PREVENTS PDIA3 DECREASE BY ACTIVATING α2-ADRENERGIC RECEPTOR TO ALLEVIATE INTESTINAL I/R IN MICE.

ABSTRACT: Background: Dexmedetomidine (DEX) attenuates intestinal I/R injury, but its mechanism of action remains to be further elucidated. Protein disulfide isomerase A3 (PDIA3) has been reported as a therapeutic protein for the prevention and treatment of intestinal I/R injury. This study was to investigate whether PDIA3 is involved in intestinal protection of DEX and explore the underlying mechanisms. Methods: The potential involvement of PDIA3 in DEX attenuation of intestinal I/R injury was tested in PDIA3 Flox/Flox mice and PDIA3 conditional knockout (cKO) in intestinal epithelium mice subjected to 45 min of superior mesenteric artery occlusion followed by 4 h of reperfusion. Furthermore, the α2-adrenergic receptor (α2-AR) antagonist, yohimbine, was administered in wild-type C57BL/6N mice intestinal I/R model to investigate the role of α2-AR in the intestinal protection conferred by DEX. Results: In the present study, we identified intestinal I/R-induced obvious inflammation, endoplasmic reticulum (ER) stress-dependent apoptosis, and oxidative stress, and all the aforementioned changes were improved by the administration of DEX. PDIA3 cKO in the intestinal epithelium have reversed the protective effects of DEX. Moreover, yohimbine also reversed the intestinal protection of DEX and downregulated the messenger RNA and protein levels of PDIA3. Conclusion: DEX prevents PDIA3 decrease by activating α2-AR to inhibit intestinal I/R-induced inflammation, ER stress-dependent apoptosis, and oxidative stress in mice.

Glucocorticoid regulation of lactate release from spinal astrocytes contributes to the induction of spinal LTP of C-fiber-evoked field potentials and the development of mechanical allodynia.

High-frequency stimulation (HFS) of the sciatic nerve leads to long-term potentiation (LTP) at C-fiber synapse and long-lasting pain hypersensitivity. The underlying mechanisms, however, are still unclear. In the present study, we investigated the involvement of astrocytes derived l-lactate in the spinal dorsal horn subsequent to glucocorticoid (GC) secretion into the plasma in this process using Sprague-Dawley rats and Aldh1L1-CreERT2 mice of either sex. We found that HFS increased l-lactate and monocarboxylate transporters 1/2 (MCT1/2) in the spinal dorsal horn. Inhibition of glycogenolysis or blocking lactate transport prevented the induction of spinal LTP following HFS. Furthermore, Chemogenetical inhibition of dorsal horn astrocytes, which were activated by HFS, prevented spinal LTP, alleviated the mechanical allodynia and the decreased the level l-lactate and GFAP expression in the dorsal horn following HFS. In contrast, Chemogenetics activation of dorsal horn astrocytes in naïve rats induced spinal LTP as well as mechanical allodynia, and increased GFAP expression and l-lactate. Application of l-lactate directly to the spinal cord of naïve rats induced spinal LTP, mechanical allodynia, and increased spinal expression of p-ERK. Importantly, HFS increased GC in the plasma and glucocorticoid receptor (GR) expression in spinal astrocytes, adrenalectomy or knocking down of GR in astrocytes by using Cre-Loxp system blocked the mechanical allodynia, prevented the spinal LTP and the enhancement of lactate after HFS. These results show that lactate released from spinal astrocytes following glucocorticoid release into the plasma enhance synaptic transmission at the C-fiber synapse and underlie pain chronicity.

HMGB1-Mediated Neutrophil Extracellular Trap Formation Exacerbates Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury.

Influx of activated neutrophils into the lungs is the histopathologic hallmark of acute lung injury (ALI) after intestinal ischemia/reperfusion (I/R). Neutrophils can release DNA and granular proteins to form cytotoxic neutrophil extracellular traps (NETs), which promotes bystander tissue injury. However, whether NETs are responsible for the remote ALI after intestinal I/R and the mechanisms underlying the dissemination of harmful gut-derived mediators to the lungs are unknown. In the C57BL/6J mouse intestinal I/R model, DNase I-mediated degradation and protein arginine deiminase 4 (PAD4) inhibitor-mediated inhibition of NET treatments reduced NET formation, tissue inflammation, and pathological injury in the lung. High-mobility group protein B1 (HMGB1) blocking prevented NET formation and protected against tissue inflammation, as well as reduced cell apoptosis and improved survival rate. Moreover, recombinant human HMGB1 administration further drives NETs and concurrent tissue toxic injury, which in turn can be reversed by neutrophil deletion via anti-Ly6G Ab i.p. injection. Furthermore, global MyD88 deficiency regulated NET formation and alleviated the development of ALI induced by intestinal I/R. Thus, HMGB1 released from necroptotic enterocytes caused ALI after intestinal I/R by inducing NET formation. Targeting NETosis and the HMGB1 pathway might extend effective therapeutic strategies to minimize intestinal I/R-induced ALI.

A novel humanized MUC1 antibody-drug conjugate for the treatment of trastuzumab-resistant breast cancer.

Mucin 1 (MUC1) has been regarded as an ideal target for cancer treatment, since it is overexpressed in a variety of different cancers including the majority of breast cancer. However, there are still no approved monoclonal antibody drugs targeting MUC1. In this study, we generated a humanized MUC1 (HzMUC1) antibody from our previously developed MUC1 mouse monoclonal antibody that only recognizes MUC1 on the surface of tumor cells. Furthermore, an antibody-drug conjugate (ADC) was generated by conjugating HzMUC1 with monomethyl auristatin (MMAE), and the efficacy of HzMUC1-MMAE on the MUC1-positive HER2+ breast cancer in vitro and in 'Xenograft' model was tested. Results from western blot analysis and immunoprecipitation revealed that the HzMUC1 antibody did not recognize cell-free MUC1-N in sera from breast cancer patients. Confocal microscopy analysis showed that HzMUC1 antibody bound to MUC1 on the surface of breast cancer cells. Results from mapping experiments suggested that HzMUC1 may recognize an epitope present in the interaction region between MUC1-N and MUC1-C. Results from colony formation assay and flow cytometry demonstrated that HzMUC1-MMAE significantly inhibited cell growth by inducing G2/M cell cycle arrest and apoptosis in trastuzumab-resistant HER2-positive breast cancer cells. Meanwhile, HzMUC1-MMAE significantly reduced the growth of HCC1954 xenograft tumors by inhibiting cell proliferation and enhancing cell death. In conclusion, our results indicate that HzMUC1-ADC is a novel therapeutic drug that can overcome trastuzumab resistance of breast cancer. HzMUC1-ADC should also be an effective therapeutic drug for the treatment of different MUC1-positive cancers in clinic.

HMGB1 signaling-regulated endoplasmic reticulum stress mediates intestinal ischemia/reperfusion-induced acute renal damage.

BACKGROUND: Ischemia/reperfusion of the intestine often leads to distant organ injury, but the mechanism of intestinal ischemia/reperfusion-induced renal dysfunction is still not clear. The present study aimed to investigate the mechanisms of acute renal damage after intestinal ischemia/reperfusion challenge and explore the role of released high-mobility group box-1 in this process. METHODS: Intestinal ischemia/reperfusion was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 1.5 hours. At different reperfusion time points, anti-high-mobility group box-1 neutralizing antibodies or ethyl pyruvate were administered to neutralize or inhibit circulating high-mobility group box-1, respectively. RESULTS: Significant kidney injury was observed after 6 hours of intestinal reperfusion, as indicated by increased serum levels of urea nitrogen and creatinine, increased expression of neutrophil gelatinase-associated lipocalin, interleukin-6, and MIP-2, and enhanced cell apoptosis, as indicated by cleaved caspase 3 levels in renal tissues. The levels of phosphorylated eIF2ɑ, activating transcription factor 4, and C/EBP-homologous protein (CHOP) were markedly elevated, indicating the activation of endoplasmic reticulum stress in the impaired kidney. High-mobility group box-1 translocated to cytoplasm in the intestine and serum concentrations of high-mobility group box-1 increased notably during the reperfusion phase. Both anti-high-mobility group box-1 antibodies and ethyl pyruvate treatment significantly reduced serum high-mobility group box-1 concentrations, attenuated endoplasmic reticulum stress in renal tissue and inhibited the development of renal damage. Moreover, the elevated expression of receptor for advanced glycation end products in the kidneys after intestinal ischemia/reperfusion was abrogated after high-mobility group box-1 inhibition. CONCLUSION: These results suggested that high-mobility group box-1 signaling regulated endoplasmic reticulum stress and promoted intestinal ischemia/reperfusion-induced acute kidney injury. High-mobility group box-1 neutralization/inhibition might serve as a pharmacological intervention strategy for these pathophysiological processes.

HMGB1-associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats.

Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor-interacting protein kinase 1/3 (RIP1/3) and phosphorylated-MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage-depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What's more, HMGB1 neutralization further protects against intestinal I/R-associated liver damage in microbiota-depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec-1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R-induced acute remote organ dysfunction.

Percutaneous US-guided Cholecystocholangiography with Microbubbles for Assessment of Infants with US Findings Equivocal for Biliary Atresia and Gallbladder Longer than 1.5 cm: A Pilot Study.

Purpose To evaluate the feasibility of ultrasonographically (US) guided percutaneous cholecystocholangiography (PCC) for early exclusion of biliary atresia (BA) in infants suspected of having BA with equivocal US findings or indeterminate type of BA and a gallbladder longer than 1.5 cm at US. Materials and Methods This study was approved by the ethics committee; written informed parental consent was obtained. From February 2016 to December 2016, nine infants (four boys, five girls; mean age, 60.2 days; median age, 57 days; age range, 23-117 days) with conjugated hyperbilirubinemia and gallbladder longer than 1.5 cm at US were referred for US-guided PCC after US findings were equivocal for BA (n = 7) or the type of BA was unclear (n = 2). PCC was performed with a US machine with incorporated contrast pulse sequencing, contrast-specific software, and a linear transducer by injecting diluted contrast material via an 18-gauge needle. Images from US and US-guided PCC were evaluated in consensus by two radiologists. US criteria for BA were fibrotic cord sign (>2 mm) and gallbladder length-to-width ratio greater than 5.2. BA was excluded at PCC when contrast material was visualized in the gallbladder, common hepatic ducts, and common bile duct and during passage to the duodenum. Patients in whom BA was diagnosed after PCC underwent surgery or liver biopsy as the reference standard. Nonparametric and Fisher exact tests were used. Results US-guided PCC was successful in all patients. There were no procedural-related complications. BA was excluded in five of the nine patients. The median serum direct bilirubin level in these patients slightly decreased 1 week after PCC, from 91.1 µmol/L (interquartile range [IQR], 81.6-113.8 µmol/L) to 65.3 µmol/L (IQR, 57.8-74.7 µmol/L); however, this difference was not statistically significant (P = .062). BA was diagnosed in four patients, with the diagnosis confirmed at surgery (n = 2) or liver biopsy (n = 2). BA in two patients with unclear type of BA was defined as type III without patency of the common bile duct in one patient and as type III with patency of the common bile duct in the other. Conclusion In this highly selected group of infants with indeterminate type of BA or inconclusive US findings, US-guided PCC enabled the diagnosis of BA in four infants and the exclusion of BA in five. US-guided PCC may be a safe and effective tool to exclude BA early in infants with equivocal US findings. © RSNA, 2017.

A rational design for improving the trypsin resistance of aflatoxin-detoxifizyme (ADTZ) based on molecular structure evaluation.

The resistance of feed enzymes against proteases is crucial in livestock farming. In this study, the trypsin resistance of aflatoxin-detoxifizyme (ADTZ) is improved. ADTZ possesses 72 lys/arg residue sites, 45 of which are scattered on the outermost layers of the molecule (RSA≧25%). These 45 lys/arg sites could be target sites for trypsin hydrolysis. By considering shape-matching (including physical and secondary bond interactions) and the "induced fit-effect", we hypothesized that some of these lys/arg sites are vulnerable to trypsin. A protein-protein docking simulation method was used to avoid the massive computational requirements and to address the intricacy of selecting candidate sites, as candidate site selection is affected by space displacement. Optimal mutants (K244Q/K213C/K270T and R356E/K357T/R623C) were predicted by computational design with protein folding energy analysis and molecular dynamics simulations. A trypsin digestion assay was performed, and the mutants displayed much higher stability against trypsin hydrolysis compared to the native enzyme. Moreover, temperature- and pH-activity profiles revealed that the designed mutations did not affect the catalytic activity of the enzyme.

Clinical benefits of aortic cross-clamping versus limb remote ischemic preconditioning in coronary artery bypass grafting with cardiopulmonary bypass: a meta-analysis of randomized controlled trials.

BACKGROUND: We assessed whether aortic cross-clamping or limb remote ischemic preconditioning improved postoperative outcomes, reduced myocardial injury and incidences of postoperative complications in patients undergoing on-pump coronary artery bypass grafting (CABG). MATERIALS AND METHODS: PubMed, EMBASE, the Cochrane Library, and ClinicalTrials databases were searched for studies comparing the effects of ischemic preconditioning with no preconditioning in adult patients undergoing on-pump CABG. The primary end points were mechanical ventilation time, the length of stay in intensive care unit and hospital, whereas the secondary end points were peak values of myocardial biomarkers and postoperative complications. Mean differences were estimated for the primary end points, as well as standard mean differences and odds ratios for the secondary end points. RESULTS: A total of 29 randomized controlled trials with 1791 patients were included. Compared with control group, aortic cross-clamping preconditioning reduced mechanical ventilation time (mean difference [95% confidence interval {CI}]) (-5.59 h [-9.21 to -1.96]), whereas limb remote ischemic preconditioning was not associated with improvement of postoperative outcomes. For myocardial biomarkers, both aortic cross-clamping and limb remote ischemic preconditioning reduced peak values of myocardial biomarkers (standard mean difference [95% CI]) (-0.48 [-0.81 to -0.14]; -0.19 [-0.36 to -0.02], respectively). Subgroup analysis showed that aortic cross-clamping preconditioning protocols with ischemia episodes <5 min did reduce the release of biomarkers (-0.69 [-1.04 to -0.34]) but those with 5 min ischemia episodes elevated them (0.40 [0.04-0.75]). Cardiovascular, cerebrovascular, renal, and intestinal complications were reported, and aortic cross-clamping preconditioning seemed to reduce the incidences of cardiac arrhythmia (odds ratio [95% CI]) (0.46 [0.27-0.80], P = 0.006). CONCLUSIONS: Cardiac surgeons could consider aortic cross-clamping or limb remote ischemic preconditioning to reduce myocardial injury during CABG. Moreover, aortic cross-clamping preconditioning is associated with a decreased risk of postoperative respiratory failure and cardiac arrhythmia.