Intervertebral disc degeneration (IVDD) is a multifaceted condition characterized by heterogeneity, wherein the balance between catabolism and anabolism in the extracellular matrix of nucleus ...pulposus (NP) cells plays a central role. Presently, the available treatments primarily focus on relieving symptoms associated with IVDD without offering an effective cure targeting its underlying pathophysiological processes. D-mannose (referred to as mannose) has demonstrated anti-catabolic properties in various diseases. Nevertheless, its therapeutic potential in IVDD has yet to be explored.
The study began with optimizing the mannose concentration for restoring NP cells. Transcriptomic analyses were employed to identify the mediators influenced by mannose, with the thioredoxin-interacting protein (Txnip) gene showing the most significant differences. Subsequently, small interfering RNA (siRNA) technology was used to demonstrate that Txnip is the key gene through which mannose exerts its effects. Techniques such as colocalization analysis, molecular docking, and overexpression assays further confirmed the direct regulatory relationship between mannose and TXNIP. To elucidate the mechanism of action of mannose, metabolomics techniques were employed to pinpoint glutamine as a core metabolite affected by mannose. Next, various methods, including integrated omics data and the Gene Expression Omnibus (GEO) database, were used to validate the one-way pathway through which TXNIP regulates glutamine. Finally, the therapeutic effect of mannose on IVDD was validated, elucidating the mechanistic role of TXNIP in glutamine metabolism in both intradiscal and orally treated rats.
In both in vivo and in vitro experiments, it was discovered that mannose has potent efficacy in alleviating IVDD by inhibiting catabolism. From a mechanistic standpoint, it was shown that mannose exerts its anti-catabolic effects by directly targeting the transcription factor max-like protein X-interacting protein (MondoA), resulting in the upregulation of TXNIP. This upregulation, in turn, inhibits glutamine metabolism, ultimately accomplishing its anti-catabolic effects by suppressing the mitogen-activated protein kinase (MAPK) pathway. More importantly, in vivo experiments have further demonstrated that compared with intradiscal injections, oral administration of mannose at safe concentrations can achieve effective therapeutic outcomes.
In summary, through integrated multiomics analysis, including both in vivo and in vitro experiments, this study demonstrated that mannose primarily exerts its anti-catabolic effects on IVDD through the TXNIP-glutamine axis. These findings provide strong evidence supporting the potential of the use of mannose in clinical applications for alleviating IVDD. Compared to existing clinically invasive or pain-relieving therapies for IVDD, the oral administration of mannose has characteristics that are more advantageous for clinical IVDD treatment.
Abstract
Background
Currently, the risk stratification of critically ill patient with chest pain is a challenge. We aimed to use machine learning approach to predict the critical care outcomes in ...patients with chest pain, and simultaneously compare its performance with HEART, GRACE, and TIMI scores.
Methods
This was a retrospective, case-control study in patients with acute non-traumatic chest pain who presented to the emergency department (ED) between January 2017 and December 2019. The outcomes included cardiac arrest, transfer to ICU, and death during treatment in ED. In the randomly sampled training set (70%), a LASSO regression model was developed, and presented with nomogram. The performance was measured in both training set (70% participants) and testing set (30% participants), and findings were compared with the three widely used scores.
Results
We proposed a LASSO regression model incorporating mode of arrival, reperfusion therapy, Killip class, systolic BP, serum creatinine, creatine kinase-MB, and brain natriuretic peptide as independent predictors of critical care outcomes in patients with chest pain. Our model significantly outperformed the HEART, GRACE, TIMI score with AUC of 0.953 (95%CI: 0.922–0.984), 0.754 (95%CI: 0.675–0.832), 0.747 (95%CI: 0.664–0.829), 0.735 (95%CI: 0.655–0.815), respectively. Consistently, our model demonstrated better outcomes regarding the metrics of accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and F1 score. Similarly, the decision curve analysis elucidated a greater net benefit of our model over the full ranges of clinical thresholds.
Conclusion
We present an accurate model for predicting the critical care outcomes in patients with chest pain, and provide substantial support to its application as a decision-making tool in ED.
Epidemiologic investigations showed that 2 of 4 patients with severe acute respiratory syndrome (SARS) identified in the winter of 2003-2004 were a waitresss at a restaurant in Guangzhou, China, that ...served palm civets as food and a customer who ate in the restaurant ashort distance from animal cages. All 6 palm civets at the restaurant were positive for SARS-associated coronavirus (SARS-CoV). Partial spike (S) gene sequences of SARS-CoV from the 2 patients were identical to 4 of 5 Sgene viral sequences from palm civets. Phylogenetic analysis showed that SARS-CoV from palm civets in the restaurant was most closely related to animal isolates. SARS cases at the restaurant were the result of recent interspecies transfer from the putative palm civet reservoir, and not the result of continued circulation of SARS-CoV in the human population.
The intrinsic relationships between deforming parameters and microstructural mechanisms for Ti-6Al-4V alloy were analyzed by processing maps. A series of thermal compression tests were carried out in ...the temperatures range of 1023~1323 K (across β-transus) and strain rates range of 0.01~10 s
-1
on a Gleeble-3500 thermo-mechanical simulator. Based on the stress-strain data collected from compression tests, a back-propagation artificial neural network (BP-ANN) model was developed, which presents reliable performance in tracking and predicting strain-stress data. By utilizing this model, the volume of stress-strain data was expanded. According to the intensive stress-strain data, the apparent activation energy was calculated to be 564.05 kJ mol
-1
and 300.20 kJ mol
-1
for α+β-phase field and single β-phase field, respectively. Moreover, the processing maps were constructed at finer intervals of temperature, from which, the stable regions with higher power dissipation efficiency (η > 0.3) and unstable regions with negative instability parameter (ξ < 0) were clarified clearly. By combining processing map with microstructure observations, two main stable softening mechanisms, i.e., globularization and dynamic recovery (DRV) were identified, and globularization-predominant (0.3 < η < 0.55) parameter domain (
< 0.1 s
-1
) in α+β-phase field and DRV-predominant (0.25 < η < 0.41) parameter domain (0.032 s
-1
<1 s
-1
) in β-phase field were recommended.
Abstract
Background
Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing ...to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (
CEBPG
), a gene implicated in myeloid differentiation and AML progression.
Methods
shRNA mediated gene interference was used to down-regulate the expression of
CEBPG
in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of
CEBPG
were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of
CEBPG
was Eukaryotic translation initiation factor 4E binding protein 1 (
EIF4EBP1
), a known repressor of translation. Knockdown of
EIF4EBP1
was used to assess its potential role in AML progression downstream of
CEBPG
.
Results
We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found
CEBPG
was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found
CEBPG
was overexpressed in AML. Moreover, we observed that
CEBPG
promotes AML cell proliferation by activating
EIF4EBP1
, thus contributing to the progression of AML. These findings indicate that
CEBPG
could act as a potential therapeutic target for AML patients.
Conclusion
In summary, we systematically explored the molecular characteristics of
CEBPG
in AML and identified
CEBPG
as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for
CEBPG
in promoting AML progression.
We report a turn-on fluorescent probe for H2S through a cascade reaction using a new trap group 4- （bromomethyl）benzoate, based on excited-state intramolecular proton transfer （ESIPT） sensing ...mechanism. The probe showed good selectivity and high sensitivity towards H2S and it was capable of detecting and imaging H2S in living HeLa cells, indicating its potential biological applications.
Objectives
To develop and evaluate a set of quantifiable elastographic features based on ultrasound real‐time strain elastography (SE) in differentiating between benign and malignant breast lesions.
...Methods
The SE and conventional B‐mode ultrasound images of 226 breast lesions (81 malignant, 145 benign) were obtained from 226 consecutive women. By using a computer‐aided tool, four elastographic features (elasticity score, lesion stiffness degree, lesion‐to‐fat strain ratio, and elastography‐to‐B‐mode lesion area ratio) were respectively calculated and evaluated. Histopathologic results were used as the reference standard. B‐mode Breast Imaging Reporting and Data System categorization was used to compare the performances between B‐mode ultrasound and SE. Sensitivity, specificity, positive and negative predictive values, and receiver operating characteristic curve analyses were performed to evaluate the diagnostic performances for three data sets (conventional B‐mode ultrasound alone, SE features alone, combined SE features).
Results
Quantifiable SE features for malignant lesions all showed significantly higher values than those for benign lesions (all P < .001). The evaluation with any individual SE feature significantly improved the specificity in breast lesion differentiation compared with B‐mode ultrasound (all P <.001). The logistic regression model combing SE features significantly improved the diagnostic performance compared with B‐mode US, with significantly increased specificity (95.2% versus 54.5%; P < .001) and area under the receiver operating characteristic curve (0.988 versus 0.921, P < .001).
Conclusions
Computer‐aided tool with SE provided further elasticity information for breast characterization. Evaluation using quantifiable SE features showed better diagnostic performance than conventional B‐mode ultrasound in breast lesion differentiation.
We report a new strategy to construct fluorescence switches by taking advantage of the E – Z isomerization of the hydrazone group. The switch, synthesized by linking pyridyl-2-aldehydehydrazone to a ...BODIPY fluorophore, was able to exist in three forms: E-BODIPY , Z-BODIPY and protonated BODIPY with different photophysical properties. Reversible ON/OFF fluorescence switching among them was realized by multiple stimuli such as irradiation and addition of acid/base.
Abstract Objectives This meta-analysis summarized the risks that reintubation impose on ventilator-associated pneumonia (VAP) and mortality. Background Extubation failure increases the probability of ...poor clinical outcomes pertaining to mechanical ventilation. Methods Literature published during a 15-year period was retrieved from PubMed, Web of Knowledge databases, the Embase (Excerpa Medica database), and the Cochrane Library. Data involving reintubation, VAP, and mortality were extracted for a meta-analysis. Results Forty-one studies involving 29,923 patients were enrolled for the analysis. The summary odds ratio (OR) between VAP and reintubation was 7.57 (95% confidence interval CI = 3.63–15.81). The merged ORs for mortality in hospital and intensive care unit were 3.33 (95% CI = 2.02–5.49) and 7.50 (95% CI = 4.60–12.21), respectively. Conclusions Reintubation can represent a threat to survival and increase the risk of VAP. The risk of mortality after reintubation differs between planned and unplanned extubation. Extubation failure is associated with a higher risk of VAP in the cardiac surgery population than in the general population.
Display omitted
•A product-imprinted polymer based organocatalyst was developed.•The organocatalyst is amphiphilic and photoswitchable.•The catalyst catalyzes aldol reaction with good conversion and ...low catalyst loading.•The catalyzed aldol reaction performs well in a mixed solvent of DMSO and water.
A series of amphiphilic molecularly imprinted polymers (MIP1, MIP2, MIP3, MIP4, MIP5, and MIP6) containing hydrophobic photoresponsive sites and hydrophilic catalytically active sites were fabricated using bifunctional monomers. These polymers were characterized by scanning electron microscopy, N2 adsorption–desorption analysis, Fourier Transform infrared spectroscopy, thermal gravimetric analysis, and ultraviolet–visible spectroscopy. The catalytic activity of the amphiphilic molecularly imprinted polymer was investigated towards the aldol reaction between p-nitroaldehyde and acetone (a molecular enlargement reaction) in a mixed solvent of DMSO and water at room temperature. The polymer catalyst MIP3 performs best, and displayed good conversions with low catalyst loading (5mol% of l-hydroxyproline with respect to the aldehyde) and photoswitching properties (photo-regulated conversion difference of 20%). Compared with the corresponding non-imprinted polymer, a higher binding capacity, higher conversion, and better photoswitching properties were obtained when the molecularly imprinted polymer was used as the catalyst, illustrating the importance of the specific cavities in the molecularly imprinted polymer.
PDF
