Roles of alcohol dehydrogenase 1 in the biological activities of Candida albicans.

Candida albicans stands as the foremost prevalent human commensal pathogen and a significant contributor to nosocomial fungal infections. In the metabolism of C. albicans, alcohol dehydrogenase 1 (Adh1) is one of the important enzymes that converts acetaldehyde produced by pyruvate decarboxylation into ethanol at the end of glycolysis. Leveraging the foundational processes of alcoholic fermentation, Adh1 plays an active role in multiple biological phenomena, including biofilm formation, interactions between different species, the development of drug resistance, and the potential initiation of gastrointestinal cancer. Additionally, Adh1 within C. albicans has demonstrated associations with regulating the cell cycle, stress responses, and various intracellular states. Furthermore, Adh1 is extracellularly localized on the cell wall surface, where it plays roles in processes such as tissue invasion and host immune responses. Drawing from an analysis of ADH1 gene structure, expression patterns, and fundamental functions, this review elucidates the intricate connections between Adh1 and various biological processes within C. albicans, underscoring its potential implications for the prevention, diagnosis, and treatment of candidiasis.

2-Methoxyestradiol synergizes with Erlotinib to suppress hepatocellular carcinoma by disrupting the PLAGL2-EGFR-HIF-1/2α signaling loop.

Erlotinib, an EGFR tyrosine kinase inhibitor has been introduced into cancer chemotherapy. However, the therapeutic effects of erlotinib in hepatocellular carcinoma (HCC) remain vaguely understood. Our previous study found that a hypoxia-mediated PLAGL2-EGFR-HIF-1/2α signaling loop in HCC decreased response to erlotinib. The current study has demonstrated that the combination of erlotinib and 2ME2 exerted synergistic antitumor effects against HCC. Further investigation showed that erlotinib increased the expression level of EGFR, HIF-2α, and PLAGL2, which contributes to the insensitivity of hypoxic HCC cells to erlotinib. The simultaneous exposure to 2ME2 effectively inhibited the expression level of EGFR, HIF-2α, and PLAGL2 that was induced by erlotinib. This contributes to the synergistic effect of the two therapeutic agents. Furthermore, the combination of erlotinib and 2ME2 induced apoptosis and inhibited the stemness of hypoxic HCC cells. Our findings potentially explain the mechanism of HCC insensitivity to erlotinib and provide a new strategy of combining EGFR and HIF1/2α inhibitors for HCC treatment.

Deep Learning and Random Forest Approach for Finding the Optimal Traditional Chinese Medicine Formula for Treatment of Alzheimer's Disease.

It has demonstrated that glycogen synthase kinase 3ß (GSK3ß) is related to Alzheimer's disease (AD). On the basis of the world largest traditional Chinese medicine (TCM) database, a network-pharmacology-based approach was utilized to investigate TCM candidates that can dock well with multiple targets. Support vector machine (SVM) and multiple linear regression (MLR) methods were utilized to obtain predicted models. In particular, the deep learning method and the random forest (RF) algorithm were adopted. We achieved R2 values of 0.927 on the training set and 0.862 on the test set with deep learning and 0.869 on the training set and 0.890 on the test set with RF. Besides, comparative molecular similarity indices analysis (CoMSIA) was performed to get a predicted model. All of the training models achieved good results on the test set. The stability of GSK3ß protein-ligand complexes was evaluated using 100 ns of MD simulation. Methyl 3- O-feruloylquinate and cynanogenin A induced both more compactness to the GSK3ß complex and stable conditions at all simulation times, and the GSK3ß complex also had no substantial fluctuations after a simulation time of 5 ns. For TCM molecules, we used the trained models to calculate predicted bioactivity values, and the optimum TCM candidates were obtained by ranking the predicted values. The results showed that methyl 3- O-feruloylquinate contained in Phellodendron amurense and cynanogenin A contained in Cynanchum atratum are capable of forming stable interactions with GSK3ß.

Comprehensive risk management of health, safety and environment for social emergency rescue organization.

During the rescue and relief work of social emergency rescue organizations, the rescue team members face significant responsibilities and risks. Social rescue organizations need to improve funding, available equipment and other aspects compared with professional emergency rescue organizations. Moreover, the development of rescue levels among emergency rescue organizations is unbalanced, and rescue teams'' comprehensive quality and skills are uneven. To understand the safety risks of these organizations before the implementation of rescue and relief tasks, the task situation and its characteristics must be assessed timely, and safety must be ensured under the premise of efficient completion of the rescue missions. Based on the theory of safety system engineering and health, safety, and environment risk management, a risk management model is established to achieve a closed-loop risk management. The risk factors in rescue and relief tasks of social rescue organizations were identified, and a health, safety and environment risk assessment index system and grading standard were established. A gray cloud model was applied for the evaluation method, the problems of information randomness, risk-level boundary fuzziness and randomness of the evaluation index data were effectively solved. Subsequently, a risk hierarchical early warning and control strategies were proposed to allocate emergency resources rationally. The proposed method was verified and found to have universal applicability and strong practicability.

Hydralazine plays an immunomodulation role of pro-regeneration in a mouse model of spinal cord injury.

Spinal cord injury (SCI) results in severe motor and sensory dysfunction with no effective therapy. Spinal cord debris (sp) from injured spinal cord evokes secondary SCI continuously. We and other researchers have previously clarified that it is mainly bone marrow derived macrophages (BMDMs) infiltrating in the lesion epicenter to clear sp, rather than local microglia. Unfortunately, the pro-inflammatory phenotype of these infiltrating BMDMs is predominant which impairs wound healing. Hydralazine, as a potent vasodilator and scavenger of acrolein, has protective effects in many diseases. Hydralazine is also confirmed to promote motor function and hypersensitivity in SCI rats through scavenging acrolein. However, few studies have explored the effects of hydralazine on immunomodulation, as well as spontaneous pain and emotional response, the important syndromes in clinical patients. It remains unclear whether hydralazine affects infiltrating BMDMs after SCI. In this study, we targeted BMDMs to explore the influence of hydralazine on immune cells in a mouse model of SCI, and also investigated the contribution of polarized BMDMs to hydralazine-induced neurological function recovery after SCI in male mice. The adult male mice underwent T10 spinal cord compression. The results showed that in addition to improving motor function and hypersensitivity, hydralazine relieved SCI-induced spontaneous pain and emotional response, which is a newly discovered function of hydralazine. Hydralazine inhibited the recruitments of pro-inflammatory BMDMs and educated infiltrated BMDMs to a more reparative phenotype involving in multiple biological processes associated with SCI pathology, including immune/inflammation response, neurogenesis, lipid metabolism, oxidative stress, fibrosis formation, and angiogenesis, etc. As an overall effect, hydralazine-treated BMDMs loaden with sp partially rescued neurological function after SCI. It is concluded that hydralazine plays an immunomodulation role of educating pro-inflammatory BMDMs to a more reparative phenotype; and hydralazine-educated BMDMs contribute to hydralazine-induced improvement of neurological function in SCI mice, which provides support for drug and cell treatment options for SCI therapy.

WITHDRAWN: Adenoviral gene delivery can convert adult human fibroblasts to neurons.

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Global burden of upper respiratory infections in 204 countries and territories, from 1990 to 2019.

BACKGROUND: Upper respiratory infections (URIs) are among the most common diseases. However, the related burden has not been comprehensively evaluated. Thus, we designed the present study to describe the global and regional burden of URIs from 1990 to 2019. METHODS: A secondary analysis was performed on the incidence, mortality, and disability-adjusted life years (DALYs) of URIs in different sex and age groups, from 21 geographic regions, 204 countries and territories, between 1990 and 2019, using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Countries and territories were categorized according to Socio-demographic Index (SDI) quintiles. FINDINGS: Globally, the incident cases of URIs reached 17·2 (95% uncertainty interval: 15·4 to 19·3) billion in 2019, which accounted for 42·83% (40·01% to 45·77%) cases from all causes in the GBD 2019 study. The age-standardized incidence rate remained stable from 1990 to 2019, while significant decreases were found in the mortality and DALY rate. The highest age-standardized incidence rates from 1990 to 2019 and the highest age-standardized DALY rates after 2011 were observed in high SDI regions. Among all the age groups, children under five years old suffered from the highest incidence and DALY rates, both of which were decreased with increasing age. Fatal consequences of URIs occurred mostly in the elderly and children under five years old. INTERPRETATION: The present study provided comprehensive estimates of URIs burden for the first time. Our findings, highlighting the substantial incidence and considerable DALYs due to URIs, are expected to attract more attention to URIs and provide future explorations in the prevention and treatment with epidemiological evidence. FUNDING: The study was funded by the National Natural Science Foundation of China (81770057).

The existence of 5-hydroxymethylcytosine and 5-formylcytosine in both DNA and RNA in mammals.

We developed a novel strategy by oxidation-derivatization combined mass spectrometry analysis for the determination of 5-hydroxymethylcytosine and 5-formylcytosine in both DNA and RNA. We reported the presence of 5-formylcytosine in RNA of mammals and found that ascorbic acid and hydroquinone can increase the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in DNA and RNA.

[Effect of ligation level of inferior mesenteric artery on postoperative defecation function in patients with rectal cancer].

OBJECTIVE: To investigate the effect of ligation level of inferior mesenteric artery (IMA) on postoperative defecation function in patients with rectal cancer. METHODS: A total of 128 rectal cancer patients who were planned to undergo low anterior resection in the First Hospital of Zibo City between January 1, 2012 and December 31, 2013 were prospectively enrolled and randomly divided into IMA high ligation group(63 cases, cutting distance of 1.0 to 1.5 cm to the root of IMA) and low ligation group(65 cases, cutting distance of 0.5 to 1.0 cm to the root of left colic artery originated from IMA). The efficacy, especially the defecation function, was observed and compared 3 months and 1 year after surgery between the two groups. RESULTS: No significant difference was found in the number of harvested lymph nodes between two groups[8(1-30) vs. 7(2-28), P=0.125], but high ligation group had greater number of metastatic lymph nodes[1(0-9) vs. 0(0-8), P=0.041]. Frequency of defecation in high ligation group was significantly higher than that in low ligation group during postoperative 3-month follow-up[5(2-10)/d vs. 3(1-8)/d, P=0.035], whereas other indexes of defecation function were not significantly different(all P>0.05). The proportion of patients needing laxatives in high ligation group was higher than that in low ligation group during postoperative 1-year follow-up [11.3%(6/53) vs. 1.7%(1/58), P=0.038], whereas other indexes of defecation function were not significantly different as well (all P>0.05). Three cases and 2 cases showed recurrence in high ligation group and low ligation group respectively during postoperative 1-year follow-up without significant difference(P=0.623). CONCLUSION: Low ligation of IMA in low anterior resection for rectal cancer is beneficial to the protection against defecation function.