Discovery of novel selective phosphodiesterase­1 inhibitors for the treatment of acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.

[Buzhong Yiqi Decoction ameliorates spleen deficiency syndrome by regulating gut microbiota].

This study aims to decipher the mechanism of Buzhong Yiqi Decoction(BZYQD) in the treatment of spleen deficiency syndrome via gut microbiota. The mouse models of spleen deficiency syndrome were established by fecal microbiota transplantation(FMT, from patients with spleen deficiency syndrome) and administration of Sennae Folium(SF, 10 g·kg~(-1)), respectively, and treated with BZYQD for 5 d. The pseudosterile mice(administrated with large doses of antibiotics) and the mice transplanted with fecal bacteria from healthy human were taken as the controls. The levels of IgA, interleukin(IL)-2, IL-1ß, interferon(IFN)-γ, tumor necrosis factor-alpha(TNF-α), and 5-hydroxytryptamine(5-HT) in the intestinal tissue of two models were measured by enzyme-linked immunosorbent assay, and the CD8~+/CD3~+ ratio was determined by flow cytometry. The composition and changes of the gut microbiota were determined by 16S rRNA high-throughput sequencing and qPCR. Furthermore, the correlation analysis was performed to study the mediating role of gut microbiota in the treatment. The results showed that BZYQD elevated the IgA level, lowered the IL-1ß, TNF-α, and 5-HT levels, and decreased the CD8~+/CD3~+ ratio in the intestinal tissue of the two models. Moreover, BZYQD had two-way regulatory effects on the levels of IL-2 and IFN-γ. BZYQD inhibited the overgrowth and reduced the richness of gut microbiota in the SF model, and improved the gut microbiota structure in the two models. Algoriphagus, Mycobacterium, and CL500＿29＿marine＿group were the common differential genera in the two models compared with the control. Acinetobacter, Parabacteroides, and Ruminococcus were the differential genera unique to the FMT model, and Sphingorhabdus, Lactobacillus, and Anaeroplasma were the unique differential genera in the SF model. BZYQD was capable of regulating all these genera. The qPCR results showed that BZYQD increased the relative abundance of Akkermansia muciniphila and decreased that of Bacteroides uniformis in the two models. The correlation analysis revealed that the levels of above intestinal cytokines were significantly correlated with characteristic gut microorganisms in different mo-dels. The IL-1ß level had a significantly positive correlation with Acinetobacter and CL500＿29＿marine＿group in the two models, while the different levels of IL-2 and IFN-γ in the two models may be related to its different gut microbiota structures. In conclusion, BZYQD could regulate the disordered gut microbiota structure in different animal models of spleen deficiency syndrome to improve the intestinal immune status, which might be one of the mechanisms of BZYQD in treating spleen deficiency syndrome.

Association of serum vitamin D levels on Helicobacter pylori infection: a retrospective study with real-world data.

OBJECTIVE: The aim of this study was to determine whether serum vitamin D levels are associated with H. pylori infection and whether low serum vitamin D levels are an independent risk factor for H. pylori infection. METHODS: We conducted a retrospective analysis of a multicenter cohort study from 2017 to 2019. A total of 415 H. pylori+ patients and 257 H. pylori- patients aged between 18 and 75 years with both 13 C-urea breath test and serum vitamin D level results were included from four hospitals. A questionnaire was used to collect information on potential factors influencing H. pylori infection. RESULTS: Serum vitamin D levels were significantly lower in the H. pylori+ group than in the H. pylori- group (16.7 ± 6.6 ng/ml vs. 19.2 ± 8.0 ng/ml, p < 0.05). Using a cutoff value of 20 ng/ml, the H. pylori infection rate was significantly higher in the vitamin D-deficient group (< 20 ng/ml) than in the vitamin D-nondeficiency group (≥ 20 ng/ml) (66.5% vs. 51.0%, p < 0.001). Ordered logistic regression analysis showed that serum vitamin D levels < 20 ng/ml (OR: 1.652, 95% CI: 1.160-2.351, p = 0.005), higher education levels (OR: 1.774, 95% CI: 1.483-2.119, p < 0.001), family size ≥ 4 (OR: 1.516, 95% CI: 1.081-2.123, p = 0.016), and lower annual income (OR: 1.508, 95% CI: 1.289-1.766, p < 0.001) were independent risk factors for H. pylori infection. CONCLUSION: Lower serum vitamin D levels may be associated with an increased risk of H. pylori infection, and lower serum vitamin D levels are an independent risk factor for increasing H. pylori infection rates. Randomized controlled trials are needed to determine whether supplementation with vitamin D can reduce H. pylori infection rates.

Newly diagnosed type 1 diabetes mellitus in a human immunodeficiency virus-infected patient with antiretroviral therapy-induced immune reconstitution inflammatory syndrome: a case report.

BACKGROUND: Diabetes that develops in human immunodeficiency virus (HIV)-infected patients who receive antiretroviral therapy (ART) is usually type 2 diabetes mellitus (T2DM); however, autoimmune diabetes, such as type 1 diabetes mellitus (T1DM) can also develop in this population. After treatment with ART, patients might experience clinical deterioration following an increase in the CD4 cell count, which is termed immune reconstitution inflammatory syndrome (IRIS). Here, we describe an HIV-infected patient on ART who developed T1DMat due to IRIS, highlighting the clinical complexity in diagnosis and treatment. CASE PRESENTATION: A 36-year-old man infected with HIV had a nadir CD4 cell count of 15.53/µL before medication, which increased to 429.09/µL after 9 months of regular ART. The fasting serum glucose at 9 months was between 96 mg/dL and 117 mg/dL. After 11 months of ART, the patient was admitted to hospital for diabetic ketoacidosis (DKA) and Graves' disease (GD). Noninsulin antidiabetics (NIADs) were prescribed following the resolution of DKA. However, poor glycemic control was noted despite well-titrated NIADs. Further investigation demonstrated poor pancreatic beta cell function and elevated anti-glutamic acid decarboxylase (anti-GAD) and anti-tyrosine phosphatase-like insulinoma antigen 2 (anti-IA2) titers. According to the results, he was diagnosed with T1DM and received multiple daily injections(MDI) of insulin. The regimen of MDI was insulin degludec as basal insulin and insulin aspart as prandial insulin. After MDI therapy, his glycemic control was improved. CONCLUSION: In this case, T1DM was ascribed to IRIS. Although this phenomenon has been demonstrated in previous case reports, further study is necessary to realize the mechanism of this association. Therefore, we emphasize that when HIV-infected patients on ART experience an unstable blood glucose level and abnormal thyroid function, physicians should consider T1DM and GD associated with ART-induced IRIS to reduce the subsequent complications and more serious endocrine dysfunction.

Network pharmacological investigation into the mechanism of Kaixinsan powder for the treatment of depression.

Kaixinsan powder (KXS), a classic prescription of traditional Chinese Medicine (TCM), is widely used in the treatment of depression, but its mechanism remains unclear. The network pharmacology method was used to constructe the "herb-component-target" network, and elucidated KXS potential mechanisms of action in the treatment of depression. Moreover, molecular docking was applied to valid the important interactions between the ingredients and the target protein. The "herb-component-target" network indicated that the ingredients of Girinimbin, Gomisin B and Asarone, and the protein targets of ESR, AR and NR3C1 mostly contribute to the antidepressant effect of KXS. KEGG pathway analysis highlighted the most significant pathways associated with depression treatment, including neuroactive ligand-receptor interaction pathway, serotonergic synapse pathway, PI3K-Akt signaling pathway and MAPK signaling pathway. Go enrichment analysis indicated that the mechanism of KXS in treating depression was involved in the biological process of GPCR signal transduction, hormone metabolism and nerve cell apoptosis. Moreover, molecular docking results showed that Polygalaxanthone III, Girinimbine and Pachymic acid performed greater binding ability with key antidepressant target 5-HTR. In conclusion, this study preliminarily revealed key active components in KXS, including Gomisin B, Asarone, Ginsenoside Rg1, Polygalaxanthone III and Pachymic acid, could interact with multiple targets (5-HTR, DR, ADRA, AR, ESR, NR3C1) and modulate the activation of multiple pathways (Neuroactive ligand -receptor interaction pathway, serotonergic synapse pathway, PI3K-Akt signaling pathway and MAPK signaling pathway).

Serial quantitative chest computed tomography imaging as prognosticators of coronavirus disease 2019 pneumonia.

In 2019, a large outbreak of a novel coronavirus disease (COVID-19) occurred in China. The purpose of this study is to quantitatively analyze the evolution of chest computed tomography (CT) imaging features in COVID-19. Nine patients with positive real-time reverse-transcriptase polymerase chain reaction results were included in this study. Totally 19 CT scans were analyzed. Lesion density, lesion volume, and lesion load were higher in the severe group than in the mild group. A significantly positive correlation was noted between major laboratory prognosticators with lesion volume and load. Lesion load at the first week of disease was significantly higher in severe group (p = 0.03). Our study revealed that several CT features were significantly different between severely and mildly infected forms of COVID-19 pneumonia. The CT lesion load value at the first week of infection may be applied as an outcome predictor of the disease.

Comparison of radiotherapy combined with nimotuzumab vs. chemoradiotherapy for locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The present study compared the effectiveness and toxicity of two treatment modalities, namely radiotherapy combined with nimotuzumab (N) and chemoradiotherapy (CRT) in patients with locally recurrent nasopharyngeal carcinoma (LR-NPC). METHODS: Patients with LR-NPC who were treated with radiotherapy were retrospectively enrolled from January 2015 to December 2018. The treatment included radiotherapy combined with N or platinum-based induction chemotherapy and/or concurrent chemotherapy. The comparison of survival and toxicity between the two treatment modalities was evaluated using the log-rank and chi-squared tests. Overall survival (OS) was the primary endpoint. RESULTS: A total of 87 patients were included, of whom 32 and 55 were divided into the N group and the CRT group, respectively. No significant differences were noted in the survival rate between the N and the CRT groups (4-year OS rates, 37.1% vs. 40.7%, respectively; P = 0.735). Mild to moderate acute complications were common during the radiation period and mainly included mucositis and xerostomia. The majority of the acute toxic reactions were tolerated well. A total of 48 patients (55.2%) demonstrated late radiation injuries of grade ≥ 3, including 12 patients (37.5%) in the N group and 36 patients (66.5%) in the CRT group. The CRT group exhibited significantly higher incidence of severe late radiation injuries compared with that of the N group (P = 0.011). CONCLUSION: Radiotherapy combined with N did not appear to enhance treatment efficacy compared with CRT in patients with LR-NPC. However, radiotherapy combined with N may be superior to CRT due to its lower incidence of acute and late toxicities. Further studies are required to confirm the current findings.

Discovery of effective phosphodiesterase 2 inhibitors with antioxidant activities for the treatment of Alzheimer's disease.

The multi-target-directed-ligand (MTDL) strategy has been widely applied in the discovery of novel drugs for the treatment of Alzheimer's disease (AD) because of the multifactorial pathological mechanisms of AD. Phosphodiesterase-2 (PDE2) has been identified to be a novel and promising target for AD. However, MTDL combining with the inhibitory activity against PDE2A and other anti-AD factors such as antioxidants has not been developed yet. Herein, a novel series of PDE2 inhibitors with antioxidant capacities were designed, synthesized, and evaluated. Most compounds showed remarkable inhibitory activities against PDE2A as well as antioxidant activities. Compound 6d was selected, which showed good IC50 of 6.1 nM against PDE2A, good antioxidant activity (ORAC (Trolox) = 8.4 eq.) and no cytotoxicity to SH-SY5Y cells. Molecular docking and dynamics simulations were applied for the rational design and explanation of structure-activity relationship (SAR) of lead compounds.

Multilevel resistive random access memory achieved by MoO3/Hf/MoO3stack and its application in tunable high-pass filter.

In this work, the multilevel resistive random access memories (RRAMs) have been achieved by using the structure of Pt/MoO3/Hf/MoO3/Pt with four stable resistance states. The devices show good retention property of each state (>104s) and large memory window (>104). The simulation and experimental study reveal that the resistive switching mechanism is ascribed to combination of the conductive filament in the stack of MoO3/Hf next to the top electrode and redox reaction at the interface of Hf/MoO3next to bottom electrode. The fitting results of current-voltage characteristics under low sweep voltage indicate that the conduction of HRSs is dominated by the Poole-Frenkel emission and that of LRS is governed by the Ohmic conduction. Based on the RRAM, the tunable high-pass filter (HPF) with configurable filtering characteristics has been realized. The gain-frequency characteristics of the programmable HPF show that the filter has high resolution and wide programming range, demonstrating the viability of the multilevel RRAMs for future spiking neural network and shrinking the programmable filters with low power consumption.

DKK1 is epigenetically downregulated by promoter methylation and inhibits bile acid-induced gastric intestinal metaplasia.

Dickkopf-related protein 1 (DKK1) is essential to gastric cancer as an inhibitor of Wnt signaling. Gastric intestinal metaplasia (GIM) is an important precancerous lesion of gastric cancer that can be activated by bile acid reflux and chronic inflammation. However, the exact mechanism of DKK1 in bile acid-induced GIM has not been completely elucidated. We aimed to explore the epigenetic alterations and biological functions of DKK1 in the development of GIM. In the present study, bile acid was found to induce the expression of intestinal markers in gastric epithelial cells, whereas DKK1 was downregulated in response to bile acid stimulation. The mRNA and protein expression levels of DKK1 were decreased in GIM tissues as evidenced by qRT-PCR and immunohistochemical staining. Surprisingly, the methylation of the DKK1 promoter increased in GIM tissues, and we discovered 28 differential methylation sites of the DKK1 promoter in GIM tissues. Bile acid was able to induce the partial methylation of the DKK1 promoter, while 5-aza could increase DKK1 expression as well as decrease intestinal markers expression in gastric epithelial cells. In conclusion, the promoter methylation and downregulation of DKK1 might play important roles in the development of GIM, especially bile acid-induced GIM.

Association between red blood cell distribution width and long-term mortality among patients undergoing percutaneous coronary intervention with previous history of cancer.

Background: The number of patients suffering from coronary heart disease with cancer is rising. There is scarce evidence concerning the biomarkers related to prognosis among patients undergoing percutaneous coronary intervention (PCI) with cancer. Thus, the aim of this study was to investigate the association between red blood cell distribution width (RDW) and prognosis in this population.Methods: A total of 172 patients undergoing PCI with previous history of cancer were enrolled in this retrospective study. The endpoint was long-term all-cause mortality. According to tertiles of RDW, the patients were classified into three groups: Tertile 1 (RDW <12.8%), Tertile 2 (RDW ≥12.8% and <13.5%) and Tertile 3 (RDW ≥13.5%).Results: During an average follow-up period of 33.3 months, 29 deaths occurred. Compared with Tertile 3, mortality of Tertile 1 and Tertile 2 was significantly lower in the Kaplan-Meier analysis. In multivariate Cox regression analysis, RDW remained an independent risk factor of mortality (HR: 1.938, 95% CI: 1.295-2.655, p < 0.001). The all-cause mortality in Tertile 3 was significantly higher than that in Tertile 1 (HR: 5.766; 95% CI: 1.426-23.310, p = 0.014).Conclusions: An elevated RDW level (≥13.5%) was associated with long-term all-cause mortality among patients undergoing PCI with previous history of cancer.

Predictive value of admission D-dimer for contrast-induced acute kidney injury and poor outcomes after primary percutaneous coronary intervention.

BACKGROUND: DD was found to be associated with acute myocardial infarction (AMI) and renal insufficiency. However, it is uncertain whether DD is an independent risk factor of CI-AKI in patients undergoing pPCI. METHODS: We prospectively enrolled 550 consecutive patients with STEMI undergoing pPCI between January 2012 and December 2016. The predictive value of admission DD for CI-AKI was assessed by receiver operating characteristic (ROC) and multivariable logistic regression analysis. CI-AKI was defined as an absolute serum creatinine increase ≥0.3 mg/dl or a relative increase in serum creatinine ≥50% within 48 h of contrast medium exposure. RESULTS: Overall, the incidence of CI-AKI was 13.1%. The ROC analysis showed that the cutoff point of DD was 0.69 µg/ml for predicting CI-AKI with a sensitivity of 77.8% and a specificity of 57.3%. The predictive value of DD was similar to the Mehran score for CI-AKI (AUCDD = 0.729 vs AUCMehran = 0.722; p = 0.8298). Multivariate logistic regression analysis indicated that DD > 0.69 µg/ml was an independent predictor of CI-AKI (odds ratio [OR] = 3.37,95% CI:1.80-6.33, p < 0.0001). Furthermore, DD > 0.69 µg/ml was associated with an increased risk of long-term mortality during a mean follow-up period of 16 months (hazard ratio = 3.41, 95%CI:1.4-8.03, p = 0.005). CONCLUSION: Admission DD > 0.69 µg/ml was a significant and independent predictor of CI-AKI and long-term mortality in patients undergoing pPCI.

Identification, Virulence and Fungicide Sensitivity of Colletotrichum gloeosporioides s.s. Responsible for Walnut Anthracnose Disease in China.

Walnut (Juglans regia L.) is an economically important woody nut and edible oil tree all over the world. However, walnut production is limited by walnut anthracnose, which is a disastrous disease that causes significant yield losses. Studying the etiology of anthracnose on walnut and the pathogens' virulence and sensitivities to fungicides would be beneficial for effective control. This study was conducted to identify the pathogen of walnut anthracnose and reveal the population diversity of pathogens through virulence, sensitivities to fungicides, and genetic variation. A total of 13 single-spore Colletotrichum isolates were collected from walnut anthracnose-diseased fruits and leaves from 13 walnut commercial orchards in Henan, Hubei, Shandong, and Shaanxi provinces in China. The isolates were identified as Colletotrichum gloeosporioides sensu stricto (s.s.) according to multilocus phylogenetic analyses (internal transcribed spacer, actin, glyceraldehyde-3-phosphate dehydrogenase, and chitin synthase), morphological as well as cultural characters, and pathogenicity. When the same walnut tissue was inoculated with different isolates, the disease lesion size was different. The results showed that the virulence of all isolates was considerably different, and the differences were not correlated with geographic origins. The virulence to walnut leaves and fruits inoculated with the same isolate was significantly different. Based on the virulence to walnut leaves and fruits, the 13 isolates were divided into three groups. Virulence of 69.2% of the isolates to walnut fruits was higher than that to leaves; 15.4% of isolates had no difference in pathogenicity, and the virulence to walnut leaves was higher for 15.4% of isolates. Tebuconazole, difenoconazole, flusilazole, and carbendazim inhibited the growth of fungal mycelia, and the concentration for 50% of maximal effect (EC50) values were 0.4 to 20.5, 0.6 to 2.6, 0.2 to 1.6, and 0.002 to 0.2 µg/ml, respectively, with average values of 6.5 ± 6.9, 1.5 ± 0.6, 0.9 ± 0.4, and 0.1 ± 0.05 µg/ml, respectively. All isolates were more sensitive to difenoconazole, flusilazole, and carbendazim than tebuconazole (P < 0.01). Isolate sensitivities to the same fungicide were different. Isolates SL-31 and TS-09 were the least sensitive to carbendazim and tebuconazole, respectively, and the resistance ratios were 87.3 and 51.6, respectively. Sensitivities to difenoconazole and flusilazole were largely consistent among all isolates, and the resistance ratios were from 1 to 4.6 and from 1 to 7, respectively. Therefore, difenoconazole and flusilazole could be chosen for disease control. The differences of pathogenicity and fungicide sensitivity were not correlated with geographic regions. These results indicated that there was high intraspecific diversity of populations in C. gloeosporioides s.s. that caused walnut anthracnose. For effective management, the targeted control strategy should be implemented based on the different geographic regions.

SOX2 interferes with the function of CDX2 in bile acid-induced gastric intestinal metaplasia.

BACKGROUND: Intestinal metaplasia (IM) is a premalignant lesion associated with gastric cancer. Both animal and clinical studies have revealed that bile acid reflux and subsequent chronic inflammation are key causal factors of IM. Previous studies indicated that SOX2, the key transcription factor in gastric differentiation, was downregulated during IM development while CDX2, the pivotal intestine-specific transcription factor was upregulated significantly. However, it remains unclear whether the downregulation of SOX2 promotes gastric IM emergence or is merely a concomitant phenomenon. In addition, the underlying mechanisms of SOX2 downregulation during IM development are unclear. METHODS: Gastric cell lines were treated with deoxycholic acid (DCA) in a dose-dependent manner. The expression of CDX2 and miR-21 in gastric tissue microarray were detected by immunohistochemistry and in situ hybridization. Coimmunoprecipitation and immunofluorescence were performed to ascertain the interaction of SOX2 and CDX2. Luciferase reporter assays were used to detect the transcriptional activity of CDX2, and confirm miR-21 binding to SOX2 3'-UTR. The protein level of SOX2, CDX2 and downstream IM-specific genes were investigated using western blotting. mRNA level of miR-21, SOX2, CDX2 and downstream IM-specific genes were detected by qRT-PCR. RESULTS: Bile acid treatment could suppress SOX2 expression and simultaneously induce expression of CDX2 in gastric cell lines. Furthermore, we demonstrated that SOX2 overexpression could significantly inhibit bile acid- and exogenous CDX2-induced IM-specific gene expression, including KLF4, cadherin 17 and HNF4α expression. In contrast, SOX2 knockdown had the opposite effect. A dual-luciferase reporter assay demonstrated that SOX2 overexpression could significantly suppress CDX2 transcriptional activity in HEK293T cells. CDX2 and SOX2 could form protein complexes in the nucleus. In addition, bile acid induced the expression of miR-21. The inhibition of SOX2 in bile acid-treated gastric cell lines was rescued by miR-21 knockdown. CONCLUSIONS: These findings suggested that SOX2 can interfere with the transcriptional activity of CDX2 in bile acid-induced IM and that miR-21 might play a key role in this process, which shed new lights in the prevention of gastric cancer.

Long Non-Coding RNA ZFAS1 as a Novel Potential Biomarker for Predicting the Prognosis of Thyroid Cancer.

BACKGROUND Thyroid cancer is a type of endocrine cancers with rapidly increased incidence. Recent studies have indicated long non-coding RNAs (lncRNAs) played crucial roles in thyroid cancer tumorigenesis and progression. However, the roles of most lncRNAs in thyroid cancer were still unclear. MATERIAL AND METHODS We used TCGA (The Cancer Genome Atlas), GSE50901, GSE29265, and GSE33630 datasets to analyze the expression pattern of ZFAS1 (ZNFX1 antisense RNA 1). The correlation between ZFAS1 and clinicopathological features in thyroid cancer was analyzed. Cell proliferation and cell cycle assays were used to validate the roles of ZFAS1 in thyroid cancer cell lines. DAVID (the database for annotation, visualization and integrated discover) system was used to perform GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis. The starBase datasets and Cytoscape was used to perform ceRNA (competitive endogenous RNA) network. RESULTS We demonstrated ZFAS1 was highly expressed in thyroid cancer compared to normal samples. Moreover, upregulation of ZFAS1 was positively correlated with clinicopathological features and poor prognosis in thyroid cancer. Functional validation showed knockdown of ZFAS1 suppressed cell proliferation and cell cycle in thyroid cancer cells. Bioinformatics analysis showed ZFAS1 was associated with translation, rRNA processing, intra-Golgi vesicle-mediated transport, ribosome, and ubiquitin-mediated proteolysis. CONCLUSIONS Our study suggested ZFAS1 could serve as a biomarker for thyroid cancer.

Negative association between free triiodothyronine level and contrast-induced acute kidney injury in patients undergoing primary percutaneous coronary intervention.

BACKGROUND: A low FT3 level is significantly associated with a variety of kidney disease and acute myocardial infarction (AMI). However, it remains unclear whether low FT3 is associated with CI-AKI in patients who underwent pPCI. METHODS: Single-center retrospective study evaluated 363 STEMI patients undergoing pPCI. Patients were classfied into 2 groups, low FT3 group (FT3 < 3.1 pmol/L) and normal FT3 group (FT3 ≥ 3.1 pmol/L);CI-AKI was defined as an increase in the serum creatinine levels of ≥50% or 0.3 mg/dL above the baseline level within 48 h after contrast medium exposure. RESULTS: Overall, 80(22.0%) patients had low FT3, and 59(16.3%) patients developed CI-AKI. The incidence of CI-AKI and in-hospital mortality was significantly higher in patients with low FT3 than normal (31.3% vs 12.0%; 15.0% vs 3.2%, respectively, both p < 0.0001). Multivariate logistic regression analysis indicated that low FT3 was an independent predictor of CI-AKI (odds ratio [OR] = 2.62, 95%CI:1.35-5.07, p < 0.05). In addition, low FT3 was associated with an increased risk of all-cause mortality during a mean follow-up period of 20 months (hazard ratio [HR] = 2.54, 95%CI:1.15-5.60, p < 0.05). CONCLUSION: Low FT3 was associated with CI-AKI, short- and long-term mortality in STEMI patients after pPCI.

Mitochondrial Retroprocessing Promoted Functional Transfers of rpl5 to the Nucleus in Grasses.

Functional gene transfers from the mitochondrion to the nucleus are ongoing in angiosperms and have occurred repeatedly for all 15 ribosomal protein genes, but it is not clear why some of these genes are transferred more often than others nor what the balance is between DNA- and RNA-mediated transfers. Although direct insertion of mitochondrial DNA into the nucleus occurs frequently in angiosperms, case studies of functional mitochondrial gene transfer have implicated an RNA-mediated mechanism that eliminates introns and RNA editing sites, which would otherwise impede proper expression of mitochondrial genes in the nucleus. To elucidate the mechanisms that facilitate functional gene transfers and the evolutionary dynamics of the coexisting nuclear and mitochondrial gene copies that are established during these transfers, we have analyzed rpl5 genes from 90 grasses (Poaceae) and related monocots. Multiple lines of evidence indicate that rpl5 has been functionally transferred to the nucleus at least three separate times in the grass family and that at least seven species have intact and transcribed (but not necessarily functional) copies in both the mitochondrion and nucleus. In two grasses, likely functional nuclear copies of rpl5 have been subject to recent gene conversion events via secondarily transferred mitochondrial copies in what we believe are the first described cases of mitochondrial-to-nuclear gene conversion. We show that rpl5 underwent a retroprocessing event within the mitochondrial genome early in the evolution of the grass family, which we argue predisposed the gene towards successful, DNA-mediated functional transfer by generating a "pre-edited" sequence.

Thermo-responsive properties driven by hydrogen bonding in aqueous cationic gemini surfactant systems.

A series of unexpected thermo-responsive phenomena were discovered in an aqueous solution of the cationic gemini surfactant, 2-hydroxypropyl-1,3-bis(alkyldimethylammonium chloride) (n-3(OH)-n(2Cl), n = 14, 16), in the presence of an inorganic salt. The viscosity change trend for the 14-3(OH)-14(2Cl) system was investigated in the 20-40 °C temperature range. As the temperature increased, the viscosity of the solution first decreased to a minimum point corresponding to 27 °C, and then increased until a maximum was reached, after which the viscosity decreased again. In the 16-3(OH)-16(2Cl) system, the gelling temperature (T(gel)) and viscosity changes upon heating were similar to those in the 14-3(OH)-14(2Cl) system above 27 °C. The reversible conversion of elastic hydrogel to wormlike micelles in the aqueous solution of the 16-3(OH)-16(2Cl) system in the presence of an inorganic salt was observed at relatively low temperatures. Various techniques were used to study and verify the phase-transition processes in these systems, including rheological measurements, cryogenic transmission electron microscopy (cryo-TEM), electric conductivity, and differential scanning calorimetry. The abovementioned phenomena were explained by the formation and destruction of intermolecular hydrogen bonds, and the transition mechanisms of the aggregates were analyzed accordingly.

MicroRNA-149*, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma.

The tumor suppressor p53 is activated in response to cellular stress to prevent malignant transformation by activation of the DNA repair machinery to preserve the cell, or by induction of apoptosis to eliminate the cell should the damage prove irrevocable. The gene encoding p53 frequently undergoes inactivating mutations in many human cancers, but WT p53 is often expressed at high levels in melanoma, which, as judged from the malignant nature of the disease, fails to act as an effective tumor suppressor. Here we show that p53 directly up-regulates microRNA-149* (miR-149*) that in turn targets glycogen synthase kinase-3α, resulting in increased expression of Mcl-1 and resistance to apoptosis in melanoma cells. Although deficiency in miR-149* undermined survival of melanoma cells and inhibited melanoma growth in a mouse xenograft model, elevated expression of miR-149* was found in fresh human metastatic melanoma isolates, which was associated with decreased glycogen synthase kinase-3α and increased Mcl-1. These results reveal a p53-dependent, miR-149*-mediated pathway that contributes to survival of melanoma cells, provides a rational explanation for the ineffectiveness of p53 to suppress melanoma, and identifies the expression of miR-149* as a mechanism involved in the increased expression of Mcl-1 in melanoma cells.

High-altitude-induced alterations in intestinal microbiota.

In high-altitude environments characterized by low pressure and oxygen levels, the intestinal microbiota undergoes significant alterations. Whether individuals are subjected to prolonged exposure or acute altitude changes, these conditions lead to shifts in both the diversity and abundance of intestinal microbiota and changes in their composition. While these alterations represent adaptations to high-altitude conditions, they may also pose health risks through certain mechanisms. Changes in the intestinal microbiota induced by high altitudes can compromise the integrity of the intestinal mucosal barrier, resulting in gastrointestinal dysfunction and an increased susceptibility to acute mountain sickness (AMS). Moreover, alterations in the intestinal microbiota have been implicated in the induction or exacerbation of chronic heart failure. Targeted modulation of the intestinal microbiota holds promise in mitigating high-altitude-related cardiac damage. Dietary interventions, such as adopting a high-carbohydrate, high-fiber, low-protein, and low-fat diet, can help regulate the effects of intestinal microbiota and their metabolic byproducts on intestinal health. Additionally, supplementation with probiotics, either through dietary sources or medications, offers a means of modulating the composition of the intestinal microbiota. These interventions may offer beneficial effects in preventing and alleviating AMS following acute exposure to high altitudes.