MIRAGE Syndrome Due to a de novo SAMD9 c.2944C > T (p.Arg982Cys) Variant: a Case Report and Relevant Literature Review.

BACKGROUND: MIRAGE syndrome is a rare autosomal dominant genetic disorder. METHODS: We studied a 15-month-old girl with growth retardation and refractory respiratory infections. RESULTS: The patient had thrombocytopenia and was positive for Epstein-Barr virus, cytomegalovirus IgM and IgG, and herpes simplex virus type I and II IgG. The genomic analysis reported a heterozygous de novo SAMD9 c.2944C > T (p.Arg982Cys) pathogenic variant. She improved after antibiotic treatments, but finally died due to severe recurrent infection. CONCLUSIONS: Patients with MIRAGE syndrome could have various clinical presentations. Infections from mixed pathogens are common, which require adequate coverage for bacteria, viruses, and fungi.

Small Molecule SHP2 Inhibitor LXQ-217 Affects Lung Cancer Cell Proliferation in Vitro and in Vivo.

BACKGROUND: SHP2 is highly expressed in a variety of cancer and has emerged as a potential target for cancer therapeutic agents. The identification of uncharged pTyr mimics is an important direction for the development of SHP2 orthosteric inhibitors. METHODS: Surface plasmon resonance analysis and cellular thermal shift assay were employed to verify the direct binding of LXQ-217 to SHP2. The inhibitory effect of LXQ-217 was characterized by linear Weaver-Burke enzyme kinetic analysis and BIOVIA Discovery Studio. The inhibition of tumor cell proliferation by LXQ-217 was characterized by cell viability assay, colony formation assays and hoechst 33258 staining. The inhibition of lung cancer proliferation in vivo was studied in nude mice after oral administration of LXQ-217. RESULTS: An electroneutral bromophenol derivative, LXQ-217, was identified as a competitive SHP2 inhibitor. LXQ-217 induced apoptosis and inhibited growth of human pulmonary epithelial cells by affecting the RAS-ERK and PI3 K-AKT signaling pathways. Long-term oral administration of LXQ-217 significantly inhibited the proliferation ability of lung cancer cells in nude mice. Moreover, mice administered LXQ-217 orally at high doses exhibited no mortality or significant changes in vital signs. CONCLUSIONS: Our findings on the uncharged orthosteric inhibitor provide a foundation for further development of a safe and effective anti-lung cancer drug.

Organic Electrochemical Transistor with MoS2 Nanosheets Modified Gate Electrode for Sensitive Glucose Sensing.

An organic electrochemical transistor (OECT) with MoS2 nanosheets modified on the gate electrode was proposed for glucose sensing. MoS2 nanosheets, which had excellent electrocatalytic performance, a large specific surface area, and more active sites, were prepared by liquid phase ultrasonic exfoliation to modify the gate electrode of OECT, resulting in a large improvement in the sensitivity of the glucose sensor. The detection limit of the device modified with MoS2 nanosheets is down to 100 nM, which is 1~2 orders of magnitude better than that of the device without nanomaterial modification. This result manifests not only a sensitive and selective method for the detection of glucose based on OECT but also an extended application of MoS2 nanosheets for other biomolecule sensing with high sensitivity.

Bioactivity-Guided Screening of Antimicrobial Secondary Metabolites from Antarctic Cultivable Fungus Acrostalagmus luteoalbus CH-6 Combined with Molecular Networking.

With the increasingly serious antimicrobial resistance, discovering novel antibiotics has grown impendency. The Antarctic abundant microbial resources, especially fungi, can produce unique bioactive compounds for adapting to the hostile environment. In this study, three Antarctic fungi, Chrysosporium sp. HSXSD-11-1, Cladosporium sp. HSXSD-12 and Acrostalagmus luteoalbus CH-6, were found to have the potential to produce antimicrobial compounds. Furthermore, the crude extracts of CH-6 displayed the strongest antimicrobial activities with 72.3-84.8% growth inhibition against C. albicans and Aeromonas salmonicida. The secondary metabolites of CH-6 were researched by bioactivity tracking combined with molecular networking and led to the isolation of two new α-pyrones, acrostalapyrones A (1) and B (2), along with one known analog (3), and three known indole diketopiperazines (4-6). The absolute configurations of 1 and 2 were identified through modified Mosher's method. Compounds 4 and 6 showed strong antimicrobial activities. Remarkably, the antibacterial activity of 6 against A. salmonicida displayed two times higher than that of the positive drug Ciprofloxacin. This is the first report to discover α-pyrones from the genus Acrostalagmus, and the significant antimicrobial activities of 4 and 6 against C. albicans and A. salmonicida. This study further demonstrates the great potential of Antarctic fungi in the development of new compounds and antibiotics.

The relationship between life events, life satisfaction, and coping style of college students.

We aimed to investigate the life events, life satisfaction, and coping style of college students, and to assess the relationship between them by performing mediating effect analysis. Our findings may provide a scientific basis for promoting the mental health of college students. Students in a medical college were selected using grade-stratified cluster sampling, and administered a standardized questionnaire survey. Out of 2,000 participants, 1827 participants provided valid questionnaires (response rate: 91.4%). The mean scores of life satisfaction and life events were 181.39 ± 30.28 and 19.32 ± 15.62, respectively. The mean score of coping style was 14.34 ± 7.54, which reflected positive coping style. Analysis of life satisfaction, life events, and factor scores showed that different grades, sibling status (whether the respondent was the only child in the family or not), family location, and life events had a significant association with life satisfaction (p < 0.001). There were significant differences in coping style between male and female students, and between students in different grades (p < 0.001). Positive coping style was found to play a partial mediating role between life events and life satisfaction, and the mediating effect accounted for 33.2% of the total effect. These results suggest that both life events and coping styles are related to college students' life satisfaction. The impact of life events on life satisfaction can be adjusted by psychological interventions to develop coping styles that can help promote the mental health of college students.

Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors.

Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene, which is involved in the RAS/MAPK cell signaling transduction process. SHP2 has been shown to contribute to the progression of various cancers and is emerging as an important target for anti-tumor drug research. However, past efforts to develop SHP2 inhibitors into drugs have been unsuccessful owing to the positively charged nature of the active site pocket tending to bind negatively charged groups that are usually non-drug-like. Here, a series of uncharged pyrazoline derivatives were designed and developed as new SHP2 inhibitors using a structure-based strategy. Compound 4o, which exhibited the strongest SHP2 inhibitory activity, bound directly to the catalytic domain of SHP2 in a competitive manner through multiple hydrogen bonds. Compound 4o affected the RAS/MAPK signaling pathway by inhibiting SHP2, and subsequently induced apoptosis and growth inhibition of HCT116 cells in vitro and in vivo. Notably, the oral administration of compound 4o in large doses showed no obvious toxicity. In summary, our findings provide a basis for the further development of compound 4o as a safe, effective and anti-tumor SHP2 inhibitor.

Exosome-delivered miR-221/222 exacerbates tumor liver metastasis by targeting SPINT1 in colorectal cancer.

MicroRNAs (miRNAs) are involved in the progression of many cancers through largely unelucidated mechanisms. The results of our present study identified a gene cluster, miR-221/222, that is constitutively upregulated in serum exosome samples of patients with colorectal carcinoma (CRC) with liver metastasis (LM); this upregulation predicts a poor overall survival rate. Using an in vitro cell coculture model, we demonstrated that CRC exosomes harboring miR-221/222 activate liver hepatocyte growth factor (HGF) by suppressing SPINT1 expression. Importantly, miR-221/222 plays a key role in forming a favorable premetastatic niche (PMN) that leads to the aggressive nature of CRC, which was further shown through in vivo studies. Overall, our results show that exosomal miR-221/222 promotes CRC progression and may serve as a novel prognostic marker and therapeutic target for CRC with LM.

HDN-1 induces cell differentiation toward apoptosis in promyelocytic leukemia cells depending on its selective effect on client proteins of Hsp90.

Heat Shock Protein 90 (Hsp90) is frequently upregulated in many cancers, and its inhibition simultaneously blocks multiple signaling pathways, resulting in cell differentiation or apoptosis. However, the complexity of Hsp90 in differentiation and its relation with apoptosis have remained unsettled. In this study, we demonstrated that HDN-1, a C-terminal inhibitor of Hsp90, induced the differentiation of HL-60 cells toward apoptosis. HDN-1 induced the differentiation of cells containing mutant AML1-ETO into mature granulocytes, which was related to its selective effect on client proteins of Hsp90. HDN-1 destabilized AML1-ETO and preserved C/EBPß at the same time, thereby induced a total increase in C/EBPß levels because of AML1-ETO negative regulation to C/EBPß expression. Neither HDN-1 nor 17-AAG (an N-terminal inhibitor of Hsp90) led to the differentiation of NB4 cells because mutant PML-RARα was not affected as a client protein of Hsp90; thus, no additional expression of C/EBPß was induced. 17-AAG did not affect the differentiation of HL-60 cells due to decreased AML1-ETO and C/EBPß levels. These results indicate that HDN-1 drives cell differentiation toward apoptosis depending on its selective influence on client proteins of Hsp90, establishing the relationship between differentiation and apoptosis and uncovering the mechanism of HDN-1 in promyelocytic leukemia cell differentiation. Moreover, HDN-1 is very promising for the development of anticancer agents with the induction of differentiation.

Regulators of calcineurin 1 deficiency attenuates tubulointerstitial fibrosis through improving mitochondrial fitness.

Renal fibrosis is the common pathological process of various chronic kidney diseases (CKD). Recent studies indicate that mitochondrial fragmentation is closely associated with renal fibrosis in CKD. However, the molecular mechanisms leading to mitochondrial fragmentation remain to be elucidated. The present study investigated the role of regulators of calcineurin 1 (RCAN1) in mitochondrial fission and renal interstitial fibrosis using conditional knockout mice in which RCAN1 was genetically deleted in tubular epithelial cells (TECs). TEC-specific deletion of RCAN1 attenuated tubulointerstitial fibrosis and epithelial to mesenchymal transition (EMT)-like phenotype change after unilateral ureteral obstruction (UUO) and ischemia reperfusion injury (IRI) through suppressing TGF-ß1/Smad3 signaling pathway. TEC-specific deletion of RCAN1 also reduced the tubular apoptosis after UUO by inhibiting cytochrome c/caspase-9 pathway. Ultrastructure analysis revealed a marked decrease in mitochondrial fragmentation in TECs of RCAN1-deficient mice in experimental CKD models. The expression of mitochondrial profission proteins dynamin-related protein 1 (Drp1) and mitochondrial fission factor (Mff) was also downregulated in obstructed kidney of TEC-specific RCAN1-deficient mice. Furthermore, TEC-specific deletion of RCAN1 attenuated the dysfunctional tubular autophagy by regulating PINK1/Parkin-induced mitophagy in CKD. RCAN1 knockdown and knockout similarly improved the mitochondrial quality control in HK-2 cells and primary cultured mouse tubular cells stimulated by TGF-ß1. Put together, our data indicated that RCAN1 plays an important role in the progression of tubulointerstitial fibrosis through regulating the mitochondrial quality. Therefore, targeting RCAN1 may provide a potential therapeutic approach in CKD.

New Polyketides from the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The species Pseudogymnoascus is known as a psychrophilic pathogenic fungus with a ubiquitous distribution in Antarctica. Meanwhile, the study of its secondary metabolites is infrequent. Systematic research of the metabolites of the fungus Pseudogymnoascus sp. HSX2#-11, guided by the method of molecular networking, led to the isolation of one novel polyketide, pseudophenone A (1), along with six known analogs (2-7). The structure of the new compound was elucidated by extensive spectroscopic investigation and single-crystal X-ray diffraction. Pseudophenone A (1) is a dimer of diphenyl ketone and diphenyl ether, and there is only one analog of 1 to the best of our knowledge. Compounds 1 and 2 exhibited antibacterial activities against a panel of strains. This is the first time to use molecular networking to study the metabolic profiles of Antarctica fungi.

Nitrogenous Compounds from the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The species Pseudogymnoascus is known as a psychrophilic pathogenic fungus which is ubiquitously distributed in Antarctica. While the studies of its secondary metabolites are infrequent. Systematic research of the metabolites of the Antarctic fungus Pseudogymnoascus sp. HSX2#-11 led to the isolation of one new pyridine derivative, 4-(2-methoxycarbonyl-ethyl)-pyridine-2-carboxylic acid methyl ester (1), together with one pyrimidine, thymine (2), and eight diketopiperazines, cyclo-(dehydroAla-l-Val) (3), cyclo-(dehydroAla-l-Ile) (4), cyclo-(dehydroAla-l-Leu) (5), cyclo-(dehydroAla-l-Phe) (6), cyclo-(l-Val-l-Phe) (7), cyclo-(l-Leu-l-Phe) (8), cyclo-(l-Trp-l-Ile) (9) and cyclo-(l-Trp-l-Phe) (10). The structures of these compounds were established by extensive spectroscopic investigation, as well as by detailed comparison with literature data. This is the first report to discover pyridine, pyrimidine and diketopiperazines from the genus of Pseudogymnoascus.

Linkage between Particulate Matter Properties and Lung Function in Schoolchildren: A Panel Study in Southern China.

While several scientific studies have linked PM2.5 to decreased lung function, there is still some degree of uncertainty regarding which particulate physicochemical properties are most harmful. We followed a panel of 57 healthy schoolchildren (857 person-days) to investigate the associations between a wide variety of PM2.5 and lung function in Heshan, China in 2016 for three periods. We monitored the daily concentrations of mass, chemical composition, size, number, surface area, and volume of particulate mixture. Associations of lung function with various particle metrics were estimated using generalized estimating equations and unconstrained distributed lag models. Random forest model was used to compare the relative importance of exposure metrics. Immediate (lag 0) associations of PM2.5 and carbonaceous aerosols with reduced FEV1 and MMEF, and accumulation-mode particles with FEV1 were found. Slightly delayed (lag 1, 2) effects on PEF were particularly prominent for Aitken-mode particles. Possible cumulative (lags 0-2) effects of PM2.5 and carbonaceous aerosols on PEF and Aitken-mode particles on FEV1, MMEF, and PEF were observed. This study provides comprehensive evidence that the physicochemical properties of particulate mixtures are associated with reduced lung function in children. Organic carbon (OC) may be an important risk factor for the decreased lung function related to PM exposure.

The Fluoro-Thiazolylhydrazone Compound TSC-3C Inhibits Triple Negative Breast Cancer (TNBC) Cell Line Activity by Promoting Apoptosis, Regulating the MAPK Pathway and Inducing Mitochondrial Dysfunction.

Triple negative breast cancer (TNBC) is the most aggressive cancer in women, and despite improved treatments, it remains a major cause of morbidity and mortality. We and others have demonstrated that different hybrid compounds targeting PARP/MAPK or other pathways to inhibit cancer progression may lead to promising therapeutic results. We introduced fluorine to alter the physical properties of the compounds. TSC-3C was one of the generated compounds. Upon treatment with TSC-3C, MDA-MB-231 cell proliferation, invasion, and migration were inhibited. TSC-3C induced MDA-MB-231 cell mitochondrial dysfunction and apoptosis, which may be caused by reducing the level of phosphorylated p44/42 MAPK (ERK1/2) and increasing the level of p-JNK. The present study may help to elucidate the role of the MAPK pathway in the development of breast cancer and may promote further research on halogenated heterocyclic compounds for the treatment of breast cancer.

Integrated assessment of health risk and climate effects of black carbon in the Pearl River Delta region, China.

BACKGROUND: Black carbon (BC) caused by incomplete combustion of fossil and bio-fuel has a dual effect on health and climate. There is a need for systematic approaches to evaluation of health outcomes and climate impacts relevant to BC exposure. OBJECTIVES: We propose and illustrate for the first time, to our knowledge, an integrated analysis of a region-specific health model with climate change valuation module to quantify the health and climate consequences of BC exposure. METHODS: Based on the data from regional air pollution monitoring stations from 2013 to 2014 in the Pearl River Delta region (PRD), China, we analyzed the carcinogenic and non-carcinogenic effects and the relative risk of cause-specific mortality due to BC exposure in three typical cities of the PRD (i.e. Guangzhou, Jiangmen and Huizhou). The radiative forcing (RF) and heating rate (HR) were calculated by the Fu-Liou-Gu (FLG) plane-parallel radiation model and the conversion of empirical formula. We further connected the health and climate impacts by calculating the excess mortalities attributed to climate warming due to BC. RESULTS: Between 2013 and 2014, carcinogenic risks of adults and children due to BC exposure in the PRD were higher than the recommended limits (1 × 10-6 to 1 × 10-4), resulting in an excess of 4.82 cancer cases per 10,000 adults (4.82 × 10-4) and an excess of 1.97 cancer cases per 10,000 children (1.97 × 10-4). Non-carcinogenic risk caused by BC was not found. The relative risks of BC exposure on mortality were higher in winter and dry season. The atmospheric RFs of BC were 26.31 W m-2, 26.41 W m-2, and 22.45 W m-2 for Guangzhou, Jiangmen and Huizhou, leading to a warming of the atmosphere in the PRD. The estimated annual excess mortalities of climate warming due to BC were 5052 (95% CI: 1983, 8139), 5121 (95% CI: 2010, 8249) and 4363 (95% CI: 1712, 7032) for Guangzhou, Jiangmen and Huizhou, respectively. CONCLUSION: Our estimates suggest that current levels of BC exposure in the PRD region posed a considerable risk to human health and the climate. Reduction of BC emission could lead to substantial health and climate co-benefits.

Minocycline Relieves Depressive-Like Behaviors in Rats With Bone Cancer Pain by Inhibiting Microglia Activation in Hippocampus.

BACKGROUND: Pain and depression are highly prevalent symptoms in cancer patients. They tend to occur simultaneously and affect each other and share biological pathways and neurotransmitters. In this study, we investigated the roles of microglia in the hippocampus in the comorbidity of bone cancer pain and depressive-like behaviors in an animal model of bone cancer pain. METHODS: Bone cancer pain was induced by injection of Walker 256 mammary gland carcinoma cells into the tibia of rats. The effects of intracerebroventricular administration of microglia inhibitor minocycline were examined. RESULTS: Carcinoma intratibia injection caused comorbidity of mechanical allodynia and depressive-like behaviors in rats and activation of microglia in the hippocampus. Both mechanical allodynia and depressive-like behaviors were attenuated by minocycline. Enzyme-linked immunosorbent assay analysis showed that the enhanced expressions of M1 microglia marker (CD 86) and the proinflammatory cytokines tumor necrosis factor-α and interleukin-1ß in the hippocampus of cancer-bearing rats were decreased by minocycline. On the other hand, minocycline also increased the expressions of M2 microglia marker (MRC1) and anti-inflammatory cytokine interleukin-10. CONCLUSIONS: The results suggest that the activation of microglia in the hippocampus plays an important role in the development of pain and depressive-like behaviors in bone cancer condition.

The correlation between family food handling behaviors and foodborne acute gastroenteritis: a community-oriented, population-based survey in Anhui, China.

BACKGROUND: Foodborne acute gastroenteritis is a significant public health concern. Food handling plays a key role in the risk of foodborne acute gastroenteritis. However, research focused on the correlation between foodborne acute gastroenteritis and food handling in the family environment is limited. The purpose of the current study was to determinate the association between food handling behaviors in the family environment and foodborne acute gastroenteritis. METHODS: A cross-sectional investigation was conducted from September 1, 2015 to August 30, 2016 in Anhui Province, China. A multistage stratified cluster sampling method was designed to select subjects. Data on foodborne acute gastroenteritis and food handling were collected via questionnaire survey. RESULTS: Of the 1516 subjects included in the study, 165 (10.9%) reported having experienced symptoms of foodborne acute gastroenteritis in the past 4 weeks. The following behaviors were more prevalent in those that experienced acute gastroenteritis: (1) infrequently thoroughly heating milk (75.6%); (2) infrequently thoroughly heating cooked food purchased from outside (71.3%); (3) infrequently thoroughly heating leftovers stored in the refrigerator (32.5%), and (4) infrequently storing leftovers in the refrigerator (41.6%). A multivariate logistic regression analysis found that foodborne acute gastroenteritis was associated with the following behaviors: (1) often eating raw seafood (P < 0.001, OR = 3.250, 95% CI = 2.136-4.946); (2) often storing raw meat and cooked meat in the same container (P < 0.001, OR = 4.291, 95% CI = 2.722-6.765); (3) infrequently thoroughly heating milk (P < 0.001, OR = 4.665, 95% CI = 2.526-8.617); (4) infrequently thoroughly heating leftovers stored in the refrigerator (P < 0.001, OR = 3.416, 95% CI = 2.139-5.454); (5) infrequently storing leftovers in the refrigerator (P < 0.05, OR = 1.775, 95% CI = 1.169-2.696); and (6) infrequently thoroughly cooking green beans (P < 0.001, OR = 2.859, 95% CI = 1.798-4.545). CONCLUSIONS: Poor food handling behaviors in the family environment are associated with foodborne acute gastroenteritis. Infrequent thorough heating and improper food storage are the most critical risk factors in foodborne acute gastroenteritis.

Molecular Targets of Active Anticancer Compounds Derived from Marine Sources.

Over the past decades, a number of novel compounds, which are produced in the marine environment, have been found to exhibit the anticancer effects. This review focuses on molecular targets of marine-derived anticancer candidates in clinical and preclinical studies. They are kinases, transcription factors, histone deacetylase, the ubiquitin-proteasome system, and so on. Specific emphasis of this review paper is to provide information on the optimization of new target compounds for future research and development of anticancer drugs, based on the identification of structures of these target molecules and parallel compounds.

Penicisulfuranols A-F, Alkaloids from the Mangrove Endophytic Fungus Penicillium janthinellum HDN13-309.

Six new epipolythiodioxopiperazine (ETP) alkaloids, penicisulfuranols A-F (1-6), were isolated from the mangrove endophytic fungus Penicillium janthinellum HDN13-309. All structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic data and ECD calculations. They belong to the unusual family of ETPs containing sulfur atoms on both α- and ß-positions of amino acid residues and a rare 1,2-oxazadecaline core moiety. In addition, compounds 1-6 also possess a rare spiro-furan ring and 1-3 showed cytotoxicity with IC50 values ranging from 0.1 to 3.9 µM.

[Diffuse alveolar hemorrhage in 4 girls].

This article reports 4 girls with clinical manifestations of recurrent cough and anemia. The age of onset was less than 4 years, and three of them had shortness of breath. None of them had acute hemoptysis. All the girls had positive results of hemosiderin test for bronchoalveolar lavage fluid. As for imaging examination, 3 patients had ground-glass opacity, and 1 had interstitial change. Three girls were given the treatment for idiopathic pulmonary hemosiderosis and had no response. Selective bronchial arteriography was performed for the 4 girls and found bronchial artery to pulmonary circulation shunt (BPS). After they were diagnosed with BPS, they were given transcatheter embolization. The girls were followed up for half a year after surgery, and none of them was readmitted due to "cough and anemia". BPS manifests as abnormal shunt between the bronchial artery and the pulmonary artery/vein and has unknown causes. It is rare in children and should be considered for children who were thought to have idiopathic pulmonary hemosiderosis and had poor response to corticosteroid therapy.

Improvement on solubility of fluticasone propionate with cyclodextrins by mechanochemical activation.

To enhance the solubility and in vitro dissolution of fluticasone propionate (FP), a novel approach was developed with mechanochemical treatment. The order of solubilizing effect of ß-CD derivatives was observed as HP-ß-CD-SBE-ß-CD-ß-CD-HE-ß-CD, consequently, HP-ß-CD showed the highest stability constant. To further improve FP solubility, FP and HP-ß-CD were grinded using a roll mill, the optimal conditions, determined through single factor experiments, were as follows: rotation frequency of 60 Hz; milling time of 6h. mass ratio of 1: 7. In comparison with pure FP, a 280-fold increase in solubility and a 2.15-fold higher dissolution rate of ground mixture was obtained. The characterization of FP and HP-ß-CD complexes had been analyzed by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and fourier transform infrared spectroscopy (FT-IR). The results suggested that the interaction between FP and HP-ß-CD was strengthened and an amorphous ground mixture was gained. After stored for 60 days, the ground mixtures were stable both chemically and physically.