[Retracted] MicroRNA­219 is downregulated in non­small cell lung cancer and inhibits cell growth and metastasis by targeting HMGA2.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell migration and invasion assay data shown in Figs. 2C and 4C were strikingly similar to data that had already been published in different form in another article written by different authors at a different research institute [Yang S, Zhang Y, Zhao X, Wang J and Shang J: microRNA­361 targets Wilms' tumor 1 to inhibit the growth, migration and invasion of non­small­cell lung cancer cells. Mol Med Rep 14: 5415­5421, 2016].  Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 16: 3557­3564, 2017; DOI: 10.3892/mmr.2017.7000].

Flow cytometric immunophenotypic differentiation patterns of bone marrow eosinophilopoiesis.

BACKGROUND: Flow cytometry has been widely used to study immunophenotypic patterns of maturation of most hematopoietic lineages in normal human bone marrow aspirates, thus allowing identification of changes in patterns in many myeloid malignancies. Eosinophils play an important role in a wide variety of disorders, including some myeloid neoplasms. However, changes in flow cytometric immunophenotypic patterns during normal and abnormal bone marrow eosinophilopoiesis have not been well studied. METHODS: Fresh bone marrow aspirates from 15 healthy donors, 19 patients with hypereosinophilic syndromes (HES), and 11 patients with systemic mastocytosis (SM) were analyzed for candidate markers that included EMR-1, Siglec-8, CCR3, CD9, CD11a, CD11b, CD11c, CD13, CD16, CD29, CD34, CD38, CD45, CD44, CD49d, CD49f, CD54, CD62L, CD69, CD117, CD125 (IL-5Rα), HLA-DR, using 10 parameter flow cytometry. Putative CD34-negative immature and mature normal eosinophil populations were first identified based on changes in expression of the above markers in healthy donors, then confirmed using fluorescence-based cell sorting and morphological evaluation of cytospin preparations. The normal immunophenotypic patterns were then compared to immunophenotypic patterns of eosinophilopoiesis in patients with HES and SM. RESULTS: The eosinophilic lineage was first verified using the human eosinophil-specific antibody EMR-1 in combination with anti-IL-5Rα antibody. Then, a combination of Siglec-8, CD9, CD11b, CCR3, CD49d, and CD49f antibodies was used to delineate normal eosinophilic maturational patterns. Early stages (eosinophilic promyelocytes/myelocytes) were identified as Siglec-8 dim/CD11b dim to moderate/CD9 dim/CCR3 dim/CD49d bright/CD49f dim, intermediate stages (eosinophilic myelocytes/metamyelocytes) as Siglec-8 moderate/CD11b moderate to bright/CD9 moderate/CCR3 moderate/CD49d moderate/CD49f moderate and mature bands/segmented eosinophils as Siglec-8 bright/CD11b bright/CD9 bright/CCR3 bright/CD49d dim/CD49f bright. Overall maturational patterns were also similar in patients with HES and SM; however, the expression levels of several surface markers were altered compared to normal eosinophils. CONCLUSION: A novel flow cytometric antibody panel was devised to detect alterations in immunophenotypic patterns of bone marrow eosinophil maturation and evaluated in normal, HES and SM samples. This approach will allow us to elucidate changes in immunophenotypic patterns of bone marrow eosinophilopoiesis in other hematological diseases.

Standardized indolent systemic mastocytosis evaluations across a healthcare system: implications for screening accuracy.

Timely diagnosis of systemic mastocytosis (SM) remains challenging due to care heterogeneity. We implemented a standardized approach for SM screening and diagnosis utilizing a novel healthcare system-wide international screening registry. A retrospective analysis assessed rates of SM, cutaneous mastocytosis (CM), and molecular diagnoses before and two years after care standardization. Accuracy of individual and combined SM screening tests - basal serum tryptase (BST) ≥11.5 and ≥20.0 ng/mL, REMA ≥2, monomorphic maculopapular CM, and elevated BST based upon tryptase genotype - was analyzed. Tryptase genotyping and high-sensitivity KIT p.D816V testing increased substantially two years following care standardization. SM diagnoses doubled from 47 to 94 and KIT p.D816V molecular diagnoses increased from 24 to 79. Mean BST and KIT p.D816V variant allele frequency (VAF) values were significantly lower in patients diagnosed after standardization. Hereditary-alpha tryptasemia prevalence was increased in SM prior to care standardization at 4/30 (13.3%) but reflected the general population prevalence two years later at 5/76 (6.6%). Elevated BST based upon genotype and BST ≥11.5 ng/mL had the highest sensitivities at 84.2% and 88.3%, respectively. Presence of monomorphic MPCM, elevated BST based upon tryptase genotype, and the combination of REMA ≥2 with elevated BST based upon tryptase genotype had specificities >90%. BST >20.0 ng/mL had low sensitivity and specificity and was not required to establish any indolent SM diagnosis. Care standardization increased SM diagnosis rates, particularly in patients with low BSTs. Stratifying BST based upon genotype had the best overall sensitivity and specificity of any indolent SM screening test and improved the REMA score specificity.

An evaluation of microplastic contamination in the marine waters and species in the coastal region of the South Yellow Sea, China.

Microplastics (MPs) contamination of marine environments poses a significant ecological risk, although impacts on species' realized niche spaces remain unclear. The current study investigates MPs distribution across pelagic habitats, benthic sediments, and key biota in the South Yellow Sea, China. Samples were collected via trawling across estuarine transects, and tissues were digested to extract MPs. Density gradient separations and vacuum-filtrations prepared particle extracts for ATR-FTIR and Micro-Raman spectroscopic characterization. Sampling along industrialized river transects reveals ubiquitous plastic particle presence, with concentrations ranging from 0 to 51.68 item/L seawater. Contamination levels reach their peak at station estuaries before dispersing offshore, indicating significant waste stream inputs. Importantly, MPs detected in demersal and pelagic fish species, as well as in bivalves, confirm exposure across trophic niches. Gastrointestinal tract and gill concentrations reached 0.6 items/g fresh tissue, reflecting significant biological uptake and in vivo retention. The greatest population of organisms occurred adjacent to polluted areas. Overall, distribution of MPs from polluted rivers to coastal food webs was evident, suggesting potential negative impacts on key ecological functions in this system. These findings underscore the need to develop upstream mitigation efforts so as to minimize MPs contamination in areas where nearshore and offshore niches intersect.

Experimentally monitored calcium dynamics at synaptic active zones during neurotransmitter release in neuron-muscle cell cultures.

Ca2+-dependent K+ (BK) channels at varicosities in Xenopus nerve-muscle cell cultures were used to quantify experimentally the instantaneous active zone [Ca2+]AZ resulting from different rates and durations of Ca2+ entry in the absence of extrinsic buffers and correlate this with neurotransmitter release. Ca2+ tail currents produce mean peak [Ca2+]AZ ~ 30 µM; with continued influx, [Ca2+]AZ reaches ~45-60 µM at different rates depending on Ca2+ driving force and duration of influx. Both IBK and release are dependent on Ca2+ microdomains composed of both N- and L-type Ca channels. Domains collapse with a time constant of ~0.6 ms. We have constructed an active zone (AZ) model that approximately fits this data, and depends on incorporation of the high-capacity, low-affinity fixed buffer represented by phospholipid charges in the plasma membrane. Our observations suggest that in this preparation, (1) some BK channels, but few if any of the Ca2+ sensors that trigger release, are located within Ca2+ nanodomains while a large fraction of both are located far enough from Ca channels to be blockable by EGTA, (2) the IBK is more sensitive than the excitatory postsynaptic current (EPSC) to [Ca2+]AZ (K1/2-26 µM vs. ~36 µM [Ca2+]AZ); (3) with increasing [Ca2+]AZ, the IBK grows with a Hill coefficient of 2.5, the EPSC with a coefficient of 3.9; (4) release is dependent on the highest [Ca2+] achieved, independent of the time to reach it; (5) the varicosity synapses differ from mature frog nmjs in significant ways; and (6) BK channels are useful reporters of local [Ca2+]AZ.

Synthesis of Chiral Diarylmethylamides via Catalytic Asymmetric Aza-Michael Addition of Amides to ortho-Quinomethanes.

Chiral diarylmethylamides are a privileged skeleton in many bioactive molecules. However, the enantioselective synthesis of such molecules remains a long-standing challenge in organic synthesis. Herein, we report a chiral bifunctional squaramide catalyzed asymmetric aza-Michael addition of amides to in situ generated ortho-quinomethanes, affording enantioenriched diarylmethylamides in good yields with excellent enantioselectivities. This work not only provides a new strategy for the construction of the diarylmethylamides but also represents the practicability of amides as nitrogen-nucleophiles in asymmetric organocatalysis.

Diastereo- and Enantioselective Synthesis of Eight-Membered N-Heterocycles from Benzofuran-Derived Azadienes and Ynones.

Enantioselective synthesis of eight-membered N-heterocycles represents a long-standing challenge in organic synthesis. Here, by combining the squaramide and DBU catalysis, a sequential asymmetric conjugate addition/cyclization reaction between benzofuran-derived azadienes and ynones has been well-developed, providing straightforward access to chiral eight-membered N-heterocycles in high yields with stereoselectivities. This protocol features the use of a bifunctional squaramide catalyst for controlling the enantioselectivity of products, while the DBU is utilized to achieve intramolecular cyclization and improve the diastereoselectivity of products.

Mepolizumab incompletely suppresses clinical flares in a pilot study of episodic angioedema with eosinophilia.

BACKGROUND: Episodic angioedema with eosinophilia (EAE) is a rare multilineage cyclic syndrome of unknown etiology characterized by episodes of angioedema, myalgia, fatigue, and fever that occur every 3 to 8 weeks and resolve between episodes without therapy. Cyclic elevations in serum IL-5 levels and neutrophils precede the increase in absolute eosinophil count (AEC) in most patients. OBJECTIVE: We sought to assess the role of IL-5-driven eosinophilia in the clinical manifestations of EAE. METHODS: An open-label pilot study of mepolizumab (700 mg intravenously monthly for 3 months followed by sequential dose reduction to the Food and Drug Administration-approved dose of 300 mg subcutaneously monthly) was conducted. The primary end point was reduction in the number and severity of clinical symptoms as assessed by patient-reported symptom questionnaires. Secondary end points were greater than or equal to 75% reduction in peak AEC after 1 dose of mepolizumab and sustained reduction in AEC after 3 doses of mepolizumab. Exploratory end points included effects of mepolizumab treatment on other cell lineages (numbers and surface marker expression), levels of plasma mediators, and biomarkers of eosinophil activation. RESULTS: Four female and 1 male (median age, 45 years) participants with EAE were enrolled. None of the 5 participants experienced a reduction in the number of symptomatic flares on mepolizumab therapy, and 1 participant withdrew before study completion because of lack of improvement. Peak AEC was reduced by 75% or more in 3 participants after the first dose of mepolizumab and in 4 participants after 3 doses. CONCLUSIONS: In a small cohort of participants with EAE, mepolizumab was unsuccessful in substantially reducing clinical symptoms despite reduction in AEC.

Facile In-Situ photocatalytic reduction of AuNPs on multilayer Core-Shell Fe3O4@SiO2@PDA magnetic nanostructures and their SERS application.

Surface-enhanced Raman scattering (SERS) is a promising analytical technique for the rapid, sensitive, and repeatable detection in various SERS application fields. Herein, a new type of potential magnetically recyclable SERS substrate was designed and rapidly synthesized via a facile three-step template method. First, the magnetic ferroferric oxide (Fe3O4) cores were prepared by a convenient solvothermal approach, and coated with a thin layer of silica by a sol-gel process in order to improve their stability in complicated environments. Next, the negatively charged polydopamine (PDA)/K6[SiW11VIVO40]·7H2O (PDA/SiW11V) outer shell was assembled upon the magnetic Fe3O4@SiO2 core-shell nanoparticles via a layer-by-layer sequential adsorption process using the stickiness of PDA. The SiW11V multilayer shell can be used as the subsequent photocatalytic reduction precursors for the in-situ loading of high-density gold nanoparticles (AuNPs), without any other organic additives. The AuNPs decorated multilayer core-shell Fe3O4@SiO2@PDA magnetic nanostructures were employed as a potential magnetically recyclable SERS substrate, and showed excellent SERS performance. Using crystal violet (CV) as a model target, the as-fabricated AuNPs modified multilayer core-shell Fe3O4@SiO2@PDA magnetic nanostructures SERS substrates exhibited significant enhancement, and pushed the detection limit down to 10-12 M. Aside from the ultrahigh sensitivity, these SERS substrates also possess an excellent reproducibility (relative standard deviation (RSD) âˆ¼ 8.3%), long-term stability (75 days), and unique chemical stability capability in different organic solvents and different environments with pH ≤ 10. Furthermore, a real-life application is also performed by the detection of melamine in spiked milk solution using the as-prepared magnetic nanostructures SERS-active substrates (limit of detection (LOD), 10-8 M). These results highlight that the rational design and controllable synthesis of multifunctional magnetic SERS substrates is a promising strategy in many different application fields such as biosensing, photoelectrocatalysis, and medical diagnosis.

False-Negative Testing for FIP1L1::PDGFRA by Fluorescence in situ Hybridization Is a Frequent Cause of Diagnostic Delay.

The imatinib-sensitive fusion gene FIP1L1::PDGFRA is the most frequent molecular abnormality identified in patients with eosinophilic myeloid neoplasms. Rapid recognition of this mutation is essential given the poor prognosis of PDGFRA-associated myeloid neoplasms prior to the availability of imatinib therapy. We report a case of a patient in whom delayed diagnosis resulted in cardiac transplantation for eosinophilic endomyocardial fibrosis. The delay in diagnosis was due, in part, to a false-negative result in fluorescence in situ hybridization (FISH) testing for FIP1L1::PDGFRA. To explore this further, we examined our cohort of patients presenting with confirmed or suspected eosinophilic myeloid neoplasms and found 8 additional patients with negative FISH results despite a positive reverse-transcriptase polymerase chain reaction test for FIP1L1::PDGFRA. More importantly, false-negative FISH results delayed the median time to imatinib treatment by 257 days. These data emphasize the importance of empiric imatinib therapy in patients with clinical features suggestive of PDGFRA-associated disease.

Metal-free and enantioselective synthesis of 1,4-benzoxazepines from para-quinone methide derivatives and α-bromohydroxamates.

A sequential asymmetric conjugate addition/cyclisation of α-bromohydroxamates with para-quinone methide derivatives has been developed, which provides enantioenriched 1,4-benzoxazepines in generally high yields (up to 95%) and good enantioselectivities (up to 97 : 3 er). This protocol not only offers a novel and straightforward strategy for constructing chiral 1,4-benzoxazepines, but also demonstrates the potential of α-bromohydroxamates as three-atom synthons in asymmetric cyclisation reactions.

Effects of Fluorine-Based Modification on Triboelectric Properties of Cellulose.

The hydroxyl groups on the cellulose macromolecular chain cause the cellulose surface to have strong reactivity. In this study, 1H, 1H, 2H, 2H-perfluorodecyltriethoxysilane (PDOTES) was used to modify cellulose to improve its triboelectric properties, and a triboelectric nanogenerator (TENG) was assembled. The introduction of fluorine groups reduced the surface potential of cellulose and turned it into a negative phase, which enhanced the ability to capture electrons. The electrical properties increased by 30% compared with unmodified cellulose. According to the principles of TENGs, a self-powered human-wearable device was designed using PDOTES-paper, which could detect movements of the human body, such as walking and running, and facilitated a practical method for the preparation of efficient wearable sensors.

Discovering miRNAs Associated With Multiple Sclerosis Based on Network Representation Learning and Deep Learning Methods.

Identifying biomarkers of Multiple Sclerosis is important for the diagnosis and treatment of Multiple Sclerosis. The existing study has shown that miRNA is one of the most important biomarkers for diseases. However, few existing methods are designed for predicting Multiple Sclerosis-related miRNAs. To fill this gap, we proposed a novel computation framework for predicting Multiple Sclerosis-associated miRNAs. The proposed framework uses a network representation model to learn the feature representation of miRNA and uses a deep learning-based model to predict the miRNAs associated with Multiple Sclerosis. The evaluation result shows that the proposed model can predict the miRNAs associated with Multiple Sclerosis precisely. In addition, the proposed model can outperform several existing methods in a large margin.

Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets.

A diverse T cell receptor (TCR) repertoire is essential for protection against a variety of pathogens, and TCR repertoire size is believed to decline with age. However, the precise size of human TCR repertoires, in both total and subsets of T cells, as well as their changes with age, are not fully characterized. We conducted a longitudinal analysis of the human blood TCRα and TCRß repertoire of CD4+ and CD8+ T cell subsets using a unique molecular identifier-based (UMI-based) RNA-seq method. Thorough analysis of 1.9 × 108 T cells yielded the lower estimate of TCR repertoire richness in an adult at 3.8 × 108. Alterations of the TCR repertoire with age were observed in all 4 subsets of T cells. The greatest reduction was observed in naive CD8+ T cells, while the greatest clonal expansion was in memory CD8+ T cells, and the highest increased retention of TCR sequences was in memory CD8+ T cells. Our results demonstrated that age-related TCR repertoire attrition is subset specific and more profound for CD8+ than CD4+ T cells, suggesting that aging has a more profound effect on cytotoxic as opposed to helper T cell functions. This may explain the increased susceptibility of older adults to novel infections.

Evaluation of Mutton Quality Characteristics of Dongxiang Tribute Sheep Based on Membership Function and Gas Chromatography and Ion Mobility Spectrometry.

Dongxiang tribute sheep have a history of use in food dishes such as "Dongxiang Handgrip," which dates back hundreds of years and is a favorite halal food in northwestern China. However, little is known about the mutton quality characteristics of Dongxiang tribute sheep. Here, we measured the sensory characteristics, nutritional quality, and flavor substances to comprehensively evaluate the mutton quality characteristics of these sheep. The mutton qualities of Dongxiang tribute, Tibetan, Ujumqin, and Hu sheep were comprehensively evaluated by membership function. Subsequently, the volatile components in mutton samples from 30 Dongxiang tribute sheep were detected via gas chromatography and ion mobility spectrometry (GC-IMS), and their fingerprints were established. The result of meat quality revealed that the shear force, the contents of protein, essential amino acid (EAA), non-essential amino acid (NEAA), and n-6/n-3 ratio of Dongxiang tribute mutton were better than the other three breeds. Membership functions were calculated for 10 physical and chemical indexes of mutton quality, and the comprehensive membership function values of the four breeds in order of highest to lowest mutton quality were Tibetan sheep (0.76) > Dongxiang tribute sheep (0.49) > Hu sheep (0.46) > Ujumqin sheep (0.33). Thirty volatile compounds were identified via GC-IMS: seven alcohols, eight aldehydes, five ketones, two esters, two phenols, one ether, one furan, one acid, two hydrocarbons, and one pyrazine. Ketones, aldehydes, and alcohols were the main volatile compounds forming the flavor of Dongxiang tribute sheep mutton. The reliability of the results was validated by PCA (principal component analysis) and similarity analyses. Our results provide reference value for consumers of mutton in China.

Next-Generation Sequencing Revealed a Distinct Immunoglobulin Repertoire with Specific Mutation Hotspots in Acute Myeloid Leukemia.

Immunoglobulin (Ig) is known as a hallmark of B-lymphocytes exerting antibody functions. However, our previous studies demonstrated that myeloblasts from acute myeloid leukemia (AML) patients could also express Ig with distinct roles. Here, we quantified Ig (IGHG and IGK) transcripts by real-time PCR and performed a comprehensive analysis of Ig repertoire (both heavy chains and light chains) in AML blasts. We found that Ig was frequently expressed by AML blasts. A higher level of AML-derived IGHG expression correlated with a significantly shorter disease-free survival. Next-generation sequencing revealed dysregulated transcripts of all five Ig classes (IGHA, IGHD, IGHE, IGHG, and IGHM) and two Ig types (IGK and IGL) in AML. VH-D-JH rearrangements in myeloblasts were biased with individual specificity rather than generally diverse as in B-cells. Compared to AML-derived IgH, AML-derived IGK was more conserved among different AML samples. The frequently shared Vκ-Jκ patterns were IGKV3-20*01/IGKJ1*01, IGKV2D-28*01/IGKJ1*01, and IGKV4-1*01/IGKJ1*01. Moreover, AML-derived IGK was different from classical IGK in B-cells for the high mutation rates and special mutation hotspots at serine codons. Findings of the distinct Ig repertoire in myeloblasts may facilitate the discovery of a new molecular marker for disease monitoring and target therapy.