bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional microRNA binding site variants
Authors: Yuan Ye , Weidhaas Joanne B.
Published: December 2018

Germline single nucleotide polymorphisms are one of the most common genetic variations. Polymorphisms that cause nonsynonymous mutations in gene coding regions are known to cause serious deleterious downstream effects. However, even polymorphisms in noncoding regions can have profound functional consequences by disrupting essential regulatory sites. Specifically, polymorphisms that alter microRNA binding sites can disrupt the regulation of hallmark biological pathways implicated in tumorigenesis and tumor progression. Many of these microRNA‐associated polymorphisms (miR‐SNPs) have recently been shown to be important biomarkers of cancer risk, prognosis, and treatment outcomes. This review will summarize the functional impact of key miR‐SNPs and define a subset of miR‐SNPs that may be clinically useful prognostic or predictive biomarkers.
Protein‐Bound Freestanding 2D Metal Film for Stealth Information Transmission
Authors: Qin Rongrong , Liu Yongchun , Tao Fei , Li Chen , Cao Wenfei , Yang Peng
Published: December 2018

The welding and sintering of nanomaterials is usually achieved at high temperatures and high pressures. Here, it is found that merging of metal nanoparticles occurs under ambient conditions in an aqueous solution via protein bonding. It is discovered that the silver nanoparticles from the in situ reduction of silver ammonium ions by glucose undergo confined nucleation and growth and are bound by ultrathin amyloid‐like β‐sheet stacking of lysozyme. This merging of silver nanoparticles creates a freestanding large‐area (e.g., 400 cm2) 2D silver film at the air/water interface with a purity up to 98% and controls nanoscale thickness. This reaction system is general to other proteins and metals, and shows the great ability for controlled synthesis of highly reflective and highly conductive silver films with elongation nearly 10 times higher than that of pure metal without protein bonding. The ultrathin protein‐bonding layer functions as a key mediator to dynamically tune the silver conductance in response to external pressures and strains. The sensors exhibit ultrasensitive capability for stealth transmission of Morse code and for silent speech recording via the detection of tiny vibrations of the human throat. This approach will shed light on the development of protein bonding of a given material for bespoke functions.
Aliphatic Aldehydes: Novel Radical Alkylating Reagents
Authors: Yang Wen‐Chao , Feng Jian‐Guo , Wu Lei , Zhang Yong‐Qiang
Published: December 2018

The emergence of radical chemistry has driven chemists to develop general and efficient radical reactions as well as to discover safe and cost‐effective radical sources. Among the various transformations, the radical‐involved alkylation reaction continues to blossom since the alkyl unit is ubiquitous in biological and pharmaceutical compounds. The utilization of aliphatic aldehydes as alkyl radical precursors via peroxides or oxygen‐initiated decarbonylation reactions has attracted great attention over the past decade due to their ready availability and the simple operation. Although examples of radical acylation reactions starting from aldehydes have been reviewed before, reviews on decarbonylative radical reactions of aliphatic aldehydes are scarce. In this review, we summarize recent significant advances in this rapidly growing area, mainly focusing on reaction design and reaction mechanisms.

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Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management
Authors: Pardanani Animesh
Published: December 2018

Overview

Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MCs) in extra‐cutaneous organs.

Diagnosis

The major criterion is presence of multifocal clusters of abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC CD25 expression, and presence of KITD816V mutation.

Risk stratification

Establishing SM subtype as per the World Health Organization classification system is an important first step. Broadly, patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, the latter includes aggressive SM (ASM), SM with associated hematological neoplasm (SM‐AHN), and mast cell leukemia (MCL). Identification of poor‐risk mutations (ie, ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Recently, clinical and hybrid clinical‐molecular risk models have been developed to more accurately assign prognosis in SM patients.

Management

ISM patients have a normal life expectancy and treatment is generally limited to anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to ameliorate disease‐related organ dysfunction. High response rates have been seen with small‐molecule inhibitors that target mutant‐KIT, including midostaurin (Food and Drug Administration approved) or avapritinib (investigational). Other options for MC cytoreduction include cladribine or interferon‐α, although head‐to‐head comparisons are lacking. Treatment of SM‐AHN primarily targets the AHN component, if an aggressive disease such as acute myeloid leukemia is present. Allogeneic stem cell transplant can be considered in such patients, or in those with relapsed/refractory advanced SM. Imatinib has a limited therapeutic role in SM; effective cytoreduction is limited to those with imatinib‐sensitive KIT mutations.
Ruxolitinib treatment for steroid refractory acute and chronic graft vs host disease in children: Clinical and immunological results
Authors: González Vicent Marta , Molina Blanca , González de Pablo Jesús , Castillo Ana , Díaz Miguel Ángel
Published: December 2018

Ruxolitinib is a promising treatment for steroid refractory graft‐vs‐host disease (GvHD). However, data concerning effects on T cells are probably involved in increased risk of opportunistic infections. We analyzed clinical and immunological changes in children with GvHD taking ruxolitinib. Twenty‐two children that underwent transplantation and received ruxolitinib were included. Ruxolitinib indication was acute and chronic GvHD in 13 and 9 patients, respectively. Overall response rate (ORR) in acute GvHD and chronic GvHD was high, of 77% and 89%, respectively. Ruxolitinib was associated with an increase in CD4 effector memory (EM), and decrease of CD4 central memory percentage. CD4 regulatory T cells percentage decreased significantly. Patients who achieved complete response to ruxolitinib had higher natural killer (NK) cells before ruxolitinib that patients who did not respond. Also there was an increase of CD4 lymphocytes percentage, with decrease of CD8 and NK cells percentage in responders against non‐responders. There were 54%, 18% and 13% of infections caused by virus, bacteria and fungi, respectively. Cumulative incidence of relapse and non‐relapse mortality was 19 ± 9%and 28 ± 10%, respectively. Overall survival and disease‐free survival rate at 2 years were 62 ± 11% and 58 ± 11%, respectively. Ruxolitinib is a promising treatment for acute and chronic GvHD with a high ORR of 77% and 89%, respectively. It produces important changes in immune system, such as increase of CD4 EM cells and decrease in NK and regulatory T cells. Now, we need pharmacokinetic studies to determine ruxolitinib dose in children and close surveillance and antimicrobial prophylaxis.
Long‐Life Room‐Temperature Sodium–Sulfur Batteries by Virtue of Transition‐Metal‐Nanocluster–Sulfur Interactions
Authors: Zhang Bin‐Wei , Sheng Tian , Wang Yun‐Xiao , Chou Shulei , Davey Kenneth , Dou Shi‐Xue , Qiao Shi‐Zhang
Published: December 2018

Room‐temperature sodium–sulfur (RT‐Na/S) batteries hold significant promise for large‐scale application because of low cost of both sodium and sulfur. However, the dissolution of polysulfides into the electrolyte limits practical application. Now, the design and testing of a new class of sulfur hosts as transition‐metal (Fe, Cu, and Ni) nanoclusters (ca. 1.2 nm) wreathed on hollow carbon nanospheres (S@M‐HC) for RT‐Na/S batteries is reported. A chemical couple between the metal nanoclusters and sulfur is hypothesized to assist in immobilization of sulfur and to enhance conductivity and activity. S@Fe‐HC exhibited an unprecedented reversible capacity of 394 mAh g−1 despite 1000 cycles at 100 mA g−1, together with a rate capability of 220 mAh g−1 at a high current density of 5 A g−1. DFT calculations underscore that these metal nanoclusters serve as electrocatalysts to rapidly reduce Na2S4 into short‐chain sulfides and thereby obviate the shuttle effect.
Molecular Scaffolds as Double‐Targeting Agents For the Diagnosis and Treatment of Neuroblastoma
Authors: Villaverde Gonzalo , Alfranca Arantzazu , Gonzalez‐Murillo África , Melen Gustavo J. , Castillo Rafael R. , Ramírez Manuel , Baeza Alejandro , Vallet‐Regí María
Published: December 2018

The selective delivery of therapeutic and imaging agents to tumoral cells has been postulated as one of the most important challenges in the nanomedicine field. Meta‐iodobenzilguanidine (MIBG) is widely used for the diagnosis of neuroblastoma (NB) due to its strong affinity for the norepinephrine transporter (NET), usually overexpressed on the membrane of malignant cells. Herein, a family of novel Y‐shaped scaffolds has been synthesized, which have structural analogues of MIBG covalently attached at each end of the Y‐structure. The cellular uptake capacity of these double‐targeting ligands has been evaluated in vitro and in vivo, yielding one specific Y‐shaped structure that is able to be engulfed by the malignant cells, and accumulates in the tumoral tissue, at significantly higher levels than the structure containing only one single targeting agent. This Y‐shaped ligand can provide a powerful tool for the current treatment and diagnosis of this disease.
Palladium‐ and Rhodium‐Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes Towards Chiral Pyrazoles
Authors: Hilpert Lukas J. , Sieger Simon V. , Haydl Alexander M. , Breit Bernhard
Published: December 2018

A complementing Pd‐ and Rh‐catalyzed dynamic kinetic resolution (DKR) of racemic allenes leading to N‐allylated pyrazoles is described. Such compounds are of enormous interest in medicinal chemistry as certified drugs and potential drug candidates. The new methods feature high chemo‐, regio‐ and enantioselectivities aside from displaying a broad substrate scope and functional group compatibility. A mechanistic rational accounting for allene racemization and trans‐alkene selectivity is discussed.
Azide Passivation of Black Phosphorus Nanosheets: Covalent Functionalization Affords Ambient Stability Enhancement
Authors: Liu Yajuan , Gao Pengfei , Zhang Taiming , Zhu Xianjun , Zhang Mengmeng , Chen Muqing , Du Pingwu , Wang Guan‐Wu , Ji Hengxing , Yang Jinlong , Yang Shangfeng
Published: December 2018

Two‐dimensional (2D) black phosphorus (BP) has a unique band structure, but it suffers from low ambient stability owing to its high reactivity to oxygen. Covalent functionalization has been demonstrated to passivate the reactive BP effectively, however the reported covalent functionalization methods are quite limited to aryl diazonium and nucleophilic additions affording P−C and P−O−C single bonds, for which the retaining of one unpaired electron in the Group 15 phosphorus atom hampers the passivation effect. Now, covalent azide functionalization of BP nanosheets (BPNSs) is reported, leading to significant enhancement of the ambient stability of BP as confirmed by UV/Vis spectroscopic studies. The most stable configuration of the azide functionalized BPNSs (f‐BPNSs) is predicted by theoretical calculations, featuring the grafting of benzoic acid moiety onto BPNSs via the unprecedented P=N double bonds formed through in situ nitrene as a reactive intermediate.
Enhanced Performance of Organic/Inorganic Hybrid Nanomaterials bearing Impregnated [PdL2] Complexes as Counter‐Electrode Catalyst for Dye‐Sensitized Solar Cells
Authors: Dayan Serkan , Özdemir Namık , Özpozan Nilgün Kalaycıoğlu
Published: December 2018

N‐coordinate Pd2+ complexes [PdL2] (L: N‐N‐quinoline‐8‐yl‐R‐benzenesulfonamides) (6–10) and [PdL2] complexes assembled on multi‐wall carbon nanotubes (MWCNTs) hybrid nanomaterials were fabricated and characterized by various techniques. The [PdL2] impregnated MWCNTs materials (11–15) were applied as a counter electrode (CE) catalyst for triiodide to iodide reduction reaction in the dye‐sensitized solar cells (DSSC) and investigated electro‐catalytic activities.

The MWCNTs‐supported [PdL2] CEs (11–15) are exhibits as Pt‐free CE with good power conversion efficiencies (PCEs), and compared to platinum and bare MWCNTs CEs and the PCE of bare MWCNTs was clearly improved by means of [PdL2] complexes (6–10). The DSSCs based on the hybrid counter electrodes (CEs) (11–15) and bare MWCNTs are indicated a relative efficiency (ƞrel) of 64.27%, 54.07%, 53.75%, 51.52% 44.82% and 27.27% concerning a Pt CE control device set at 100%. The report emphasizes that [PdL2] impregnated MWCNTs type counter electrodes (CEs) (11–15) are promising as effectively catalyst in working device design, particularly taking into account the eco‐friendly approach of the hybrids.
Synthetic Methodology for Structurally Defined and Insulated Molecular Wires Bearing Non‐centrosymmetric Conjugated Axle Components via Iterative Intramolecular Slippage
Authors: Chou Sheng‐Ying , Masai Hiroshi , Tsuda Susumu , Terao Jun
Published: December 2018

Insulated molecular wires (IMWs) bearing non‐centrosymmetric conjugated axle components were precisely synthesized via iterative cross‐coupling reactions in organic solvents and subsequent intramolecular slippage transformation in aqueous solvents. This programmable synthetic procedure selectively afforded both insulated and uninsulated molecular wires bearing oligo(phenylene ethynylene) and permethylated α‐cyclodextrins with well‐defined conjugation lengths and supramolecular structures. High selectivity of this method was confirmed by NMR and mass spectroscopic analyses. The resultant IMWs exhibited distinct optical properties because of different conjugation lengths and insulated structures. This synthetic strategy for structurally defined IMWs bearing non‐centrosymmetric conjugated axle components could provide a platform for obtaining diverse functionalized materials useful in the fields of non‐centrosymmetric molecular machines and molecular electronics.
microRNA‐96 protects pancreatic β‐cell function by targeting PAK1 in gestational diabetes mellitus
Authors: Li Lei , Wang Shan , Li Hongyan , Wan Jipeng , Zhou Qian , Zhou Yu , Zhang Chunhua
Published: December 2018

Gestational diabetes mellitus (GDM) is a disease condition in which a woman develops high blood sugar levels during pregnancy, which might be induced by multiple factors. Among those relative factors, microRNA (miRNA) is well‐known to be involved in GDM development. In this study, we investigated the role of miRNA in GDM by analyzing miRNA expression profiling in placenta tissues from healthy or GDM pregnancies. We found that miR‐96 was the most down‐regulated miRNA in GDM samples. Furthermore, miRNA target gene prediction revealed that p21‐activated kinase 1 (PAK1) is a potential target of miR‐96. Functional assays showed that miR‐96 enhanced β‐cell function, whereas PAK1 inhibited β‐cell function and cell viability. Our findings demonstrate that miR‐96 plays a critical role in GDM development by regulating PAK1 expression, insulin secretion, and β‐cell function. © 2018 BioFactors, 44(6):539–547, 2018
Bioinformatic analysis of the prognostic value of the lncRNAs encoding snoRNAs in hepatocellular carcinoma
Authors: Zhu Qingyao , Yang Hongjie , Cheng Peng , Han Qian
Published: December 2018

Some lncRNAs can encode small nucleolar RNAs (snoRNAs), called small nucleolar RNA host genes (SNHGs), which exert diverse regulatory effects on cellular processes. In this study, using RNA‐seq and survival data in the Cancer Genome Atlas (TCGA)‐Liver Hepatocellular Carcinoma (LIHC), we examined the expression profile of some SNHG genes and explored their prognostic value in hepatocellular carcinoma (HCC). Level‐3 RNA‐sequencing data, the clinicopathological and survival data of patients with primary HCC were downloaded from the UCSC Xena browser (https://xenabrowser.net/), for a secondary analysis. Results showed that SNHG1, GAS5, SNHG3‐7 and SNHG10‐12 were significantly upregulated in HCC tissues (N = 49) compared with adjacent normal tissues (N = 49). After adjustment for confounding factors, the multivariate analysis confirmed that increased SNHG4 expression was independently associated with shorter OS (HR: 1.319, 95%CI: 1.131–1.537, P < 0.001), while increased GAS5 expression was an independent predictor of shorter RFS (HR: 1.287, 95% CI: 1.027–1.612, P = 0.028). Using the methylation data obtained from the Infinium HumanMethylation450 BeadChip, we found that SNHG4 expression was not likely to be modulated by methylation in HCC. In comparison, the methylation status of 5 CpG sites (cg07177756, cg17025683, cg16290996, cg03044573 and cg06644515) showed a moderately negative correlation (Pearson's r = −0.54, P < 0.001) with GAS5 expression. Based on these findings, we infer that SNHG4 and GAS5 might be valuable prognostic markers in HCC. DNA hypomethylation might play an important role in elevated GAS5 transcription in HCC. © 2018 BioFactors, 45(2):244–252, 2019
Characterization of thin gelatin hydrogel membranes with balloon properties for dynamic tissue engineering
Authors: Jepsen Morten Leth , Nielsen Line Hagner , Boisen Anja , Almdal Kristoffer , Dufva Martin
Published: December 2018

Cell or tissue stretching and strain are present in any in vivo environment, but is difficult to reproduce in vitro. Here, we describe a simple method for casting a thin (about 500 μm) and soft (about 0.3 kPa) hydrogel of gelatin and a method for characterizing the mechanical properties of the hydrogel simply by changing pressure with a water column. The gelatin is crosslinked with mTransglutaminase and the area of the resulting hydrogel can be increased up 13‐fold by increasing the radial water pressure. This is far beyond physiological stretches observed in vivo. Actuating the hydrogel with a radial force achieves both information about stiffness, stretchability, and contractability, which are relevant properties for tissue engineering purposes. Cells could be stretched and contracted using the gelatin membrane. Gelatin is a commonly used polymer for hydrogels in tissue engineering, and the discovered reversible stretching is particularly interesting for organ modeling applications.
Engineering an EGFR‐binding Gp2 domain for increased hydrophilicity
Authors: Du Feifan , Kruziki Max A. , Zudock Elizabeth J. , Zhang Yi , Lown Patrick S. , Hackel Benjamin J.
Published: December 2018

The Gp2 domain is a 45 amino‐acid scaffold that has been evolved for specific, high‐affinity binding towards multiple targets and was proven useful in molecular imaging and biological antagonism. It was hypothesized that Gp2 may benefit from increased hydrophilicity for improved physiological distribution as well as for physicochemical robustness. We identified seven exposed hydrophobic sites for hydrophilic mutations and experimentally evaluated single mutants, which yielded six mutations that do not substantially hinder expression, binding affinity or specificity (to epidermal growth factor receptor), and thermal stability. Eight combinations of these mutations improved hydrophilicity relative to the parental Gp2 clone as assessed by reverse‐phase high‐performance liquid chromatography (p < 0.05). Secondary structures and refolding abilities of the selected single mutants and all multimutants were unchanged relative to the parental ligand. A variant with five hydrophobic‐to‐hydrophilic mutations was identified with enhanced solubility as well as reasonable binding affinity (
K
d = 53–63 nM), recombinant yield (1.3 ± 0.8 mg/L), and thermal stability (
T
m = 53 ± 3°C). An alternative variant with a cluster of three leucine‐to‐hydrophilic mutations was identified with increased solubility, nominally increased binding affinity (
K
d = 13–28 nM) and reasonable thermal stability (
T
m = 54.0 ± 0.6°C) but reduced yield (0.4 ± 0.3 mg/L). In addition, a ≥7°C increase in the midpoint of thermal denaturation was observed in one of the single mutants (T21N). These mutants highlight the physicochemical tradeoffs associated with hydrophobic‐to‐hydrophilic mutation within a small protein, improve the solubility and hydrophilicity of an existent molecular imaging probe, and provide a more hydrophilic starting point for discovery of new Gp2 ligands towards additional targets.
Increased biomass and lipid production by continuous cultivation of Nannochloropsis salina transformant overexpressing a bHLH transcription factor
Authors: Kang Nam Kyu , Kim Eun Kyung , Sung Min‐Gyu , Kim Young Uk , Jeong Byeong‐ryool , Chang Yong Keun
Published: December 2018

Microalgae are promising feedstocks for sustainable and eco‐friendly production of biomaterials, which can be improved by genetic engineering. It is also necessary to optimize the processes to produce biomaterials from engineered microalgae. We previously reported that genetic improvements of an industrial microalga Nannochloropsis salina by overexpressing a basic helix‐loop‐helix transcription factor (NsbHLH2). These transformants showed an improved growth and lipid production particularly during the early phase of culture under batch culture. However, they had faster uptake of nutrients, resulting in earlier starvation and reduced growth during the later stages. We attempted to optimize the growth and lipid production by growing one of the transformants in continuous culture with variable dilution rate and feed nitrogen concentration. Relative to wild‐type, NsbHLH2 transformant consumed more nitrate at a high dilution rate (0.5 day
−1), and had greater biomass production. Subsequently, nitrogen limitation at continuous cultivation led to an increased fatty acid methyl ester production by 83.6 mg l
−1 day
−1. To elucidate genetic mechanisms, we identified the genes containing E‐boxes, known as binding sites for bHLH transcription factors. Among these, we selected 18 genes involved in the growth and lipid metabolism, and revealed their positive contribution to the phenotypes via quantitative real‐time polymerase chain reaction. These results provide proof‐of‐concept that NsbHLH2 can be used to produce biomass and lipids.
Enhancing cofactor recycling in the bioconversion of racemic alcohols to chiral amines with alcohol dehydrogenase and amine dehydrogenase by coupling cells and cell‐free system
Authors: Liu Ji , Li Zhi
Published: December 2018

Alcohol dehydrogenase (ADH) and amine dehydrogenase (AmDH)‐catalyzed one‐pot cascade conversion of an alcohol to an amine provides a simple preparation of chiral amines. To enhance the cofactor recycling in this reaction, we report a new concept of coupling whole‐cells with the cell‐free system to enable separated intracellular and extracellular cofactor regeneration and recycling. This was demonstrated by the respective biotransformation of racemic 4‐phenyl‐2‐butanol 1a and 1‐phenyl‐2‐propanol 1b to (R)‐4‐phenylbutan‐2‐amine 3a and (R)‐1‐phenylpropan‐2‐amine 3b. Escherichia coli cells expressing S‐enantioselective CpsADH, R‐enantioselective PfODH, and NADH oxidase (NOX) was developed to oxidize racemic alcohols 1a–b to ketones 2a–b with full conversion via intracellular NAD+ recycling. AmDH and glucose dehydrogenase (GDH) were used to convert ketones 2a–b to amines (R)‐3a–b with 89–94% conversion and 891–943 times recycling of NADH. Combining the cells and enzymes for the cascade transformation of racemic alcohols 1a–b gave 70% and 48% conversion to the amines (R)‐3a and (R)‐3b in 99% ee, with a total turnover number (TTN) of 350 and 240 for NADH recycling, respectively. Improved results were obtained by using the E. coli cells with immobilized AmDH and GDH: (R)‐3a was produced in 99% ee with 71–84% conversion and a TTN of 1410‐1260 for NADH recycling, the highest value so far for the ADH–AmDH‐catalyzed cascade conversion of alcohols to amines. The concept might be generally applicable to this type of reactions.
Engineering self‐flocculating Halomonas campaniensis for wastewaterless open and continuous fermentation
Authors: Ling Chen , Qiao Guan‐Qing , Shuai Bo‐Wen , Song Kun‐Nan , Yao Wen‐Xi , Jiang Xiao‐Ran , Chen Guo‐Qiang
Published: December 2018

Halomonas has been developed as a platform for the next generation industrial biotechnology allowing open and nonsterile growth without microbial contamination under a high‐salt concentration and alkali pH. To reduce downstream cost associated with continuous centrifugation and salt containing wastewater treatment, Halomonas campaniensis strain LS21 was engineered to become self‐flocculating by knocking out an
etf operon encoding two subunits of an electron transferring flavoprotein in the predicted electron transfer chain. Self‐flocculation could be attributed to the decrease of the surface charge and increase of the cellular hydrophobicity resulted from deleted
etf. A wastewaterless fermentation strategy based on the self‐flocculating
H. campaniensis was developed for growth and the production of poly‐3‐hydroxybutyrate (PHB) as an example. Most microbial cells flocculated and precipitated to the bottom of the bioreactor within 1 min after stopping the aeration and agitation. The supernatant can be used again without sterilization or inoculation for the growth of the next batch after collecting the precipitated cell mass. The wastewaterless process was conducted for four runs without generating wastewater. PHB accumulation by the self‐flocculent strain was enhanced via promoter and ribosome binding site optimizations, the productivities of cell dry weight and PHB were increased from 0.45 and 0.18 g·L
−1·hr
−1 for the batch process compared to 0.82 and 0.33 g·L
−1·hr
−1 for the wastewaterless continuous process, respectively. This has clearly demonstrated the advantages of the wastewaterless process in that it not only reduces wastewater but also increases cell growth and product formation efficiency in a given period of time.
Preparation and characterization of bosentan monohydrate/ε‐polycaprolactone nanoparticles obtained by electrospraying
Authors: Giménez Virna M. , Sperandeo Norma , Faudone Sonia , Noriega Sandra , Manucha Walter , Kassuha Diego
Published: December 2018

The electrospraying technique provides nano and microparticles that can be used as drug delivery systems. The aims of this study were, firstly, to optimize the influent parameters of electrospraying for the manufacture of a Bosentan (BOS) nanoparticulate platform, and secondly, to evaluate its physicochemical properties and in vitro biopharmaceutical behavior. Particles were characterized by scanning electron microscopy (SEM), powder X‐ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetry (TG) and Fourier transformed Infrared spectroscopy (FTIR). Drug loading, encapsulation efficiency and kinetic dissolution were determined. Additionally, Bosentan release assays at 24 and 72 h were performed in vitro to evaluate biopharmaceutical properties of nano‐scaffolds by diffusion technique through dialysis bag. The nanostructures had heterogeneous sizes predominantly smaller than 550 nm and they were semicrystalline according to PXRD, indicating a partial amorphization of BOS during the encapsulation in the polymer matrix. FT‐IR and DSC showed an absence of chemical interactions between BOS and ε‐Polycaprolactone (PCL), suggesting that both components behaved as a physical mixture in these particles. The drug loading was 25.98%, and the encapsulation efficiency was 58.51%. Additionally, the release assays showed an extended and controlled release of BOS, in comparison to non‐encapsulated BOS. These data also showed to fit with the Cubic Root kinetic dissolution. As a conclusion, we demonstrate that the use of electrospraying for the manufacture of BOS (or similar drugs) controlled release nanoplatforms would represent an interesting contribution in the development of new therapeutic alternatives for the treatment of pathologies such as pulmonary hypertension and other related diseases. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 35: e2748, 2019.
A Covalent Inhibitor for Glutathione S‐Transferase Pi (GSTP1‐1) in Human Cells
Authors: Shishido Yuko , Tomoike Fumiaki , Kuwata Keiko , Fujikawa Haruka , Sekido Yoshitaka , Murakami‐Tonami Yuko , Kameda Tomoshi , Abe Naoko , Kimura Yasuaki , Shuto Satoshi , Abe Hiroshi
Published: December 2018

Glutathione S‐transferase π (GSTP1‐1) is overexpressed in many types of cancer and is involved in drug resistance. Therefore, GSTP1‐1 is an important target in cancer therapy, and many GST inhibitors have been reported. We had previously developed an irreversible inhibitor, GS‐ESF, as an effective GST inhibitor; however, its cellular permeability was too low for it to be used in inhibiting intracellular GST. We have now developed new irreversible inhibitors by introducing sulfonyl fluoride (SF) into chloronitrobenzene (CNB). The mechanism of action was revealed to be that CNBSF first reacts with glutathione (GSH) through an aromatic substitution in the cell, then the sulfonyl group on the GSH conjugate with CNBSF reacts with Tyr108 of GST to form a sulfonyl ester bond. Our new inhibitor irreversible inhibited GSTP1‐1 both in vitro and in cellulo with a long duration of action.
Initial results from the off‐label use of the SAPIEN S3 valve for percutaneous transcatheter pulmonary valve replacement: A multi‐institutional experience
Authors: Sinha Sanjay , Aboulhosn Jamil , Asnes Jeremy , Bocks Martin , Zahn Evan , Goldstein Bryan H. , Zampi Jeffrey , Hellenbrand William , Salem Morris , Levi Daniel
Published: December 2018

Objectives

To describe a multi‐center experience of percutaneous transcatheter pulmonary valve replacement (TPVR) using the Edwards Sapien S3 Valve.

Background

Off‐label use of the Sapien S3 valve can allow for TPVR in patients with congenital heart disease (CHD) and large diameter dysfunctional right ventricular outflow tract (RVOT). The initial experience at five centers with the SAPIEN S3 valve for TPVR is presented with a focus on procedural techniques, success, complications, and efficacy.

Methods

A retrospective review was performed of all patients with CHD and dysfunctional RVOT who underwent TPVR using Sapien S3 valve. Imaging data, procedural elements, and clinical follow‐up data were collected to evaluate acute and short‐term results.

Results

A total of 50 patients underwent percutaneous placement of the Sapien S3 in the pulmonary position. Of these, 38 were placed into “native RVOTs”, measuring 24–32 mm in diameter, as assessed by compliant balloon sizing. In all cases, the valve was implanted after introduction and there were no cases of valve embolization. On follow up (range 1–9 months, median 3 months), no patients had significant obstruction or regurgitation through or around the valve requiring intervention. There were no procedural deaths. Major complications included severe aortic compression (n = 1) and tricuspid valve (TV) injury related to valve placement (n = 2) and prestenting (n = 1).

Conclusions

TPVR in patients with large diameter dysfunctional RVOTs can be effectively performed with the Sapien S3. All procedures were technically successful with no embolizations, no perivalvular leaks, and excellent short‐term valve function. Tricuspid valve injury from implantation of an uncovered valve was a serious procedural complication.
Management of common femoral artery occlusive disease: A review of endovascular treatment strategies and outcomes
Authors: Wong Gordon , Lahsaei Saba , Aoun Joe , Garcia Lawrence A.
Published: December 2018

Isolated atherosclerotic lesions of the common femoral artery (CFA) are rare but can produce significant claudication and critical limb ischemia. To date, the “gold standard” treatment for this entity has been common femoral endarterectomy (CFE) with or without patch angioplasty. However, surgery does have significant early postoperative complications, with a 15% combined mortality/morbidity.

This manuscript sought to perform a comprehensive review of all studies and available data on endovascular treatment of isolated CFA disease and compare its utility to the traditional gold standard treatment. Twenty‐one studies from 1987 to 2018 were included exploring the various CFA endovascular therapies (percutaneous transluminal angioplasty, intravascular stenting, drug‐coated balloons, and directional atherectomy employed to treat CFA disease, in terms of efficacy, safety, and complications). As a conclusion, endovascular interventions provide acceptable short‐term technical outcomes for CFA disease while limiting procedural complications. While only two randomized controlled trials compare short and long‐term outcomes of surgical versus endovascular treatment, further studies are required to clarify the role of endovascular therapy.
A Versatile Dynamic Light Scattering Strategy for the Sensitive Detection of Plant MicroRNAs Based on Click‐Chemistry‐Amplified Aggregation of Gold Nanoparticles
Authors: Lu Xiaohui , Fan Wenjiao , Feng Qinya , Qi Yan , Liu Chenghui , Li Zhengping
Published: December 2018

Plant microRNAs (miRNAs) are naturally 2′‐O‐methylated at the 3′‐terminal; as a consequence, they cannot be efficiently detected by traditional target‐triggered polymerization reactions. Here, a simple but robust enzyme‐free sensing strategy was developed for plant miRNA analysis by using dynamic light scattering (DLS) to monitor the crosslinking of gold nanoparticles (AuNPs) amplified by click chemical ligation. Combining the enzyme‐free cycling chemical‐ligation‐mediated signal amplification, and the intrinsic outstanding ability of DLS for discriminating the extremely low level of particle aggregation in a large pool of monodisperse AuNPs, high sensitivity was achieved and as low as 78.6 fm plant miRNA could be easily detected.
Enantioselective Acyl Migration Reactions of Furanyl Carbonates with Chiral DMAP Derivatives
Authors: Fujii Kazuki , Mitsudo Koichi , Mandai Hiroki , Korenaga Toshinobu , Suga Seiji
Published: December 2018

An efficient enantioselective acyl migration reaction of furanyl carbonates was developed to construct all‐carbon quaternary stereogenic centers. In some cases, the reactions required only 0.05 mol % (minimum 500 ppm) of catalyst and showed a high turnover frequency value (TOF; 3640 h−1). Multigram‐scale reactions (10 grams) also proceeded with high enantioselectivity (>99:1 e.r.) in quantitative yield. The catalyst was robust and easily recovered in 98 % yield. A wide range of functional groups were tolerated (15 examples, >98 % yield, up to >99:1 e.r.), and a variety of optically active 3,3′‐disubstituted benzofuranone derivatives, which are useful intermediates for the synthesis of natural products and pharmaceuticals, were efficiently obtained. Control experiments on the catalyst structure (e.g., catalyst 1 a vs. 1 a′ and 1 a′′) and computational calculations revealed that both the catalytic activity and enantioselectivity should be enhanced by hydrogen bonding between catalyst and substrate. Moreover, this system was applied to the challenging γ‐selective acyl migration reaction of furanyl carbonates with high γ‐selectivity and high enantioselectivity (α:γ=10:90, 95:5 e.r.).
High‐sensitivity cardiac troponin T as a predictor of acute Total occlusion in patients with non‐ST‐segment elevation acute coronary syndrome
Authors: Baro Rocío , Haseeb Sohaib , Ordoñez Santiago , Costabel Juan P.
Published: December 2018

Background

A large percentage of patients with non‐ST‐segment acute coronary syndrome (NSTE‐ACS) present with acute total occlusion (TO) of some major epicardial vessel that does not generate electrocardiographic changes. Ongoing research into the methods of accurately predicting acute TO have not yielded great success.

Hypothesis

High‐sensitivity cardiac troponin T (hs‐cTnT) has a good predictive value for the presence of acute TO of the culprit artery in patients with NSTE‐ACS.

Methods

A single‐center retrospective study of 1011 patients diagnosed with NSTE‐ACS who underwent coronary angiography and hs‐cTnT measured on admission. The predictive value of hs‐cTnT in the presence of acute TO was assessed by the area under the ROC curve.

Results

The mean age of the population was 67.12 ± 13.18 and 74.1% were male. 7.3% of the patients presented with acute TO. The AUC for hs‐cTnT to predict acute TO was 0.95. A hs‐cTnT value of 1006 ng/L (71.8 fold of the URL) best predicted the presence of acute TO, with a sensitivity of 86% and specificity of 95% positive predictive value (PPV): 86% and negative predictive value (NPV): 94%.

Conclusions

Hs‐cTnT was a good predictor of acute TO in patients with NSTE‐ACS. Hs‐cTnT values greater than 1006 ng/L were highly predictive of acute TO of a major coronary vessel.
Atherothrombotic risk stratification after acute myocardial infarction: The Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention in the light of the French Registry of Acute ST Elevation or non‐ST Elevation Myocardial Infarction registries
Authors: Puymirat Etienne , Bonaca Marc , Fumery Maxime , Tea Victoria , Aissaoui Nadia , Lemesles Gilles , Bonello Laurent , Ducrocq Grégory , Cayla Guillaume , Ferrières Jean , Schiele François , Simon Tabassome , Danchin Nicolas ,   for the FAST‐MI investigators
Published: December 2018

Background

Guidelines recommend using risk stratification tools in acute myocardial infarction (AMI) to assist decision‐making. The Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS‐2P) has been recently developed to characterize long‐term risk in patients with MI.

Hypothesis

We aimed to assess the TRS‐2P in the French Registry of Acute ST Elevation or non‐ST elevation MI registries.

Methods

We used data from three 1‐month French registries, conducted 5 years apart, from 2005 to 2015, including 13 130 patients with AMI (52% ST‐elevation myocardial infarction [STEMI]). Atherothrombotic risk stratification was performed using the TRS‐2P score. Patients were divided in to three categories: G1 (low‐risk, TRS‐2P = 0/1); G2 (intermediate‐risk, TRS‐2P = 2); and G3 (high‐risk, TRS‐2P ≥ 3). Baseline characteristics and outcomes were analyzed according to TRS‐2P categories.

Results

A total of 12 715 patients (in whom TRS‐2P was available) were included. Prevalence of G1, G2, and G3 was 43%, 24%, and 33% respectively. Clinical characteristics and management significantly differed according to TRS‐2P categories. TRS‐2P successfully defined residual risk of death at 1 year (C‐statistic 0.78): 1‐year survival was 98% in G1, 94% in G2, and 78.5% in G3 (P < 0.001). Using Cox multivariate analysis, G3 was independently associated with higher risk of death at 1 year (hazard ratio [HR] 4.61; 95% confidence interval [CI]: 3.61‐5.89), as G2 (HR 2.08; 95% CI: 1.62‐2.65) compared with G1. The score appeared robust and correlated well with mortality in STEMI and NSTEMI populations, as well as in each cohort separately.

Conclusions

The TRS‐2P appears to be a robust risk score, identifying patients at high risk after AMI irrespective of the type of MI and historical period.
Utility of fine needle aspiration cytology to diagnose intraoral tuberculosis and other oral granulomatous lesions
Authors: Agarwal Radhika , Singh Meeta , Sharma Sushil , Jaiswal Ankita , Jain Shyama Lata , Khurana Nita , Meher Ravi
Published: December 2018

Objective

Tuberculosis (TB) is a common granulomatous disease leading to high morbidity and mortality worldwide. Though rare, oral tuberculosis (OTB) may manifest during the primary and/or secondary stages of the illness. We studied the manifestations and incidence of oral granulomatous lesions (OGL) and OTB diagnosed on fine needle aspiration cytology (FNAC).

Study design

In this retrospective study, we present a review of 149 cases of benign and inflammatory lesions of oral mucosa diagnosed between 2008 and 2016.

Result

Of the 280 oral FNAC performed during the 9 y study period, 149 cases were diagnosed as benign and inflammatory lesions among which 12 (4.3%) showed granulomatous lesions. Four out of 12 cases were diagnosed as OTB. One (0.011%) was a case of Primary OTB with no associated pulmonary or extrapulmonary manifestations of TB and three had associated lymphadenopathy including one with pulmonary TB. Per the clinical records, all four patients responded well to anti tubercular treatment (ATT) rendered under directly observed treatment short course (DOTS) supervision with regular visits and monitoring.

Conclusions

Although oral mucosal TB is a rare presentation, clinicians and pathologists need to consider it early in the differential diagnosis of primary and secondary oral mucosal lesions. Such patients should be further evaluated for pulmonary TB and tuberculous lymphadenitis.
Porous barriers? Assessment of gene flow within and among sympatric long‐eared bat species
Authors: Andriollo Tommy , Ashrafi Sohrab , Arlettaz Raphaël , Ruedi Manuel
Published: December 2018

Species are the basic units for measuring biodiversity and for comprehending biological interactions. Yet, their delineation is often contentious, especially in groups that are both diverse and phenotypically conservative. Three cryptic species of long‐eared bats, Plecotus auritus, P. austriacus, and P. macrobullaris, co‐occur over extensive areas of Western Europe. The latter is a fairly recent discovery, questioning the overall diversity of the entire Plecotus complex. Yet, high morphological and acoustic similarities compromise the reliable identification of long‐eared bats in the field. We postulate that such extensive phenotypic overlap, along with the recurrent observation of morphologically intermediate individuals, may hide rampant interspecific hybridization. Based on a geographic sampling centered on areas of sympatry in the Alps and Corsica, we assessed the level of reproductive isolation of these three Plecotus species with mitochondrial and nuclear markers, looking at both inter‐ and intraspecific genetic population structuring. No sign of hybridization was detected between these three species that appear well separated biologically. Genetic structuring of populations, however, reflected different species‐specific responses to environmental connectivity, that is, to the presence of orographic or sea barriers. While the Alpine range and the Ligurian Sea coincided with sharp genetic discontinuities in P. macrobullaris and P. austriacus, the more ubiquitous P. auritus showed no significant population structuration. There were clear phylogeographic discrepancies between microsatellite and mitochondrial markers at the intraspecific level, however, which challenges the reliance on simple barcoding approaches for the delineation of sound conservation units.
Skeletal muscle wasting in chronic heart failure
Authors: Suzuki Tsuyoshi , Palus Sandra , Springer Jochen
Published: December 2018

Patients suffering from chronic heart failure (CHF) show an increased prevalence (~20% in elderly CHF patients) of loss of muscle mass and muscle function (i.e. sarcopenia) compared with healthy elderly people. Sarcopenia, which can also occur in obese patients, is considered a strong predictor of frailty, disability, and mortality in older persons and is present in 5–13% of elderly persons aged 60–70 years and up to 50% of all octogenarians. In a CHF study, sarcopenia was associated with lower strength, reduced peak oxygen consumption (peak VO2, 1173 ± 433 vs. 1622 ± 456 mL/min), and lower exercise time (7.7 ± 3.8 vs. 10.22 ± 3.0 min, both P < 0.001). Unfortunately, there are only very limited therapy options. Currently, the main intervention remains resistance exercise. Specialized nutritional support may aid the effects of resistance training. Testosterone has significant positive effects on muscle mass and function, and low endogenous testosterone has been described as an independent risk factor in CHF in a study with 618 men (hazard ratio 0.929, P = 0.042). However, the use of testosterone is controversial because of possible side effects. Selective androgen receptor modulators have been developed to overcome these side effects but are not yet available on the market. Further investigational drugs include growth hormone, insulin‐like growth factor 1, and several compounds that target the myostatin pathway. The continuing development of new treatment strategies and compounds for sarcopenia, muscle wasting regardless of CHF, and cardiac cachexia makes this a stimulating research area.
Human anti‐NKp46 antibody for studies of NKp46‐dependent NK cell function and its applications for type 1 diabetes and cancer research
Authors: Berhani Orit , Glasner Ariella , Kahlon Shira , Duev‐Cohen Alexandra , Yamin Rachel , Horwitz Elad , Enk Jonatan , Moshel Ofra , Varvak Alexandar , Porgador Angel , Jonjic Stipan , Mandelboim Ofer
Published: December 2018

Natural killer (NK) cells are innate lymphocytes that efficiently eliminate cancerous and infected cells. NKp46 is an important NK activating receptor shown to participate in recognition and activation of NK cells against pathogens, tumor cells, virally infected cells, and self‐cells in autoimmune conditions, including type I and II diabetes. However, some of the NKp46 ligands are unknown and therefore investigating human NKp46 activity and its critical role in NK cell biology is problematic. We developed a unique anti‐human NKp46 monocloncal antibody, denoted hNKp46.02 (02). The 02 mAb can induce receptor internalization and degradation. By binding to a unique epitope on a particular domain of NKp46, 02 lead NKp46 to lysosomal degradation. This downregulation therefore enables the investigation of all NKp46 activities. Indeed, using the 02 mAb we determined NK cell targets which are critically dependent on NKp46 activity, including certain tumor cells lines and human pancreatic beta cells. Most importantly, we showed that a toxin‐conjugated 02 inhibits the growth of NKp46‐positive cells; thus, exemplifying the potential of 02 in becoming an immunotherapeutic drug to treat NKp46‐dependent diseases, such as, type I diabetes and NK and T cell related malignancies.
Stimuli‐Responsive Phosphorus‐Based Polymers
Authors: Teasdale Ian
Published: December 2018

This microreview details recent developments in stimuli‐responsive polymers with phosphorus in the main‐chain, in particular polyphosphazenes and polyphosphoesters. The presence of phosphorus in the polymers endows unique properties onto the macromolecules, which can be utilized for the preparation of materials capable of physically responding to specific stimuli. Achieving the desired responsiveness has been much facilitated by recent developments in synthetic polymer chemistry, in particular controlled synthesis and backbone functionalization phosphorus‐based polymers, in order to achieve the required properties and hence responsiveness of the materials. The development of phosphorus‐based polymers which respond to the most important stimuli are discussed, namely, pH, oxidation, reduction, temperature and biological triggers. The polymers are placed in the context not just of each other but also with reference to state‐of‐the‐art organic polymers.