bluuebunny/crossref_metadata_2025_split huggingface dataset:
Administration of Fenofibrate Markedly Elevates Fabp3 in Rat Liver and Plasma and Confounds Its Use as a Preclinical Biomarker of Cardiac and Muscle Toxicity
Authors: Kochansky Christopher J. , Lyman Michael J. , Fauty Scott E. , Vlasakova Katerina , D'mello Anil P. 
Published: December 2018

AbstractProteins involved in lipid homeostasis are often regulated through the nuclear peroxisome proliferator‐activated receptors (PPAR). PPARα is the target for the fibrate‐class of drugs. Fenofibrate has been approved for its lipid‐lowering effects in patients with hypercholesterolemia and hypertriglyceridemia. We were interested in understanding the expression of the energy transporters in energy‐utilizing tissues like liver, heart, muscle, and adipose tissues in rat with the hypothesis that the change in transporter expression would align with the known lipid‐lowering effects of PPARα agonists like fenofibrate. We found that several fatty‐acid transporter proteins had significantly altered levels following 8 days of fenofibrate dosing. The mRNA levels of the highly abundant Fatp2 and Fatp5 in rat liver increased approximately twofold and decreased fourfold, respectively. Several fatty‐acid‐binding proteins and acyl‐CoA‐binding proteins had a significant increase in mRNA abundance but not the major liver fatty‐acid‐binding protein, Fabp1. Of particular interest was the increased liver expression of Fabp3 also known as heart‐fatty acid binding protein (H‐FABP or FABP3). FABP3 has been proposed as a circulating clinical biomarker for cardiomyopathy and muscle toxicity, as well as a preclinical marker for PPARα‐induced muscle toxicity. Here, we show that fenofibrate induces liver mRNA levels of Fabp3 ~5000‐fold resulting in an approximately 50‐fold increase in FABP3 protein levels in the whole liver. This increased liver expression complicates the interpretation and potential use of FABP3 as a specific biomarker for PPARα‐induced muscle toxicities.
Predicting temperature impacts on aquatic productivity: Questioning the metabolic theory of ecology's “canonical” activation energies
Authors: Wang Qing , Lyu Zhao , Omar Said , Cornell Stephen , Yang Zhou , Montagnes David J. S. 
Published: December 2018

AbstractMicroalgae contribute ~ 50% to global primary production, most of which is consumed by protozoa. Determining the thermal‐sensitivity of this trophic interaction is, therefore, fundamental to predicting impacts of climate change. Here, we question the application of current predictive approaches. Thermal responses are commonly described by the Arrhenius function: , where r is a rate (e.g., growth), A is a scaling factor, Ea is the activation energy, k is the Boltzmann‐constant, and T is absolute temperature. The influential metabolic theory of ecology (MTE) proposes that estimates of Ea for heterotrophs and autotrophs are 0.65 eV and 0.32 eV, respectively; when applied to specific growth rate of algae and protozoa, this difference has significant predictive consequences. Through literature review and statistical evaluation, we show that the MTE predictions do not apply to taxon‐specific responses of protozoa (n = 103) or algae (n = 183), with mean Ea of 0.71 eV (95% confidence interval [CI]: 0.69–0.74) and 0.61 eV (95% CI: 0.58–0.63), respectively. To obtain these, we fitted a series of models where Ea was constant within a defined group (e.g., protozoa), and the amplitude A depended on the individual responses within the group. Then, by applying the MTE and our predictions to a generic protozoan‐algal, predator‐prey model we show that: (1) the “canonical” MTE values lead to misrepresenting productivity by several fold; (2) a general response encompassing both groups (0.69 eV) should suffice for such models; and (3) applying our new responses has substantial effects on algal‐protozoan population dynamics over temperature shifts of ~ 5°C.
MR‐guided laser interstitial thermal therapy in the treatment of recurrent intracranial meningiomas
Authors: Rammo Richard , Scarpace Lisa , Nagaraja Tavarekere , Lee Ian 
Published: December 2018

ObjectiveRecurrent meningiomas can prove problematic for treatment, especially if anaplastic, as options are limited primarily to surgery and radiation therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive technique for achieving immediate cytoreduction. This study seeks to determine the utility of LITT in the setting of recurrent meningiomas.Materials and MethodsPatients undergoing LITT for tumor treatment at our institution between November 2014 and February 2016 were identified. Those with biopsy‐confirmed meningiomas were reviewed with attention to ablation volume, survival, demographic data, and complications. Data from imaging performed at set intervals post‐operatively were available for all.ResultsFour patients were identified, three of whom had successful treatment with a total of four ablations. The one case that did not result in a successful ablation was due to problems with stereotactic placing of the laser catheter. One patient had a grade 1 meningioma, with the other two being Grade 3. Immediate ablation volumes averaged 75% of preoperative tumor volume and increased to 97% at 2 weeks before dropping to 65% at 3 months. One patient had acute hemiparesis with speech difficulty, which resolved after 6 months. At date of last follow‐up, two of three had progression at an average of nine weeks, and one had no progression at 28 weeks.ConclusionLITT appeared to be a potentially viable treatment for recurrent meningiomas. Ablation volumes increased over time, but not beyond the initial meningioma volume. Larger studies are needed to better determine complications and outcomes. Lasers Surg. Med. 51:245–250, 2019. © 2018 Wiley Periodicals, Inc.
Genetic variations in familial hypercholesterolemia and cascade screening in East Asians
Authors: Chan Melody Lok‐Yi , Cheung Ching‐Lung , Lee Alan Chun‐Hong , Yeung Chun‐Yip , Siu Chung‐Wah , Leung Jenny Yin‐Yan , Pang Ho‐Kwong , Tan Kathryn Choon‐Beng 
Published: December 2018

AbstractBackgroundFamilial hypercholesterolemia (FH) is a monogenic disorder of lipoprotein metabolism leading to an increased risk of premature cardiovascular disease. Genetic testing for FH is not commonly used in Asian countries. We aimed to define the genetic spectrum of FH in Hong Kong and to test the feasibility of cascade genetic screening.MethodsNinety‐six Chinese subjects with a clinical diagnosis of FH were recruited, and family‐based cascade screening incorporating genetic testing results was performed.ResultsForty‐two distinct mutations were identified in 67% of the index FH cases. The majority of causative mutations were in the LDLR gene. The three commonest mutations in the LDLR gene were NM_000527.4(LDLR): c.1241 T>G, NM_000527.4(LDLR): c.1474G>A, and NM_000527.4(LDLR): c. 682G>A, and nine novel variants were identified. The NM_000384.2(APOB): c.10579 C>T variant of the APOB gene was found in 5% of the index subjects. The presence of causative mutation significantly increased the odds of successful family recruitment for screening with an OR of 3.7 (95% CI: 1.53–9.11, p = 0.004).ConclusionApproximately two‐third of the subjects in this clinically ascertained sample of patients with FH had a discrete genetic basis. Genetic identification improves the response rate and efficiency of family screening.
A prospective, multicenter study of a novel, miniaturized rechargeable sacral neuromodulation system: 12‐month results from the RELAX‐OAB study
Authors: Blok Bertil , Van Kerrebroeck Philip , de Wachter Stefan , Ruffion Alain , Van der Aa Frank , Jairam Ranjana , Perrouin‐Verbe Marie Aimée , Elneil Sohier 
Published: December 2018

AimsHistorically, providing SNM therapy required use of a non‐rechargeable implantable pulse generator (IPG) with an average device lifespan of 4.4 years. Multiple device replacement surgeries are necessary with this device for long‐term overactive bladder (OAB) management. A longer‐lived device can reduce and potentially eliminate the need for replacement surgeries, thereby improving the long‐term safety and cost‐effectiveness of SNM therapy. The objective of this study was to evaluate the safety and efficacy of a miniaturized, rechargeable SNM system.MethodsThis prospective, multi‐center study implanted 51 subjects with the SNM system in a single stage procedure without an external trial period. Subjects had overactive bladder as demonstrated on a 3‐day voiding diary (≥8 voids/day and/or ≥2 incontinence episodes over 72‐h). Outcome measures at 1‐year follow‐up included quality of life (evaluated by ICIQ‐OABqol questionnaire), therapy responder rates (≥50% reduction in voids and/or leaks or <8 voids per day), subject satisfaction questionnaire, and adverse events (AEs).ResultsAt 1‐year, 94% of Test Responders continued to respond to r‐SNM therapy based on bladder diary criteria. Subjects experienced significant improvement of 21.1 points on the ICIQ‐OABqol. 84% of subjects were satisfied with r‐SNM therapy and 98% found their charging experience acceptable. Device‐related AEs occurred in 21% of subjects, with discomfort due to stimulation occurring in 20% of subjects. This AE was resolved with reprogramming in all instances.ConclusionsThe Axonics r‐SNM System provides sustained clinically significant improvements in OAB subjects after 1‐year. Subjects were satisfied with r‐SNM therapy and reported an easy and acceptable recharging experience.
Novel immediate/sustained‐release formulation of acetaminophen‐ibuprofen combination (Paxerol®) for severe nocturia associated with overactive bladder: A multi‐center, randomized, double blinded, placebo‐controlled, 4‐arm trial
Authors: Lee King C. , Rauscher Frank , Kaminesky Jed , Ryndin Igor , Xie Lei , Zhao Yunzhu , Khusid Johnathan A. , Weiss Jeffrey P. 
Published: December 2018

AimTo determine short‐term efficacy and safety of Paxerol®, novel immediate:sustained (50%:50%) release tablets containing 325 mg acetaminophen and 150 mg ibuprofen per tablet.MethodsOne of three dose levels, corresponding to the amounts in 1, 2, and 3 tablets, of Paxerol and placebo were administered for 14 consecutive days to patients with severe nocturia (defined in this study as an average nocturnal voids [NV] ≥2.5) associated with overactive bladder (OAB). Changes in NV, as well as Nocturia Quality of Life (NQOL), duration of first uninterrupted sleep (DFUS), and total hours of nightly sleep (THNS) associated with treatment were assessed. Short‐term safety/tolerability was assessed throughout the study and for at least 30 days post‐treatment.ResultsPaxerol at all three doses reduced NV to a greater degree than placebo (average NV −1.1, −1.4, −1.3 voids for low, mid, and high doses, respectively, vs −0.3 void for placebo). NQOL and THNS were similar between baseline and treatment values in all four groups. There were also no between‐group differences. Paxerol at high dose tended to (although not statistical significantly) increase DFUS to a greater degree than placebo (1.2 vs 0.4 h, P = 0.057). There were no treatment related adverse events in any of the four groups.ConclusionsThis study demonstrates short‐term efficacy and short‐term safety of Paxerol in patients with severe nocturia associated with OAB. The results warrant further investigation of the long‐term efficacy and safety of Paxerol in larger patient populations.
Two‐stage phase separation of cellulose acetate membranes modified with plasma‐treated natural zeolite: Response surface modeling
Authors: Safarpour Mahdie , Barzin Jalal , Khataee Alireza , Kordkatooli Zahra 
Published: December 2018

Cellulose acetate (CA) microfiltration membranes were prepared by two‐stage vapor‐induced phase separation (VIPS) and immersion precipitation. To improve the hydrophilicity and permeability of the membranes at low operating pressures, plasma‐treated natural zeolite was incorporated into the membranes. A response surface methodology based on the three‐level central composite design (CCD) was used to model and optimize the casting solution composition of the membranes with the aim of maximizing membranes permeability. Three independent variables for CCD optimization were concentration of CA, polyvinylpyrrolidone (PVP) pore former, and plasma‐treated zeolite additive. The results showed that a second‐order polynomial model could properly predict the response (pure water flux) at any input variable values with a satisfying determination coefficient (R2) of 0.954. Also, analysis of variance (ANOVA) confirmed the adequacy of the obtained model. The permeability of the prepared membranes increased by increasing zeolite loading from 0.10 to 0.50 wt%, which was related to the membranes morphology and porosity and confirmed by scanning electron microscopy (SEM) images. Pure water flux of the membranes decreased by increasing CA concentration while an optimum PVP amount was required to reach the maximum flux. The result of the bubble point analysis well matched with surface SEM images of the membranes and permeability trend predicted by CCD model. Also, the prepared CA membranes with different compositions showed no toxicity for mouse L929 fibroblast, which indicated their nontoxic and biocompatible nature.
Toward Standardization of Mesenchymal Stromal Cell‐Derived Extracellular Vesicles for Therapeutic Use: A Call for Action
Authors: Roura Santiago , Bayes‐Genis Antoni 
Published: December 2018

AbstractExtracellular vesicles (EVs), which include a variety of nano‐sized membrane‐encapsulated particles, are released to the extracellular microenvironment by the vast majority of cells and carry lipids, proteins, mRNA, and miRNA or non‐coding RNA. Increasing evidence suggests the great versatility and potential of EV‐based applications in humans. In this issue, van Balkom et al. explore and compare the reported proteomic signature of mesenchymal stromal cell (MSC)‐derived small EVs. In particular, their paper offers a valuable approach and point of view on MSC‐EV manufacturing and therapeutic potential. Briefly, van Balkom et al. aimed to identify a common protein signature that may be useful in ensuring the homogeneity of therapeutic MSC‐EVs. In addition to excessive variability in EV‐producing cell sources and culture conditions, the harvesting time for the EV‐containing conditioned medium, and EV isolation procedure, the authors found a specific protein signature from the publicly available MSC‐EVs proteome. In light of their findings and those from the plentiful studies published in this continuously growing area of research, potential focus areas and issues are outlined for the more rational design and optimization of MSC‐EV production and potency for therapeutics.
Intramolecular and intermolecular bifurcated hydrogen bonds in 2‐pyrrolyl‐7‐hydroxy‐2‐methylidene‐2,3‐dihydro‐1H‐inden‐1‐one
Authors: Chipanina Nina N. , Oznobikhina Larisa P. , Sigalov Mark V. , Shainyan Bagrat A. 
Published: December 2018

AbstractCyclic and linear dimers as well as the solvate H‐bonded complexes of the Z and E isomers of 2‐pyrrolyl‐7‐hydroxy‐2‐methylidene‐2,3‐dihydro‐1H‐inden‐1‐one 1 were investigated by theoretical calculations, and their formation was proved by FT‐IR and UV spectroscopy. In dimers, both strengthening and weakening of the intramolecular component of the bifurcated hydrogen bond are observed depending on the type of the formed intermolecular hydrogen bond. The effect of proton donors MeOH, HCN, and proton acceptor DMSO on the intramolecular components in solvent H‐bonded complexes is discussed. A larger energy gap in the 1‐E than in 1‐Z isomer allows to predict photoinduced isomeric transition 1‐Е → 1‐Z in nonpolar aprotic solvents.
Theoretical elaboration about the excited state dynamical behaviors for a novel fluorescent sensor
Authors: Zhang Tianjie , Zhang Qiaoli , Lu Xuemei , Jia Min , Song Xiaoyan , Yang Dapeng 
Published: December 2018

AbstractUsing the density functional theory (DFT) and time‐dependent density functional theory (TDDFT) methods, we theoretically explore a novel fluorescent sensor molecule (abbreviated as “2”) (Sensors Actuat B‐Chem. 2018, 263, 585). Because of its symmetry, three stable structures can be located, ie, 2‐enol, 2‐SPT, and 2‐DPT forms in both S0 and S1 states. Via comparing the bond lengths and bond angles involved in the hydrogen bonding moieties, we find the dual intramolecular hydrogen bonds should be strengthened in the S1 state. And based on infrared (IR) vibrational simulations, we further confirm the strengthening dual hydrogen bonds. Upon the photo‐excitation process, the charge redistribution via frontier molecular orbitals (MOs) reveals the tendency of excited state intramolecular proton transfer (ESIPT) reaction. In addition, the constructed S0‐state and S1‐state potential energy curves demonstrate that the excited state single proton transfer (ESSPT) should be the most supported one from 2‐enol to 2‐SPT form. In view of the S1‐state stable 2‐SPT and 2‐DPT structures as well as the fluorescence peaks of them, we can further confirm the ESSPT mechanism for 2 chemosensor. This work not only clarifies the excited state behaviors of 2 system but also successfully explain the previous experimental phenomenon.
Increases in Tumor N‐Glycan Polylactosamines Associated with Advanced HER2‐Positive and Triple‐Negative Breast Cancer Tissues
Authors: Scott Danielle A. , Casadonte Rita , Cardinali Barbara , Spruill Laura , Mehta Anand S. , Carli Franca , Simone Nicole , Kriegsmann Mark , Del Mastro Lucia , Kriegsmann Joerg , Drake Richard R. 
Published: December 2018

PurposeUsing a recently developed matrix‐assisted laser desorption/ionization imaging mass spectrometry (MALDI‐IMS) method, human breast cancer formalin‐fixed paraffin‐embedded (FFPE) tissue sections and tissue microarrays (TMA) are evaluated for N‐linked glycan distribution in the tumor microenvironment.Experimental designTissue sections representing multiple human epidermal growth factor receptor 2 (HER2) receptor–positive and triple‐negative breast cancers (TNBC) in both TMA and FFPE slide format are processed for high resolution N‐glycan MALDI‐IMS. An additional FFPE tissue cohort of primary and metastatic breast tumors from the same donors are also evaluated.ResultsThe cumulative N‐glycan MALDI‐IMS analysis of breast cancer FFPE tissues and TMAs indicate the distribution of specific glycan structural classes to stromal, necrotic, and tumor regions. A series of high‐mannose, branched and fucosylated glycans are detected predominantly within tumor regions. Additionally, a series of polylactosamine glycans are detected in advanced HER2+, TNBC, and metastatic breast cancer tissues. Comparison of tumor N‐glycan species detected in paired primary and metastatic tissues indicate minimal changes between the two conditions.Conclusions and clinical relevanceThe prevalence of tumor‐associated polylactosamine glycans in primary and metastatic breast cancer tissues indicates new mechanistic insights into the development and progression of breast cancers. The presence of these glycans could be targeted for therapeutic strategies and further evaluation as potential prognostic biomarkers.
Imperfect repeats in the functional amyloid protein FapC reduce the tendency to fragment during fibrillation
Authors: Rasmussen Casper B. , Christiansen Gunna , Vad Brian S. , Lynggaard Carina , Enghild Jan J. , Andreasen Maria , Otzen Daniel 
Published: December 2018

ABSTRACTFunctional amyloid (FA) is widespread in bacteria and serves multiple purposes such as strengthening of biofilm and contact with eukaryotic hosts. Unlike pathological amyloid, FA has been subjected to evolutionary optimization which is likely to be reflected in the aggregation mechanism. FA from different bacteria, including Escherichia coli (CsgA) and Pseudomonas (FapC), contains a number of imperfect repeats which may be key to efficient aggregation. Here we report on the aggregative behavior of FapC constructs which represent all single, double, and triple deletions of the protein's three imperfect repeats. Analysis of the fibrillation kinetics by the program Amylofit reveals that the removal of these repeats increases the tendency of the growing fibrils to fragment and also generally increases aggregation half‐times. Remarkably, even the mutant lacking all three repeats was able to fibrillate, although fibrillation was much more irregular and led to significantly altered and destabilized fibrils. We conclude that imperfect repeats can promote fibrillation efficiency thanks to their modular design, though the context of the imperfect repeats also plays a significant role.
Reducing proteolytic liability of a MMP‐14 inhibitory antibody by site‐saturation mutagenesis
Authors: Lee Ki Baek , Dunn Zachary , Ge Xin 
Published: December 2018

AbstractPlaying pivotal roles in tumor growth and metastasis, matrix metalloproteinase‐14 (MMP‐14) is an important cancer target. Potent inhibitory Fab 3A2 with therapy‐desired high selectivity has been isolated from a synthetic antibody library carrying long CDR‐H3s. However, like many standard mechanism protease inhibitors, Fab 3A2 can be cleaved by high concentrations of MMP‐14 after extended incubation at acidic pH. Edman sequencing of generated 3A2 fragments indicated that cleavage occurred within its CDR‐H3 between residues N100h (P1) and L100i (P1’). To improve proteolytic stability of 3A2, three positions adjacent to its cleavage site (P1, P1’, and P3’) were subjected to site‐saturation mutagenesis (SSM). Mutations at P1’ (L100i) resulted in loss of inhibition function, while screening of 3A2 Fab mutants at P1 (N100h) or P3’ (A100k) positions identified four clones exhibiting improvements in both stability and inhibition potency. The majority of these mutants with improved stability were substitutions to either hydrophobic (Lue, Trp) or basic residues (Arg, Lys, His). Combinations of these beneficial mutations resulted in a double mutant N100hR/A100kR, which prolonged half‐life twofold with an inhibition potency KI of 6.6 nM. Enzyme kinetics and competitive ELISA suggested that N100hR/A100kR was a competitive inhibitor overlapping its binding epitope with that of nTIMP‐2. This study demonstrated that site‐directed mutagenesis at or near the cleavage position reduced proteolytic liability of standard mechanism protease inhibitors especially inhibitory antibodies.
Crystallographic identification of spontaneous oxidation intermediates and products of protein sulfhydryl groups
Authors: Wang Jimin 
Published: December 2018

AbstractIn the absence of protective reducing agents, Cys residues in purified proteins can be oxidized spontaneously by oxygen in the air, as frequently observed in protein crystal structures. However, the formation of an O‐bridge via dehydration mechanism between a peroxidized Cys side chain and a primary amine of Lys side chain in proteins has not yet been reported. When an electron density feature was observed for an extra group or an extra atom between side chains of Cys‐245 and Lys‐158 in the crystal structure of histidinol phosphate phosphatase, mass spectrometric analysis was carried out for its chemical identification. That analysis led to a conclusion that this extra density corresponded to a methylene group. It was then proposed that these two residues were able to absorb CO2 and reduced it to CH2 spontaneously. Further examination of other protein structures in the PDB showed that the formation of this cross‐linking species was a widespread phenomenon. This claim is examined in this study using methods recently developed for quantification of electrons around nucleus as the means for direct chemical identification. It is found that an O‐bridge is actually formed between Cys and Lys side chains, instead of a CH2‐bridge.