bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanoionic devices: Interface nanoarchitechtonics for physical property tuning and enhancement
Authors: Tsuchiya Takashi , Terabe Kazuya , Yang Rui , Aono Masakazu
Published: September 2016

Nanoionic devices have been developed to generate novel functions overcoming limitations of conventional materials synthesis and semiconductor technology. Various physical properties can be tuned and enhanced by local ion transport near the solid/solid interface. Two electronic carrier doping methods can be used to achieve extremely high-density electronic carriers: one is electrostatic carrier doping using an electric double layer (EDL); the other is electrochemical carrier doping using a redox reaction. Atomistic restructuring near the solid/solid interface driven by a DC voltage, namely, interface nanoarchitechtonics, has huge potential. For instance, the use of EDL enables high-density carrier doping in potential superconductors, which can hardly accept chemical doping, in order to achieve room-temperature superconductivity. Optical bandgap and photoluminescence can be controlled for various applications including smart windows and biosensors. In situ tuning of magnetic properties is promising for low-power-consumption spintronics. Synaptic plasticity in the human brain is achieved in neuromorphic devices.
Improved cartilage regeneration by implantation of acellular biomaterials after bone marrow stimulation: a systematic review and meta-analysis of animal studies
Authors: Pot Michiel W. , Gonzales Veronica K. , Buma Pieter , IntHout Joanna , van Kuppevelt Toin H. , de Vries Rob B.M. , Daamen Willeke F.
Published: September 2016

Microfracture surgery may be applied to treat cartilage defects. During the procedure the subchondral bone is penetrated, allowing bone marrow-derived mesenchymal stem cells to migrate towards the defect site and form new cartilage tissue. Microfracture surgery generally results in the formation of mechanically inferior fibrocartilage. As a result, this technique offers only temporary clinical improvement. Tissue engineering and regenerative medicine may improve the outcome of microfracture surgery. Filling the subchondral defect with a biomaterial may provide a template for the formation of new hyaline cartilage tissue. In this study, a systematic review and meta-analysis were performed to assess the current evidence for the efficacy of cartilage regeneration in preclinical models using acellular biomaterials implanted after marrow stimulating techniques (microfracturing and subchondral drilling) compared to the natural healing response of defects. The review aims to provide new insights into the most effective biomaterials, to provide an overview of currently existing knowledge, and to identify potential lacunae in current studies to direct future research. A comprehensive search was systematically performed in PubMed and EMBASE (via OvidSP) using search terms related to tissue engineering, cartilage and animals. Primary studies in which acellular biomaterials were implanted in osteochondral defects in the knee or ankle joint in healthy animals were included and study characteristics tabulated (283 studies out of 6,688 studies found). For studies comparing non-treated empty defects to defects containing implanted biomaterials and using semi-quantitative histology as outcome measure, the risk of bias (135 studies) was assessed and outcome data were collected for meta-analysis (151 studies). Random-effects meta-analyses were performed, using cartilage regeneration as outcome measure on an absolute 0–100% scale. Implantation of acellular biomaterials significantly improved cartilage regeneration by 15.6% compared to non-treated empty defect controls. The addition of biologics to biomaterials significantly improved cartilage regeneration by 7.6% compared to control biomaterials. No significant differences were found between biomaterials from natural or synthetic origin or between scaffolds, hydrogels and blends. No noticeable differences were found in outcome between animal models. The risk of bias assessment indicated poor reporting for the majority of studies, impeding an assessment of the actual risk of bias. In conclusion, implantation of biomaterials in osteochondral defects improves cartilage regeneration compared to natural healing, which is further improved by the incorporation of biologics.
The HOSPITAL score as a predictor of 30 day readmission in a retrospective study at a university affiliated community hospital
Authors: Robinson Robert
Published: September 2016

Introduction

Hospital readmissions are common, expensive, and a key target of the Medicare Value Based Purchasing (VBP) program. Risk assessment tools have been developed to identify patients at high risk of hospital readmission so they can be targeted for interventions aimed at reducing the rate of readmission. One such tool is the HOSPITAL score that uses seven readily available clinical variables to predict the risk of readmission within 30 days of discharge. The HOSPITAL score has been internationally validated in large academic medical centers. This study aims to determine if the HOSPITAL score is similarly useful in a moderate sized university affiliated hospital in the midwestern United States.

Materials and Methods

All adult medical patients discharged from the SIU-SOM Hospitalist service from Memorial Medical Center (MMC) from October 15, 2015 to March 16, 2016, were studied retrospectively to determine if the HOSPITAL score was a significant predictor of hospital readmission within 30 days.

Results

During the study period, 998 discharges were recorded for the hospitalist service. The analysis includes data for the 931 discharges. Patients who died during the hospital stay, were transferred to another hospital, or left against medical advice were excluded. Of these patients, 109 (12%) were readmitted to the same hospital within 30 days. The patients who were readmitted were more likely to have a length of stay greater than or equal to 5 days (55% vs. 41%,p= 0.005) and were more likely to have been admitted more than once to the hospital within the last year (100% vs. 49%,p< 0.001). A receiver operating characteristic evaluation of the HOSPITAL score for this patient population shows a C statistic of 0.77 (95% CI [0.73–0.81]), indicating good discrimination for hospital readmission. The Brier score for the HOSPITAL score in this setting was 0.10, indicating good overall performance. The Hosmer–Lemeshow goodness of fit test shows aχ2value of 1.63 with apvalue of 0.20.

Discussion

This single center retrospective study indicates that the HOSPITAL score has good discriminatory ability to predict hospital readmissions within 30 days for a medical hospitalist service at a university-affiliated hospital. This data for all causes of hospital readmission is comparable to the discriminatory ability of the HOSPITAL score in the international validation study (C statistics of 0.72 vs. 0.77) conducted at considerably larger hospitals (975 average beds vs. 507 at MMC) for potentially avoidable hospital readmissions.

Conclusions

The internationally validated HOSPITAL score may be a useful tool in moderate sized community hospitals to identify patients at high risk of hospital readmission within 30 days. This easy to use scoring system using readily available data can be used as part of interventional strategies to reduce the rate of hospital readmission.
Spatial heterogeneity of physicochemical properties explains differences in microbial composition in arid soils from Cuatro Cienegas, Mexico
Authors: Pajares Silvia , Escalante Ana E. , Noguez Ana M. , García-Oliva Felipe , Martínez-Piedragil Celeste , Cram Silke S. , Eguiarte Luis Enrique , Souza Valeria
Published: September 2016

Arid ecosystems are characterized by high spatial heterogeneity, and the variation among vegetation patches is a clear example. Soil biotic and abiotic factors associated with these patches have also been well documented as highly heterogeneous in space. Given the low vegetation cover and little precipitation in arid ecosystems, soil microorganisms are the main drivers of nutrient cycling. Nonetheless, little is known about the spatial distribution of microorganisms and the relationship that their diversity holds with nutrients and other physicochemical gradients in arid soils. In this study, we evaluated the spatial variability of soil microbial diversity and chemical parameters (nutrients and ion content) at local scale (meters) occurring in a gypsum-based desert soil, to gain knowledge on what soil abiotic factors control the distribution of microbes in arid ecosystems. We analyzed 32 soil samples within a 64 m2plot and: (a) characterized microbial diversity using T-RFLPs of the bacterial 16S rRNA gene, (b) determined soil chemical parameters, and (c) identified relationships between microbial diversity and chemical properties. Overall, we found a strong correlation between microbial composition heterogeneity and spatial variation of cations (Ca2, K+) and anions (HCO${}_{3}^{-}$, Cl−, SO${}_{4}^{2-}$) content in this small plot. Our results could be attributable to spatial differences of soil saline content, favoring the patchy emergence of salt and soil microbial communities.
Contribution of new particle formation to the total aerosol concentration at the high‐altitude site Jungfraujoch (3580 m asl, Switzerland)
Authors: Tröstl Jasmin , Herrmann Erik , Frege Carla , Bianchi Federico , Molteni Ugo , Bukowiecki Nicolas , Hoyle Christopher R. , Steinbacher Martin , Weingartner Ernest , Dommen Josef , Gysel Martin , Baltensperger Urs
Published: September 2016

Previous modeling studies hypothesized that a large fraction of cloud condensation nuclei (CCN) is attributed to new particle formation (NPF) in the free troposphere. Despite the potential importance of this process, only few long‐term observations have been performed to date. Here we present the results of a 12 month campaign of NPF observations at the high‐altitude site Jungfraujoch (JFJ, 3580 m above sea level (asl)). Our results show that NPF significantly adds to the total aerosol concentration at the JFJ and only occurs via previous precursor entrainment from the planetary boundary layer (PBL). Freshly nucleated particles do not directly grow to CCN size (90 nm) within observable time scales (maximum 48 h). The contribution of NPF to the CCN concentration is low within this time frame compared to other sources, such as PBL entrainment of larger particles. A multistep growth mechanism is proposed which allows previously formed Aitken mode particles to add to the CCN concentration. A parametrization is derived to explain formation rates at the JFJ, showing that precursor concentration, PBL influence, and global radiation are the key factors controlling new particle formation at the site.
Dynamic triggering of small local earthquakes in the central Himalaya
Authors: Mendoza Manuel M. , Ghosh Abhijit , Rai Shyam S.
Published: September 2016

We present the first observation of remote dynamic triggering of local microearthquakes in central Himalaya caused by the teleseismic waves from the 2007 Mw 8.5 Sumatra earthquake that occurs ~4500 km away. We find small local earthquakes in the Kumaon‐Garhwal Himalaya triggered by teleseismic long‐period surface waves. Interestingly, an elevated level of seismicity persists for a week or so after the arrival of the teleseismic waves. The teleseismic waves impart ~9 kPa of peak dynamic stresses, suggesting that the Himalayan faults in this area are sensitive to small stress changes. This heightened and protracted seismicity indicates that the transient dynamic stresses may have triggered secondary processes, such as slow slip, that may be responsible for the persistence of this earthquake sequence. The region is thought to be close to a large damaging earthquake in the near future. This study provides improved constraints on the factors controlling the earthquake cycle.
Comparison of auroral ionospheric and field‐aligned currents derived from Swarm and ground magnetic field measurements
Authors: Juusola L. , Kauristie K. , Vanhamäki H. , Aikio A. , van de Kamp M.
Published: September 2016

Derivation of the auroral ionospheric currents from magnetic field measurements can produce drastically different results depending on the data and method used. We have cross tested several methods for obtaining instantaneous field‐aligned and horizontal currents from Swarm satellite and International Monitor for Auroral Geomagnetic Effects (IMAGE) ground magnetic field measurements. We found that Swarm can yield latitude profiles of the east‐west component of the divergence‐free current density at most at ∼200 km resolution, typically resolving the electrojets. The north‐south divergence‐free component, on the other hand, is not always well reproduced due to the small longitudinal distance between the side‐by‐side flying satellite pair. Swarm can yield the field‐aligned and curl‐free current density at a wider range of latitude resolutions (∼7.5–200 km) than the divergence‐free current density. While 7.5 km is suitable for comparison with auroras, 200 km typically resolves the Regions 1 and 2 field‐aligned currents. IMAGE can yield maps of the divergence‐free current density at ∼50 km resolution. Induced telluric currents should be accounted for in the derivation. Not accounting for them in the Swarm analysis, however, does not appear to introduce significant errors. Ionospheric conductances can be estimated by combining the total horizontal current density, consisting of the curl‐free and divergence‐free components, with the electric field measurements. Our results indicate that Swarm can only yield these at ∼200 km scale size when there is no significant dependence on longitude. However, combining the divergence‐free current from IMAGE with the curl‐free current and electric field from Swarm could yield conductance maps at ∼50 km resolution.
Temporal variability in the Antarctic Polar Front (2002–2014)
Authors: Freeman Natalie M. , Lovenduski Nicole S. , Gent Peter R.
Published: September 2016

We investigate intraannual to interannual variability in the Antarctic Polar Front (PF) using weekly PF realizations spanning 2002–2014 (found at doi.pangaea.de/10.1594/PANGAEA.855640). While several PF studies have used gradient maxima in sea surface temperature (SST) or height to define its location, results from this study are based on a PF defined using SST measurements that avoid cloud contamination and the influence of steric sea level change. With a few regional exceptions, we find that the latitudinal position of the PF does not vary seasonally, yet its temperature exhibits a clear seasonal cycle. Consistent with previous studies, the position and intensity of the PF is largely influenced by bathymetry; generally, over steep topography, we find that the front intensifies and interannual variability in its position is low. We also investigate drivers of PF variability in the context of large‐scale climate variability on various spatial and temporal scales, but find that the major modes of Southern Hemisphere climate variability explain only a tiny fraction of the interannual PF variance. Over the study time period, the PF intensifies at nearly all longitudes while exhibiting no discernible meridional displacement in its zonal mean path.
Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies
Authors: Park Hye‐Jin , Lee Kang‐Woo , Park Eun S. , Oh Stephanie , Yan Run , Zhang Jie , Beach Thomas G. , Adler Charles H. , Voronkov Michael , Braithwaite Steven P. , Stock Jeffry B. , Mouradian M. Maral
Published: September 2016

Objective

Protein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α‐Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho‐Ser129 phosphatase. The objective of this study was to investigate PP2A in α‐synucleinopathies.

Methods

We compared the state of PP2A methylation, as well as the expression of its methylating enzyme, leucine carboxyl methyltransferase (LCMT‐1), and demethylating enzyme, protein phosphatase methylesterase (PME‐1), in postmortem brains from PD and DLB cases as well as age‐matched Controls. Immunohistochemical studies and quantitative image analysis were employed.

Results

LCMT‐1 was significantly reduced in the substantia nigra (SN) and frontal cortex in both PD and DLB. PME‐1, on the other hand, was elevated in the PD SN. In concert with these changes, the ratio of methylated PP2A to demethylated PP2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP2A or total B55α subunit were detected.

Interpretation

These findings support the hypothesis that PP2A dysregulation in α‐synucleinopathies may contribute to the accumulation of hyperphosphorylated α‐synuclein and to the disease process, raising the possibility that pharmacological means to enhance PP2A phosphatase activity may be a useful disease‐modifying therapeutic approach.
Clues for Cellular Structure Optimization in Aluminum Foams
Authors: Lázaro Jaime , Solórzano Eusebio , Rodríguez‐Pérez Miguel A.
Published: September 2016

This work studies the different stages of the fabrication of aluminum foams from PM precursors and aims on finding the parameters affecting the generation of defects in the cellular structure. Results show that foam's cellular anisotropy is directly related to the structural anisotropy of the initial precursor and the way it starts expanding. Homogenization heat treatment to the precursor material can then reduce foam's cellular anisotropy. On the other hand, the amount of broken cell walls depends not only on the expansion grade, but more significantly on the cooling conditions at the end of the foaming process, being this a possible key to reduce and control their generation.
11q terminal deletion and combined immunodeficiency (Jacobsen syndrome): Case report and literature review on immunodeficiency in Jacobsen syndrome
Authors: Blazina Štefan , Ihan Alojz , Lovrečić Luca , Hovnik Tinka
Published: September 2016

Antibody deficiency is common finding in patients with Jacobsen syndrome (JS). In addition, there have been few reports of T‐cell defects in this condition, possibly because most of the reported patients have not been specifically evaluated for T‐cell function. In this article, we present a child with an 11q deletion and combined immunodeficiency and we perform a literature overview on immunodeficiency in JS. Our patient presented with recurrent bacterial and prolonged viral infections involving the respiratory system, as well as other classic features of the syndrome. In addition to low IgM, IgG4, and B‐cells, also low recent thymic emigrants, helper and naïve T‐cells were found. We propose that patients with Jacobsen syndrome need thorough immunological evaluations as T‐cell dysfunction might be more prevalent than previously reported. Patients with infections consistent with T‐cell defects should be classified as having combined immunodeficiency. © 2016 Wiley Periodicals, Inc.
Evidence for troponin C (TNNC1) as a gene for autosomal recessive restrictive cardiomyopathy with fatal outcome in infancy
Authors: Ploski Rafal , Rydzanicz Malgorzata , Ksiazczyk Tomasz M. , Franaszczyk Maria , Pollak Agnieszka , Kosinska Joanna , Michalak Ewa , Stawinski Piotr , Ziolkowska Lidia , Bilinska Zofia T. , Werner Bozena
Published: September 2016

Restrictive cardiomyopathy is a rare form of pediatric cardiac disease, for which the known genes include MYH7, TNNT2, TNNI3, ACTC1, and DES. We describe a pediatric proband with fatal restrictive cardiomyopathy associated with septal hypertrophy and compound heterozygosity for TNNC1 mutations (NM_003280: p.A8V [c.C23T] and p.D145E [c.C435A]). This association between restrictive cardiomyopathy and TNNC1 mutations was strengthened by prospective observations on the second pregnancy in the family which revealed, in the presence of the same TNNC1 genotype, prenatally diagnosed hypertrophic cardiomyopathy which evolved into restrictive cardiomyopathy, heart failure and death at the age of 9 months. Contrary to previous reports, family and population analyses showed that each of the TNNC1 variants was not pathogenic when present alone. Our results (i) confirm that genetic backgrounds of hypertrophic cardiomyopathy and restrictive cardiomyopathy overlap and (ii) indicate that TNNC1 is a likely novel gene for autosomal recessive restrictive cardiomyopathy. © 2016 Wiley Periodicals, Inc.
Vesicourethral reflux‐induced renal failure in a patient with ICF syndrome due to a novel DNMT3B mutation
Authors: Kutluğ Seyhan , Ogur Gönül , Yilmaz Aysegül , Thijssen Peter E. , Abur Ummet , Yildiran Alisan
Published: September 2016

ICF syndrome is a primary immunodeficiency disease characterized by hypo‐ or agammaglobulinemia, centromeric instability mainly on chromosomes 1, 9, and 16 and facial anomalies. ICF syndrome presents with frequent respiratory tract infections in infancy. A 20‐month‐old female patient was referred to our clinic due to frequent lower respiratory tract infections. ICF syndrome was considered because of comorbidity of hypogammaglobulinemia, facial anomalies, and neuromotor growth retardation. Metaphase chromosome analysis revealed centromeric instability on chromosomes 1, 9, and 16 and through Sanger a previously unreported homozygous missense mutation (c.1805T>C; [p.V602A]) was identified in the DNMT3B, confirming ICF1. The patient was found to have a breakdown in renal function 1 year later; the urinary system was examined and bilateral vesicoureteral reflux was found, warranting the need for dialysis in time. This report expands the mutation spectrum of ICF1 and is the first to describe bilateral vesicoureteral reflux accompanying ICF syndrome. © 2016 Wiley Periodicals, Inc.
Detecting celiac disease in patients with Down syndrome
Authors: Sharr Christianne , Lavigne Jenifer , Elsharkawi Ibrahim M. A. , Ozonoff Al , Baumer Nicole , Brasington Campbell , Cannon Sheila , Crissman Blythe , Davidson Emily , Florez Jose C. , Kishnani Priya , Lombardo Angela , Lyerly Jordan , McDonough Mary Ellen , Schwartz Alison , Berrier Kathryn L. , Sparks Susan , Stock‐Guild Kara , Toler Tomi L. , Vellody Kishore , Voelz Lauren , Skotko Brian G.
Published: September 2016

The main purposes of this undertaking were to determine how often patients with Down syndrome (DS) are screened for celiac disease (CD) across five DS specialty clinics, which symptoms of CD are most often reported to DS specialty providers at these clinics, and, how many individuals were diagnosed with CD by these clinics. This was accomplished by following 663 individuals with DS for 1 year, across five clinics in different states specializing in the comprehensive care of people with DS. Of the 663 participants, 114 individuals were screened for CD at their visit to a DS specialty clinic. Protracted constipation (43.2%) and refractory behavioral problems (23.7%) were symptoms most often reported to DS specialty providers. During the 1 year study period, 13 patients screened positive for CD by serology. Of those, eight underwent duodenal biopsy, and three were diagnosed with CD. We conclude that CD is an important consideration in the comprehensive care of individuals with DS. However, while symptoms are common, diagnoses are infrequent in DS specialty clinics. © 2016 Wiley Periodicals, Inc.
Utility of genetic evaluation in infants with congenital heart defects admitted to the cardiac intensive care unit
Authors: Ahrens‐Nicklas Rebecca C. , Khan Shama , Garbarini Jennifer , Woyciechowski Stacy , D'Alessandro Lisa , Zackai Elaine H. , Deardorff Matthew A. , Goldmuntz Elizabeth
Published: September 2016

Congenital heart defects (CHDs) are heterogeneous and present with a spectrum of severity, with roughly 25% of patients requiring intervention before age 1. The etiology of disease is unknown in many individuals; however, there is a rapidly expanding understanding of genetic risk factors that may contribute to pathogenesis. Through this work, we sought to evaluate the diagnostic yield of a clinical genetics evaluation and associated genetic testing among infants with critical CHDs. Furthermore, we aimed to both determine the utility of microarray and establish a strong baseline that can be used in future studies of the impact of exome sequencing in this population. We completed a retrospective chart review of 364 infants with CHDs admitted to the Cardiac Intensive Care Unit who underwent a clinical genetics evaluation. A genetic diagnosis was established in 25% of patients: 9% of infants were diagnosed prenatally, while 16% were diagnosed postnatally. Cardiac lesion subtype greatly influenced the diagnostic yield. On physical exam, the presence of dysmorphic features, as assessed by a clinical geneticist, was associated with a sevenfold increased likelihood of reaching a diagnosis. Directed by clinical acumen, diagnostic rates varied by testing modality with rates of 23% for karyotype, 12% for fluorescent in situ hybridization or multiplex‐dependent ligation probe analysis, 9% for genome wide microarray, and 17% for targeted gene sequencing. Careful consideration of lesion subtype and physical exam findings clarify populations of infants with CHD that benefit from a genetics evaluation and inform an efficient testing paradigm. © 2016 Wiley Periodicals, Inc.
Apolipoprotein E genotypes and plasma levels in mild cognitive impairment conversion to Alzheimer's disease: A follow‐up study
Authors: Scarabino Daniela , Broggio Elisabetta , Gambina Giuseppe , Maida Carlotta , Gaudio Maria Rosa , Corbo Rosa Maria
Published: September 2016

Mild cognitive impairment (MCI) is the transition stage between the normal aging process and dementia itself. The most common clinical phenotype is amnestic MCI (aMCI) [subtypes: single domain (sMCI) and multiple domains (mMCI)], which is considered prodromal to Alzheimer's disease (AD). The APOE (apolipoprotein E) e4 allele is the most important genetic risk factor for AD, but its association with MCI onset and conversion to AD is controversial. In this follow‐up study of 88 aMCI patients (68% sMCI and 32% mMCI at baseline), we examined APOE genotypes and plasma levels in relation to MCI development and progression based on their clinical/cognitive data obtained at baseline and follow‐up assessment (mean follow‐up time = 6.6 ± 3.4 years). A control sample (n = 164) was collected in previous investigations. The overall conversion rate to mMCI or AD was 52.2%. The APOE e4 allele was associated with a higher risk of developing MCI (OR: 2.23; 95%CI: 1.22–4.08). The conversion rate in the e4 allele carriers (32% of the sample) was 71%, and the e4 allele was associated with a higher risk of conversion to mMCI/AD (OR: 4.1; 95%CI: 1.2–13.6). APOE e2 allele carriers were 7% (all sMCI) and none progressed to mMCI/AD. Among MCI subjects, e4 carriers had the lowest plasma apoE levels (37.8 ± 12.5 mg/L), and e2 carriers had the highest (78.6 ± 38.1 mg/L). APOE e4 is a risk allele for the development and progression of aMCI, the APOE e2 allele seems to be protective, and apoE levels associated to them are an integral part of their action. © 2016 Wiley Periodicals, Inc.
Insights into N‐Heterocyclic Carbene‐Catalyzed [4+2] Annulation Reaction of Enals with Nitroalkenes: Mechanisms, Origin of Chemo‐ and Stereoselectivity, and Role of Catalyst
Authors: Zheng Linjie , Wang Yang , Wei Donghui , Qiao Yan
Published: September 2016

In this paper, density functional theory (DFT) calculations have been employed to investigate the detailed mechanisms, origin of chemo‐ and stereoselectivity, and role of catalyst for the reaction of enals with nitroalkenes catalyzed by N‐heterocyclic carbenes (NHCs). The calculated results disclose that the reaction contains seven steps, that is, the nucleophilic attack on the α, β‐unsaturated aldehyde by NHC, the [1, 2]‐proton transfer for the formation of Breslow intermediate, the β‐protonation for affording enolate intermediate, the nucleophilic addition on the Re/Si face of enolate by the nitroalkenes, the [1, 5] proton transfer, the ring‐closure process, and the regeneration of NHC. The addition on the Re/Si face of enolate is identified to be the stereocontrolling step, in which the chiral centers including α‐carbon of enals and β‐carbon of nitroalkenes are formed. Moreover, the reaction pathway leading to the RR‐configured product has the lowest Gibbs free energy barrier, which is in agreement with the experimental observation. Furthermore, the analyses of electrophilic and nucleophilic Parr functions and global reactivity indices (GRIs) have been performed to explore the origin of chemoselectivity and the role of catalyst. This theoretical work would provide valuable insights for the rational design of more effective organocatalyst for this kind of reactions with high stereoselectivities.
Encapsulation of AGE‐Breaker Alagebrium by Cucurbit[7]uril Improved the Stability of Both Its Carbonyl α‐Hydrogen and Thiazolium C2‐Hydrogen
Authors: Li Shengke , Ding Yuan‐Fu , Yin Hang , Wang Chunming , Bardelang David , Wang Lian‐Hui , Wang Ruibing
Published: September 2016

As determined by both 1H NMR and UV/Vis spectroscopic titration, ESI‐MS, isothermal titration calorimetry, and DFT molecular modeling, advanced glycation end products (AGE) breaker alagebrium (ALA) formed 1:1 guest–host inclusion complexes with cucurbit[7]uril (CB[7]), with a binding affinity, Ka, in the order of magnitude of 105 m−1, thermodynamically driven by both enthalpy (ΔH=−6.79 kcal mol−1) and entropy (TΔS=1.21 kcal mol−1). For the first time, a dramatic inhibition of keto–enol tautomerism of the carbonyl α‐hydrogen of ALA has been observed, as evidenced by over an order of magnitude decrease of both the first step rate constant, k1, and the second step rate constant, k2, during hydrogen/deuterium exchange in D2O. Meanwhile, as expected, the reactivity of C2‐hydrogen was also inhibited significantly, with an upshift of 2.09 pKa units. This discovery will not only provide an emerging host molecule to modulate keto–enol tautomerism, but also potentially lead to a novel supramolecular formulation of AGE‐breaker ALA for improved stability and therapeutic efficacy.
Physiologically based pharmacokinetic–pharmacodynamic modeling to predict concentrations and actions of sodium‐dependent glucose transporter 2 inhibitor canagliflozin in human intestines and renal tubules
Authors: Mori Kazumi , Saito Ryuta , Nakamaru Yoshinobu , Shimizu Makiko , Yamazaki Hiroshi
Published: September 2016

Canagliflozin is a recently developed sodium‐glucose cotransporter (SGLT) 2 inhibitor that promotes renal glucose excretion and is considered to inhibit renal SGLT2 from the luminal side of proximal tubules. Canagliflozin reportedly inhibits SGLT1 weakly and suppresses postprandial plasma glucose, suggesting that it also inhibits intestinal SGLT1. However, it is difficult to measure the drug concentrations of these assumed sites of action directly. The pharmacokinetic–pharmacodynamic (PK/PD) relationships of canagliflozin remain poorly characterized. Therefore, a physiologically based pharmacokinetic (PBPK) model of canagliflozin was developed based on clinical data from healthy volunteers and it was used to simulate luminal concentrations in intestines and renal tubules. In small intestine simulations, the inhibition ratios for SGLT1 were predicted to be 40%–60% after the oral administration of clinical doses (100–300 mg/day). In contrast, inhibition ratios of canagliflozin for renal SGLT2 and SGLT1 were predicted to be approximately 100% and 0.2%–0.4%, respectively. These analyses suggest that canagliflozin only inhibits SGLT2 in the kidney. Using the simulated proximal tubule luminal concentrations of canagliflozin, the urinary glucose excretion rates in canagliflozin‐treated diabetic patients were accurately predicted using the renal glucose reabsorption model as a PD model. Because the simulation of canagliflozin pharmacokinetics was successful, this PBPK methodology was further validated by successfully simulating the pharmacokinetics of dapagliflozin, another SGLT2 inhibitor. The present results suggest the utility of this PBPK/PD model for predicting canagliflozin concentrations at target sites and help to elucidate the pharmacological effects of SGLT1/2 inhibition in humans. Copyright © 2016 John Wiley & Sons, Ltd.
Thermische Leitfähigkeit von Stahlfaserbeton – eine theoretische Betrachtung
Authors: Fessel Dustin , Simon Peter , Guder Tom , Dehn Frank
Published: September 2016

Für die Bemessung von Stahlbeton‐ und Spannbetontragwerken im Brandfall ist die Kenntnis der thermischen Leitfähigkeit λc des Betons eine der wesentlichen Eingangsgrößen. Im Fall der Zugabe von Stahlfasern zum Beton gibt es bislang widersprüchliche Aussagen, inwieweit sich diese auf die thermische Leitfähigkeit und somit auf den Feuerwiderstand auswirkt. Vor diesem Hintergrund wurden experimentell ermittelte und in der Literatur dokumentierte Untersuchungsergebnisse ausgewertet und systematisch durch eigene theoretische Betrachtungen sowie anhand eines computergestützten Evaluationsverfahrens ergänzt. Unter der Annahme der Gültigkeit der in DIN EN 1992‐1‐2:2010 angegebenen temperaturabhängigen Unter‐ und Obergrenze für die thermische Leitfähigkeit, auf der Grundlage theoretischer Betrachtungen zum Wärmewiderstand von Beton sowie anhand von Vergleichsrechnungen mittels eines numerischen Modells konnte gezeigt werden, dass sich für in der Praxis übliche Stahlfasergehalte von bis zu 1 Vol.‐% eine vernachlässigbare Änderung der thermischen Leitfähigkeit gegenüber normal‐ und hochfesten Betonen ohne Stahlfasern ergibt. Für andere Betonarten, die sich insbesondere hinsichtlich Betonrohdichte, Art, Größe und Anordnung von Poren sowie bzgl. des physikalischen und chemischen Wasserbindevermögens von normal‐ und hochfestem Beton unterscheiden, sollten jedoch gesonderte Betrachtungen angestellt werden.
Solution and solid state conformational preferences of a family of cyclic disulphide bridged tetrapeptides
Authors: Berger Nadja , Li Fee , Mallick Bert , Brüggemann J. Thomas , Sander Wolfram , Merten Christian
Published: September 2016

A set of cyclic tetrapeptides of the general form cyclo (Boc‐Cys‐Pro‐X‐Cys‐OMe) with X being L‐/D‐Ala, L‐/D‐Val, and L‐/D‐Trp was synthesized. These peptides serve as model systems for structure elucidation in solution and feature a variety of structural motifs — namely a β‐turn with intramolecular hydrogen bonding interactions, cis/trans isomerism, and a disulphide bond. In this work, we performed a comprehensive structural analysis focussing on their β‐turn conformational preferences using NMR, VCD, and Raman spectroscopy. Our results provide evidence for a strong influence of a single stereocenter on the structures of the peptides whereas solvent polarity does not significantly affect them. Additionally, the solid state conformational preferences were studied by crystal structure analysis. Overall, a general trend for the conformational preferences of this set of peptides can be concluded from the results of the complementary investigations.
Development and validation of a high performance liquid chromatography quantification method of levo‐tetrahydropalmatine and its metabolites in plasma and brain tissues: application to a pharmacokinetic study
Authors: Abdallah Inas A. , Huang Peng , Liu Jing , Lee David Y. , Liu‐Chen Lee‐Yuan , Hassan Hazem E.
Published: September 2016

Levo‐tetrahydropalmatine (l‐THP) is an alkaloid isolated from Chinese medicinal herbs of the Corydalis and Stephania genera. It has been used in China for more than 40 years mainly as an analgesic with sedative/hypnotic effects. Despite its extensive use, its metabolism has not been quantitatively studied, nor there a sensitive reliable bioanalytical method for its quantification simultaneously with its metabolites. As such, the objective of this study was to develop and validate a sensitive and selective HPLC method for simultaneous quantification of l‐THP and its desmethyl metabolites l‐corydalmine (l‐CD) and l‐corypalmine (l‐CP) in rat plasma and brain tissues. Rat plasma and brain samples were processed by liquid–liquid extraction using ethyl acetate. Chromatographic separation was achieved on a reversed‐phase Symmetry® C18 column (4.6 × 150 mm, 5 μm) at 25°C. The mobile phase consisted of acetonitrile–methanol–10 mm ammonium phosphate (pH 3) (10:30:60, v/v) and was used at a flow rate of 0.8 mL/min. The column eluent was monitored at excitation and emission wavelengths of 230 and 315 nm, respectively. The calibration curves were linear over the concentration range of 1–10,000 ng/mL. The intra‐ and interday reproducibility studies demonstrated accuracy and precision within the acceptance criteria of bioanalytical guidelines. The validated HPLC method was successfully applied to analyze samples from a pharmacokinetic study of l‐THP in rats. Taken together, the developed method can be applied for bioanalysis of l‐THP and its metabolites in rodents and potentially can be transferred for bioanalysis of human samples.
Evaluating the efficiency of phiC31 integrase‐mediated monoclonal antibody expression in CHO cells
Authors: Ahmadi Maryam , Mahboudi Fereidoun , Akbari Eidgahi Mohammad Reza , Nasr Reza , Nematpour Fatemeh , Ahmadi Samira , Ebadat Saeedeh , Aghaeepoor Mojtaba , Davami Fatemeh
Published: September 2016

Traditional methods to generate CHO cell lines rely on random integration(s) of the gene of interest and result in unpredictable and unstable protein expression. In comparison, site‐specific recombination methods increase the recombinant protein expression by inserting transgene at a locus with specific expression features. PhiC31 serine integrase, catalyze unidirectional integration that occurs at higher frequency in comparison with the reversible integration carried out by recombinases such as Cre. In this study, using different ratios of phiC31 serine integrase, we evaluated the phiC31 mediated gene integration for expression of a humanized IgG1 antibody (mAb0014) in CHO‐S cells. Light chain (LC) and heavy chain (HC) genes were expressed in one operon under EF1α promoter and linked by internal ribosome entry site (IRES) element. The clonal selection was carried out by limiting dilution. Targeted integration approach increased recombinant protein yield and stability in cell pools. The productivity of targeted cell pools was about 4 mg/L and about 40 µg/L in the control cell pool. The number of integrated transgenes was about 19 fold higher than the control cells pools. Our results confirmed that the phiC31 integrase leads to mAb expression in more than 90% of colonies. The productivity of the PhiC31 integrated cell pools was stable for three months in the absence of selection as compared with conventional transfection methods. Hence, utilizing PhiC31 integrase can increase protein titer and decrease the required time for protein expression. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1570–1576, 2016
Modification of an Enzyme Biocatalyst for the Efficient and Selective Oxidative Demethylation of para‐Substituted Benzene Derivatives
Authors: Chao Rebecca R. , Lau Ian C.‐K. , De Voss James J. , Bell Stephen G.
Published: September 2016

The bacterial CYP199A4 enzyme is able to oxidise a narrow range of aromatic acids, which includes 4‐methoxybenzoic acid, efficiently. A serine 244 to aspartate variant was identified with enhanced activity for a wide range of para‐methoxy‐substituted benzenes. Substrates in which the acidic benzoic acid moiety is replaced with a phenol and the amide, aldehyde and bromide analogues were all oxidised with high activity by the S244D mutant (product formation rate >600 nmol nmolCYP−1 min−1) with turnover numbers of up to 20 000. If the carboxylate moiety was modified to a nitro, ketone, boronic acid, hydroxymethyl or nitrile group, these substrates were also oxidised at a significantly higher activity by S244D than the wild‐type enzyme. 3,4‐Dimethoxybenzaldehyde was demethylated selectively and oxidatively to 3‐methoxy‐4‐hydroxybenzaldehyde by the S244D mutant 84‐fold more rapidly than with the wild‐type enzyme. CYP199A4 would have applications in the catalytic regioselective oxidative demethylation of suitably substituted benzene substrates under mild conditions and in the presence of more oxidatively sensitive functional groups, such as an aldehyde.
Selectivity and Lifetime Effects in Zeolite‐Catalysed Baeyer–Villiger Oxidation Investigated in Batch and Continuous Flow
Authors: Yakabi Keiko , Milne Kirstie , Buchard Antoine , Hammond Ceri
Published: September 2016

In this manuscript, we investigate the kinetic, mechanistic and lifetime aspects of the Baeyer–Villiger oxidation of cyclohexanone with Sn‐β as catalyst and H2O2 as oxidant, with the aim of: 1) elucidating the overall reaction network, 2) closing the carbon balance, particularly at high levels of conversion, and 3) examining the intensification of this process in the continuous regime. The results presented herein conclusively demonstrate that this reaction is highly selective for the desired product (ϵ‐caprolactone) only below conversions of 60 %. Above this level of conversion, unavoidable hydrolysis of ϵ‐caprolactone to 6‐hydroxyhexanoic acid is observed, which consumes the desired product and leads to a reduction in catalytic activity through poisoning. By elucidating the reaction network and working under optimised conditions, we show the potential viability of this methodology to operate continuously over a 180 h period, both at high levels of productivity (324 g (cyclohexanone converted) cm−3 (reactor volume) kg−1 (catalyst) h−1) and selectivity (70 % at 60 % conversion). Over 5000 substrate turnovers were observed during this period, an order of magnitude higher than previously noted for this particular catalyst system.
Relation between Hydrogen Evolution and Hydrodesulfurization Catalysis
Authors: Šarić Manuel , Moses Poul Georg , Rossmeisl Jan
Published: September 2016

A relation between hydrogen evolution and hydrodesulfurization catalysis was found by density functional theory calculations. The hydrogen evolution reaction and the hydrogenation reaction in hydrodesulfurization share hydrogen as a surface intermediate and, thus, have a common elementary step, which indicates that the same catalyst should perform well for both hydrogen evolution and hydrogenation. If that catalyst also fulfills additional criteria for breaking carbon–sulfur bonds and releasing hydrogen sulfide, it will be a good hydrodesulfurization catalyst. The hydrogen evolution reaction is normally performed at room temperature and standard pressure, whereas the hydrodesulfurization reaction is driven by high temperature and pressure. Owing to the very different operating conditions, the adsorption free energy of hydrogen differs between hydrodesulfurization and the hydrogen evolution reaction, which makes the connection between the two less obvious.
Synthesis and Deprotonation of Aminophosphane Complexes: First K/N(H)R Phosphinidenoid Complexes and Access to a Complex with a P2N‐Ring Ligand
Authors: Majhi Paresh Kumar , Kyri Andreas Wolfgang , Schmer Alexander , Schnakenburg Gregor , Streubel Rainer
Published: September 2016

Synthesis of 1,1′‐bifunctional aminophosphane complexes 3 a–e was achieved by the reaction of Li/Cl phosphinidenoid complex 2 with various primary amines (R=Me, iPr, tBu, Cy, Ph). Deprotonation of complex 3 a (R=Me) with potassium hexamethyldisilazide yielded a mixture of K/NHMe phosphinidenoid complex 4 a and potassium phosphanylamido complex 4 a′. Treatment of complex 3 c (R=tBu) and e (R=Ph) with KHMDS afforded the first examples of K/NHR phosphinidenoid complexes 4 c and e. The reaction of complex 3 c with 2 molar equivalents of KHMDS followed by PhPCl2 afforded complexes 5 c,c′, which possess a P2N‐ring ligand. All complexes were characterized by NMR, IR, MS, and microanalysis, and additionally, complexes 3 b–e and 5 c′ were scrutinized by single‐crystal X‐ray crystallography.
Site‐Specific Isotope‐Labeling of Inosine Phosphoramidites and NMR Analysis of an Inosine‐Containing RNA Duplex
Authors: Dallmann Andre , Beribisky Alexander V. , Gnerlich Felix , Rübbelke Martin , Schiesser Stefan , Carell Thomas , Sattler Michael
Published: September 2016

Structural features and internal dynamics of inosine‐containing RNAs are poorly understood. NMR studies of such RNAs require 13C,15N‐labeling, which cannot be achieved using in vitro transcription as inosine and guanosine are not distinguished by RNA polymerase. Herein, we report the synthesis of an inosine phosphoramidite with selective 13C8 and 15N7‐isotope incorporation in the base and uniform 13C‐labeling of the ribose. Chemical synthesis of an RNA duplex containing four consecutive IU base pairs with this optimized isotope‐labeling scheme greatly simplifies NMR spectra and resolves signal overlap. The absence of detectable NMR signals of imino protons and unusual inter‐residue NOE correlations in this RNA indicate deviations from standard A‐form geometry, consistent with reduced stability of this duplex seen in UV melting studies compared to its nonedited RNA counterparts. These studies indicate that the introduction of IU base pairs distorts and destabilizes RNA helices significantly compared to the also noncanonical GU base‐pairs. Our optimized isotope‐labeling scheme enables high‐resolution NMR studies of inosine‐edited RNAs.
Chirality Relay in 2,2′‐Substituted 1,1′‐Binaphthyl: Access to Propeller Chirality of the Tricoordinate Boron Center
Authors: Wang Chen , Sun Zuo‐Bang , Xu Qing‐Wen , Zhao Cui‐Hua
Published: September 2016

It is a challenging issue to achieve propeller chirality for triarylboranes owing to the low transition barrier between the P and M forms of the boron center. Herein, we report a new strategy to achieve propeller chirality of triarylboranes. It was found that the chirality relay from axially chiral 1,1′‐binaphthyl to propeller chirality of the trivalent boron center can be realized when a Me2N and a Mes2B group (Mes=mesityl) are introduced at the 2,2′‐positions of the 1,1′‐binaphthyl skeleton (BN‐BNaph) owing to the strong π–π interaction between the Me2N‐bonded naphthyl ring and the phenyl ring of one adjacent Mes group, which not only exerts great steric hindrance on the rotation of the two Mes groups but also gives unequal stability to the two configurations of the boron center for a given configuration of the binaphthyl moiety. The stereostructures of the boron center were fully characterized through 1H NMR spectroscopy, X‐ray crystal analyses, and theoretical calculations. Detailed comparisons with the analog BN‐Ph‐BNaph, in which the Mes2B group is separated from 1,1′‐binaphthyl by a para‐phenylene spacer, confirmed the essential role of π–π interaction for the successful chirality relay in BN‐BNaph.
Production of Pure Aqueous 13C‐Hyperpolarized Acetate by Heterogeneous Parahydrogen‐Induced Polarization
Authors: Kovtunov Kirill V. , Barskiy Danila A. , Shchepin Roman V. , Salnikov Oleg G. , Prosvirin Igor P. , Bukhtiyarov Andrey V. , Kovtunova Larisa M. , Bukhtiyarov Valerii I. , Koptyug Igor V. , Chekmenev Eduard Y.
Published: September 2016

A supported metal catalyst was designed, characterized, and tested for aqueous phase heterogeneous hydrogenation of vinyl acetate with parahydrogen to produce 13C‐hyperpolarized ethyl acetate for potential biomedical applications. The Rh/TiO2 catalyst with a metal loading of 23.2 wt % produced strongly hyperpolarized 13C‐enriched ethyl acetate‐1‐13C detected at 9.4 T. An approximately 14‐fold 13C signal enhancement was detected using circa 50 % parahydrogen gas without taking into account relaxation losses before and after polarization transfer by magnetic field cycling from nascent parahydrogen‐derived protons to 13C nuclei. This first observation of 13C PHIP‐hyperpolarized products over a supported metal catalyst in an aqueous medium opens up new possibilities for production of catalyst‐free aqueous solutions of nontoxic hyperpolarized contrast agents for a wide range of biomolecules amenable to the parahydrogen induced polarization by side arm hydrogenation (PHIP‐SAH) approach.