bluuebunny/crossref_metadata_2025 huggingface dataset:
Poor sleep quality in patients with multiple sclerosis: gender differences
Authors: Vitkova Marianna , Rosenberger Jaroslav , Gdovinova Zuzana , Szilasiova Jarmila , Mikula Pavol , Groothoff Johan W. , Reijneveld Sijmen A. , van Dijk Jitse P.
Published: September 2016

Objectives

Most of the psychological and physical factors associated with poor sleep quality in patients with multiple sclerosis (MS) have a different prevalence in women and men, but whether or not these factors contribute differently to sleep quality in women and men with MS remains unclear. The aim of this study was to identify possible gender differences in factors related to poor sleep quality in MS patients.

Material and Methods

We collected data from 153 patients with MS. Patients filled out the Pittsburgh Sleep Quality Index (PSQI), the Hospital Anxiety and Depression Scale, and one item of the Short Form‐36 regarding pain.

Results

The best model of predictors of poor sleep quality consisting of gender, depression, anxiety, pain, and the interaction between gender and pain showed that the only variable interacting with gender, which was significantly associated with poor sleep quality was pain (odds ratio [OR] for interaction of pain with male gender was 15.4, 95% CI: 2.4; 39.5). Separate models for men and women consisting of pain, depression, anxiety, after adjustment for age, disease duration, and disability showed that pain was the only variable associated with poor sleep quality in men (OR = 12.7, 95% CI: 1.9; 29.6), whereas depression (OR = 4.1, 95% CI: 1.3; 13.2) and anxiety (OR = 6.8, 95% CI: 2.4; 19.1) were in women.

Conclusions

Factors contributing to poor sleep quality in MS patients differ by gender. Depression and anxiety are associated with poor sleep quality in women, whereas pain is in men. This highlights the need to apply gender‐specific approaches to the treatment of sleep disorders.
Identification of Sternbin and Naringenin as Detoxified Metabolites from the Rice Flavanone Phytoalexin Sakuranetin by Pyricularia oryzae
Authors: Katsumata Shun , Hamana Kazuho , Horie Kiyotaka , Toshima Hiroaki , Hasegawa Morifumi
Published: September 2016

Sakuranetin (1) is a flavanone phytoalexin that has been reported to play an important role in disease resistance in rice plants. The rice blast fungus Pyricularia oryzae (syn. Magnaporthe oryzae) has been reported to metabolize 1 to lower its antifungal activity. Here, two flavanones, sternbin (2) and naringenin (3), were identified as metabolites of 1 in P. oryzae suspension culture by liquid chromatography tandem mass spectrometry (LC/MS/MS). The inhibition of 1, 2, and 3 on P. oryzae mycelial growth were 45%, 19%, and 19%, respectively, at a concentration of 100 μm. Thus, 2 and 3 are detoxified metabolites of 1 by P. oryzae.
Reassigning Sense Codon AGA to Encode Noncanonical Amino Acids in Escherichia coli
Authors: Wang Yiyan , Tsao Meng‐Lin
Published: September 2016

A new method has been developed to reassign the rare codon AGA in Escherichia coli by engineering an orthogonal tRNA/aminoacyl–tRNA synthetase pair derived from Methanocaldococcus jannaschii. The tRNA mutant was introduced with a UCU anticodon, and the synthetase was evolved to correctly recognize the modified tRNA anticodon loop and to selectively charge a target noncanonical amino acid (NAA) onto the tRNA. In order to maximize the efficiency of AGA codon reassignment, while avoiding the lethal effects caused by global codon reassignment in cellular proteins, an inducible promoter (araBAD) was utilized to provide temporal controls for overexpression of the aminoacyl–tRNA synthetase and switch on codon reassignment. Using this system, we were able to efficiently incorporate p‐acetylphenylalanine, O‐methyl‐tyrosine, and p‐iodophenylalanine into proteins in response to AGA codons. Also, we found that E. coli strain GM10 was optimal in achieving the highest AGA reassignment rates. The successful reassignment of AGA codons reported here provides a new avenue to further expand the genetic code.
Facile Synthesis of Sulfur–Polypyrrole as Cathodes for Lithium–Sulfur Batteries
Authors: Xin Peiming , Jin Bo , Li Huan , Lang Xingyou , Yang Chuncheng , Gao Wang , Zhu Yongfu , Zhang Wenqi , Dou Shixue , Jiang Qing
Published: September 2016

To explore the potential application of lithium–sulfur batteries (LSBs) in the emerging electric vehicle market, sulfur–polypyrrole (S‐PPy) is prepared by a facile ball‐milling route, in which polypyrrole is synthesized by using ferric chloride as an oxidant in a self‐degrading template method. Compared with sulfur, S‐PPy possesses a higher discharge capacity, much better cycling stability, and better rate performance. At a current density of 200 mA g−1, the discharge capacity of S‐PPy is maintained at 675 mA h g−1 after 150 cycles, and even at a current density of 1675 mA g−1, the retained discharge capacity is still 617 mA h g−1 after 100 cycles. The retained discharge capacity of pure sulfur, however, is only 150 mA h g−1 after 150 cycles at a current density of 200 mA g−1. These results indicate that S‐PPy, with its facile, low‐cost, and eco‐friendly synthesis, could be a potential cathode material for LSBs.
The Weakness of B−H⋅⋅⋅π Interactions: Much Softer than a Hydrogen Bond
Authors: Grunenberg Jörg
Published: September 2016

Recently, a new type of non‐covalent interaction, the B−H⋅⋅⋅π interaction, was introduced. Nevertheless, the unique determination of individual, non‐covalent bond strengths in complex molecular systems is a non‐trivial task with often controversial results. The utilization of generalized compliance constants (relaxed force constants) is proposed as unique bond‐strength descriptors for classical and non‐classical hydrogen bonds. The strength of recently proposed B−H⋅⋅⋅π bonds is discussed.
Immunotherapy for prostate cancer: False promises or true hope?
Authors: Rekoske Brian T. , McNeel Douglas G.
Published: September 2016

Prostate cancer is the most commonly diagnosed cancer, and the second leading cause of cancer‐related death for men in the United States. Despite the approval of several new agents for advanced disease, each of these has prolonged survival by only a few months. Consequently, new therapies are sorely needed. For other cancer types, immunotherapy has demonstrated dramatic and durable treatment responses, causing many to hope that immunotherapies might provide an ideal treatment approach for patients with advanced prostate cancer. However, apart from sipuleucel‐T, prostate cancer has been conspicuously absent from the list of malignancies for which immunotherapies have received recent approval from the US Food and Drug Administration. This has left some wondering whether immunotherapy will “work” for this disease. In this review, the authors describe current developments in immunotherapy, including approaches to engage tumor‐targeting T cells, disrupt immune regulation, and alter the immunosuppressive tumor microenvironment. The authors then describe the recent application of these approaches to the treatment of prostate cancer. Given the Food and Drug Administration approval of 1 agent, and the finding that several others are in advanced stages of clinical testing, the authors believe that immunotherapies offer real hope to improve patient outcomes for men with prostate cancer, especially as investigators begin to explore rational combinations of immunotherapies and combine these therapies with other conventional therapies. Cancer 2016;122:3598‐607. © 2016 American Cancer Society.
Relation of comorbidities and patient navigation with the time to diagnostic resolution after abnormal cancer screening
Authors: Whitley Elizabeth M. , Raich Peter C. , Dudley Donald J. , Freund Karen M. , Paskett Electra D. , Patierno Steven R. , Simon Melissa , Warren‐Mears Victoria , Snyder Frederick R. ,   for the Patient Navigation Research Program Investigators
Published: September 2016

BACKGROUND

Whether patient navigation improves outcomes for patients with comorbidities is unknown. The aims of this study were to determine the effect of comorbidities on the time to diagnostic resolution after an abnormal cancer screening test and to examine whether patient navigation improves the timeliness and likelihood of diagnostic resolution for patients with comorbidities in comparison with no navigation.

METHODS

A secondary analysis of comorbidity data collected by Patient Navigation Research Program sites using the Charlson Comorbidity Index (CCI) was conducted. The participants were 6,349 patients with abnormal breast, cervical, colon, or prostate cancer screening tests between 2007 and 2011. The intervention was patient navigation or usual care. The CCI data were highly skewed across projects and cancer sites, and the CCI scores were categorized as 0 (CCI score of 0 or no comorbidities identified; 76% of cases); 1 (CCI score of 1; 16% of cases), or 2 (CCI score ≥ 2; 8% of cases). Separate adjusted hazard ratios for each site and cancer type were obtained, and then they were pooled with a meta‐analysis random effects methodology.

RESULTS

Patients with a CCI score ≥ 2 had delayed diagnostic resolution after an abnormal cancer screening test in comparison with those with no comorbidities. Patient navigation reduced delays in diagnostic resolution, with the greatest benefits seen for those with a CCI score ≥ 2.

CONCLUSIONS

Persons with a CCI score ≥ 2 experienced significant delays in timely diagnostic care in comparison with patients without comorbidities. Patient navigation was effective in reducing delays in diagnostic resolution among those with CCI scores > 1. Cancer 2017;123:312–318. © 2016 American Cancer Society.
Whole‐exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene
Authors: Silvestri Valentina , Zelli Veronica , Valentini Virginia , Rizzolo Piera , Navazio Anna Sara , Coppa Anna , Agata Simona , Oliani Cristina , Barana Daniela , Castrignanò Tiziana , Viel Alessandra , Russo Antonio , Tibiletti Maria Grazia , Zanna Ines , Masala Giovanna , Cortesi Laura , Manoukian Siranoush , Azzollini Jacopo , Peissel Bernard , Bonanni Bernardo , Peterlongo Paolo , Radice Paolo , Palli Domenico , Giannini Giuseppe , Chillemi Giovanni , Montagna Marco , Ottini Laura
Published: September 2016

BACKGROUND

Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole‐exome sequencing (WES) and targeted gene sequencing were applied to high‐risk, BRCA1/2 mutation–negative MBC cases.

METHODS

Germ‐line DNA of 1 male and 2 female BRCA1/2 mutation–negative breast cancer (BC) cases from a pedigree showing a first‐degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high‐risk, BRCA1/2 mutation–negative MBC cases from an Italian multicenter study of MBC. A case‐control series of 433 BRCA1/2 mutation–negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study.

RESULTS

WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N‐acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation–negative MBC cases. NAT1 c.97C>T was not found in the case‐control series.

CONCLUSIONS

These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation–negative families with multiple MBC and FBC cases. Cancer 2017;123:210–218. © 2016 American Cancer Society.
Next‐generation sequencing adds value to the preoperative diagnosis of pancreatic cysts
Authors: Rosenbaum Matthew W. , Jones Martin , Dudley Jonathan C. , Le Long P. , Iafrate A. John , Pitman Martha B.
Published: September 2016

BACKGROUND

The diagnosis of a pancreatic cyst as mucinous or high‐risk dictates the need for follow‐up or surgery. Molecular analysis of aspirated pancreatic cyst fluid (PCF) can provide valuable information not obtained by carcinoembryonic antigen (CEA) analysis or cytology.

METHODS

All patients who underwent molecular analysis of PCF between March 2013 and June 2015 were reviewed, including pathology, imaging, and follow‐up. Molecular testing was performed using a patented, anchored multiplex polymerase chain reaction next‐generation sequencing (NGS) platform, which sequenced numerous hotspots in 39 genes linked with malignancy. Performance of NGS and cytology was calculated using final outcome, as determined by clinicopathologic follow‐up.

RESULTS

The study cohort included 113 PCFs from 105 patients. In total, 119 variants were detected in 67 PCFs (59%). Variants were more common in intraductal papillary mucinous neoplasms (IPMNs)/cancer than in nonmucinous cysts (P < .005). The inclusion of v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)/guanine nucleotide‐binding protein (GNAS) variants improved the classification of IPMNs as mucinous from 50% by microscopy to 100%. Seventy‐five percent of cancers had high‐grade atypia versus 0% of IPMNs and nonmucinous cysts (P < .002). Variants in tumor protein 53 (TP53), SMAD family member 4 (SMAD4), cyclin‐dependent kinase inhibitor 2A (CDKN2A), and notch1 (NOTCH1) were detected only in malignant cysts. Cytology was similarly specific (100%) for detecting malignant cysts but was more sensitive than the identification of late mutations by NGS (75% vs 46%).

CONCLUSIONS

The detection of KRAS/GNAS variants improves the identification of mucinous neoplasms. Variants in TP53, SMAD4, CDKN2A, and NOTCH1 support the diagnosis of a high‐risk cyst requiring surgery or additional sampling. Although molecular analysis is not a replacement for cytopathology, it does provide valuable information for accurate preoperative diagnosis, helping to classify mucinous neoplasms and high‐risk cysts that require surgical resection. Cancer Cytopathol 2017;125:41‐47. © 2016 American Cancer Society.
Shear Flows of an Ideal Fluid and Elliptic Equations in Unbounded Domains
Authors: Hamel François , Nadirashvili Nikolai
Published: September 2016

We prove that, in a two‐dimensional strip, a steady flow of an ideal incompressible fluid with no stationary point and tangential boundary conditions is a shear flow. The same conclusion holds for a bounded steady flow in a half‐plane. The proofs are based on the study of the geometric properties of the streamlines of the flow and on one‐dimensional symmetry results for solutions of some semilinear elliptic equations. Some related rigidity results of independent interest are also shown in n‐dimensional slabs in any dimension n.© 2016 Wiley Periodicals, Inc.
Clopidogrel pharmacogenetics: Beyond candidate genes and genome‐wide association studies
Authors: Lewis JP , Shuldiner AR
Published: September 2016

While it is well established that genetic variation is a significant contributor to interindividual variability in clopidogrel efficacy, candidate gene and genome‐wide approaches have failed to reproducibly identify genetic determinants of antiplatelet response, apart from variants in CYP2C19, prompting the need for more innovative study designs. Herein, we highlight the potential benefit of exome sequencing of patients at the extremes of clopidogrel responsivity through examination of data reported in this issue of Clinical Pharmacology & Therapeutics.
0.3‐V bulk‐driven programmable gain amplifier in 0.18‐µm CMOS
Authors: Kulej Tomasz , Khateb Fabian
Published: September 2016

A new solution for an ultra low voltage bulk‐driven programmable gain amplifier (PGA) is described in the paper. While implemented in a standard n‐well 0.18‐µm complementary metal–oxide–semiconductor (CMOS) process, the circuit operates from 0.3 V supply, and its voltage gain can be regulated from 0 to 18 dB with 6‐dB steps. At minimum gain, the PGA offers nearly rail‐to‐rail input/output swing and the input referred thermal noise of 2.37 μV/Hz1/2, which results in a 63‐dB dynamic range (DR). Besides, the total power consumption is 96 nW, the signal bandwidth is 2.95 kHz at 5‐pF load capacitance and the third‐order input intercept point (IIP3) is 1.62 V. The circuit performance was simulated with LTspice. Copyright © 2016 John Wiley & Sons, Ltd.
Testing for the erythropoiesis‐stimulating agent Sotatercept/ACE‐011 (ActRIIA‐Fc) in serum by means of Western blotting and LC‐HRMS
Authors: Walpurgis Katja , Thomas Andreas , Vogel Matthias , Reichel Christian , Geyer Hans , Schänzer Wilhelm , Thevis Mario
Published: September 2016

Sotatercept (formerly ACE‐011) is a glycosylated, dimeric fusion protein composed of the extracellular domain of the human activin receptor type IIA (ActRIIA) and the Fc region of human IgG1. The protein‐based drug candidate acts as a ligand trap which competitively binds to activin A and other members of the transforming growth factor beta superfamily, thus blocking signalling through ActRIIA. Since the inhibition of activin A was found to significantly increase bone formation and quality, Sotatercept was originally developed for the treatment of diseases involving bone loss. But as the protein therapeutic also stimulates erythropoiesis by a mechanism independent of the EPO receptor, it has been evaluated for the treatment of anaemia in rare blood diseases such as beta thalassemia. Due to its positive effects on erythropoiesis and bone formation, Sotatercept may also be misused as performance‐enhancing agent in sports. Within this study, two complementary detection assays for Sotatercept and related ActRIIA‐Fc fusion proteins in serum samples were developed. While the first assay combines affinity purification and Western blotting to generically detect ActRIIA‐Fc fusion proteins irrespective of their amino acid sequence, the liquid chromatography‐high resolution mass spectrometry (LC‐HRMS) method is highly specific for proteolytic peptides originating from the receptor and Fc domain of Sotatercept. Both approaches can readily be modified to include other pharmaceutical proteins such as therapeutic antibodies, and serve as proof‐of‐concept for the capability of the approach to detect TGF‐β inhibitors and Fc fusion proteins in doping control serum samples. Copyright © 2016 John Wiley & Sons, Ltd.
Catalyst recycling in the hydroaminomethylation of methyl oleate: A route to novel polyamide monomers
Authors: Vorholt Andreas J. , Immohr Sarah , Ostrowski Karoline A. , Fuchs Sarah , Behr Arno
Published: September 2016

This article describes the development of an effective thermomorphic multicomponent solvent (TMS) system for the production of branched polyamide monomers. In this system, methyl oleate, a renewable from fats and oils, and a functionalized amine are used as starting materials in a tandem catalytic reaction, which merges different reaction steps into a single preparative step. This particular TMS system consisted of a heptane/acetonitrile solvent mixture and made reusing the precious rhodium catalyst possible in three recycle runs. A constant yield of 61–65% was obtained for each run due to low‐catalyst leaching. Fortunately, the catalyst system does not require any additional phosphorous ligands and allows high yields. A scale‐up for the production of 10–11 g of the desired product in each run was realized. Subsequent hydrogenation of the product directly provided an amine ester, which is a valuable polyamide monomer.

Practical applications: A method was developed to enable access to primary amines via hydroaminomethylation and hydrogenation. The product, a nitrile ester, is a valuable intermediate for polyamide monomers. This nitrile ester was successfully hydrogenated to an amine ester, which features a potential polyamide monomer directly. A catalyst recycle of the homogeneous rhodium complex within the hydroaminomethylation of methyl oleate and an amino nitrile was successfully carried out, enabling constant homogeneous catalyst activity over the course of three recycle runs. A scale‐up to obtain 10–11 g of the hydroaminomethylation product was realized.

A general method is described for the conversion of methyl oleate within a hydroaminomethylation reaction. The catalyst can be recovered and reused. Valuable polyamide intermediates were obtained.
Investigation of the sensitivity of turbulent closures and coupling of hybrid RANS‐LES models for predicting flow fields with separation and reattachment
Authors: Kumar G. , Lakshmanan S. K. , Gopalan H. , De A.
Published: September 2016

Hybrid models have found widespread applications for simulation of wall‐bounded flows at high Reynolds numbers. Typically, these models employ Reynolds‐averaged Navier–Stokes (RANS) and large eddy simulation (LES) in the near‐body and off‐body regions, respectively. A number of coupling strategies between the RANS and LES regions have been proposed, tested, and applied in the literature with varying degree of success. Linear eddy‐viscosity models (LEVM) are often used for the closure of turbulent stress tensor in RANS and LES regions. LEVM incorrectly predicts the anisotropy of Reynolds normal stress at the RANS‐LES interface region. To overcome this issue, use of non‐linear eddy‐viscosity models (NLEVM) have started receiving attention. In this study, a generic non‐linear blended modeling framework for performing hybrid simulations is proposed. Flow over the periodic hills is used as the test case for model evaluation. This case is chosen due to complex flow physics with simplified geometry. Analysis of the simulations suggests that the non‐linear hybrid models show a better performance than linear hybrid models. It is also observed that the non‐linear closures are less sensitive to the RANS‐LES coupling and grid resolution. Copyright © 2016 John Wiley & Sons, Ltd.
LA‐ICP‐MS U–Pb geochronology of zircons from granitoids and modern river sands in Guyang, North China Craton and their tectonic significance
Authors: Liu C. , Zeng F. G. , Sun B. L. , Li P. P.
Published: September 2016

The Palaeo‐Asian Ocean (PAO) was located between Siberia and the North China Craton (NCC). The time of its closure, as well as the crustal architecture of the surrounding region, are still uncertain. In this paper, we address these problems using LA‐ICP‐MS U‐Pb ages of zircon grains in three magmatic rocks and three river sand samples of the Guyang area at the northern margin of the NCC. The magmatic rocks yield early Carboniferous crystallization ages of 340.3 ± 7.5 Ma, 331.7 ± 2.3 Ma and 341.1 ± 1.9 Ma for the main granitic pluton, a granodiorite dyke and a diorite enclave, respectively. They were the product of subduction of the PAO underneath the NCC. The detrital zircon U‐Pb ages in the river sand samples are dominated by two groups at 2550–2400 and 290–260 Ma, with subordinate groups at 2700–2600, 2000–1800 and 320–300 Ma, dispersed Early Palaeoproterozoic grains and a minor but important group of Cretaceous grains in sands of the Aibugai River. These results, combined with previous geochronological data, permit a re‐assessment of the tectonic evolution of the northern margin of the NCC. The events at ~2.5 Ga reflect major crustal reworking and cratonization of the northern margin of the NCC, which then became a stable platform lasting until the Carboniferous. The period between 2.0 and 1.8 Ga was characterized by major collisions related to formation of the Khondalite Belt and the Trans‐North China Orogen. In the Carboniferous, subduction of the PAO underneath the northern margin of the NCC developed a zoned distribution of magmatic rocks. The PAO is now constrained to have closed in the Early Permian by the collision of the NCC and Siberia. The youngest group of Cretaceous zircons reflects magmatic events related to lithosphere thinning beneath the Eastern Block of the NCC. Copyright © 2016 John Wiley & Sons, Ltd.
Gray matter regions statistically mediating the cross‐sectional association of eotaxin and set‐shifting among older adults with major depressive disorder
Authors: Smagula Stephen F. , Karim Helmet T. , Lenze Eric J. , Butters Meryl A. , Wu Gregory F. , Mulsant Benoit H. , Reynolds Charles F. , Aizenstein Howard J.
Published: September 2016

Objective

Eotaxin is a chemokine that exerts negative effects on neurogenesis. We recently showed that peripheral eotaxin levels correlate with both lower gray matter volume and poorer executive performance in older adults with major depressive disorder. These findings suggest that the relationship between eotaxin and set‐shifting may be accounted for by lower gray matter volume in specific regions. Prior studies have identified specific gray matter regions that correlate with set‐shifting performance, but have not examined whether these specific gray matter regions mediate the cross‐sectional association between eotaxin and set‐shifting.

Method

In 27 older adults (mean age: 68 ± 5.2 years) with major depressive disorder, we performed a whole brain (voxel‐wise) analysis testing whether/where gray matter density statistically mediates the cross‐sectional association of eotaxin and set‐shifting performance.

Results

We found the association between eotaxin and set‐shifting performance was fully statistically mediated by lower gray matter density in left middle cingulate, right pre‐/post‐central, lingual, inferior/superior frontal, cuneus, and middle temporal regions.

Conclusion

The regions identified above may be both susceptible to a potential neurodegenerative effect of eotaxin, and critical to preserving set‐shifting function. Longitudinal and intervention studies are needed to further evaluate whether targeting eotaxin levels will prevent neurodegeneration and executive impairment in older adults with depression. Copyright © 2016 John Wiley & Sons, Ltd.
Separate spatial and temporal frequency tuning to visual motion in human MT+ measured with ECoG
Authors: Gaglianese Anna , Harvey Ben M. , Vansteensel Mariska J. , Dumoulin Serge O. , Ramsey Nick F. , Petridou Natalia
Published: September 2016

The human middle temporal complex (hMT+) has a crucial biological relevance for the processing and detection of direction and speed of motion in visual stimuli. Here, we characterized how neuronal populations in hMT+ encode the speed of moving visual stimuli. We evaluated human intracranial electrocorticography (ECoG) responses elicited by square‐wave dartboard moving stimuli with different spatial and temporal frequency to investigate whether hMT+ neuronal populations encode the stimulus speed directly, or whether they separate motion into its spatial and temporal components. We extracted two components from the ECoG responses: (1) the power in the high‐frequency band (HFB: 65–95 Hz) as a measure of the neuronal population spiking activity and (2) a specific spectral component that followed the frequency of the stimulus's contrast reversals (SCR responses). Our results revealed that HFB neuronal population responses to visual motion stimuli exhibit distinct and independent selectivity for spatial and temporal frequencies of the visual stimuli rather than direct speed tuning. The SCR responses did not encode the speed or the spatiotemporal frequency of the visual stimuli. We conclude that the neuronal populations measured in hMT+ are not directly tuned to stimulus speed, but instead encode speed through separate and independent spatial and temporal frequency tuning. Hum Brain Mapp 38:293–307, 2017. © 2016 Wiley Periodicals, Inc.
Subcortical roles in lexical task processing: Inferences from thalamic and subthalamic event‐related potentials
Authors: Tiedt Hannes O. , Ehlen Felicitas , Krugel Lea K. , Horn Andreas , Kühn Andrea A. , Klostermann Fabian
Published: September 2016

Subcortical functions for language capacities are poorly defined, but may be investigated in the context of deep brain stimulation. Here, we studied event‐related potentials recorded from electrodes in the subthalamic nucleus (STN) and the thalamic ventral intermediate nucleus (VIM) together with surface‐EEG. Participants completed a lexical decision task (LDT), which required the differentiation of acoustically presented words from pseudo‐words by button press. Target stimuli were preceded by prime‐words. In recordings from VIM, a slow potential shift apparent at the lower electrode contacts persisted during target stimulus presentation (equally for words and pseudo‐words). In contrast, recordings from STN electrodes showed a short local activation on prime‐words but not target‐stimuli. In both depth‐recording regions, further components related to contralateral motor responses to target words were evident. On scalp level, mid‐central activations on (pseudo)lexical stimuli were obtained, in line with the expression of N400 potentials. The prolonged activity recorded from VIM, exclusively accompanying the relevant LDT phase, is in line with the idea of thalamic “selective engagement” for supporting the realization of the behavioral focus demanded by the task. In contrast, the phasic prime related activity rather indicates “procedural” STN functions, for example, for trial sequencing or readiness inhibition of prepared target reactions. Hum Brain Mapp 38:370–383, 2017. © 2016 Wiley Periodicals, Inc.
Creative females have larger white matter structures: Evidence from a large sample study
Authors: Takeuchi Hikaru , Taki Yasuyuki , Nouchi Rui , Yokoyama Ryoichi , Kotozaki Yuka , Nakagawa Seishu , Sekiguchi Atsushi , Iizuka Kunio , Yamamoto Yuki , Hanawa Sugiko , Araki Tsuyoshi , Makoto Miyauchi Carlos , Shinada Takamitsu , Sakaki Kohei , Sassa Yuko , Nozawa Takayuki , Ikeda Shigeyuki , Yokota Susumu , Daniele Magistro , Kawashima Ryuta
Published: September 2016

The importance of brain connectivity for creativity has been theoretically suggested and empirically demonstrated. Studies have shown sex differences in creativity measured by divergent thinking (CMDT) as well as sex differences in the structural correlates of CMDT. However, the relationships between regional white matter volume (rWMV) and CMDT and associated sex differences have never been directly investigated. In addition, structural studies have shown poor replicability and inaccuracy of multiple comparisons over the whole brain. To address these issues, we used the data from a large sample of healthy young adults (776 males and 560 females; mean age: 20.8 years, SD = 0.8). We investigated the relationship between CMDT and WMV using the newest version of voxel‐based morphometry (VBM). We corrected for multiple comparisons over whole brain using the permutation‐based method, which is known to be quite accurate and robust. Significant positive correlations between rWMV and CMDT scores were observed in widespread areas below the neocortex specifically in females. These associations with CMDT were not observed in analyses of fractional anisotropy using diffusion tensor imaging. Using rigorous methods, our findings further supported the importance of brain connectivity for creativity as well as its female‐specific association. Hum Brain Mapp 38:414–430, 2017. © 2016 Wiley Periodicals, Inc.
Proteasome inhibitors in AL amyloidosis: focus on mechanism of action and clinical activity
Authors: Jelinek T. , Kryukova E. , Kufova Z. , Kryukov F. , Hajek R.
Published: September 2016

Proteasome inhibitors are the backbone in the treatment of multiple myeloma with 3 of its representatives (bortezomib, carfilzomib, and ixazomib) having already been approved. There is a different situation altogether in the treatment of amyloid light chain (AL) amyloidosis where owing to the rarity of this entity neither of these drugs has currently gained approval. Amyloid light chain plasma cells are possibly more vulnerable to bortezomib than myeloma plasmocytes because of a slightly distinct mechanism of action, which is described in depth in this manuscript. Bortezomib is highly active and rapidly effective as a single agent and even more potent in combination with dexamethasone and alkylators. Bortezomib‐based regimens have become a standard part of the initial treatment of AL amyloidosis in the majority of centers. We have reviewed all available data on bortezomib in various combinations and settings. Carfilzomib seems to be effective but also toxic in these fragile patients with a high rate of cardiac events. Oral ixazomib has shown a surprisingly high efficacy with manageable toxicity and has received the Food and Drug Administration Breakthrough Therapy designation in 2014 for relapsed AL amyloidosis patients. In this review we have comprehensively described the current available knowledge of these 3 proteasome inhibitors and their use in AL amyloidosis.
Water isotopic variability in Mallorca: a path to understanding past changes in hydroclimate
Authors: Dumitru Oana A. , Forray Ferenc L. , Fornós Joan J. , Ersek Vasile , Onac Bogdan P.
Published: September 2016

This paper reports the first results on δ18O and δ2H analysis of precipitations, cave drip waters, and groundwaters from sites in Mallorca (Balearic Islands, western Mediterranean), a key region for paleoclimate studies. Understanding the isotopic variability and the sources of moisture in modern climate systems is required to develop speleothem isotope‐based climate reconstructions. The stable isotopic composition of precipitation was analysed in samples collected between March 2012 and March 2013. The values are in the range reported by GNIP Palma station. Based on these results, the local meteoric water line (LMWL) δ2H = 7.9 (±0.3) δ18O + 10.8 (±2.5) was derived, with slightly lower slope than Global Meteoric Water Line. The results help tracking two main sources of air masses affecting the study sites: rain events with the highest δ18O values (> −5‰) originate over the Mediterranean Sea, whereas the more depleted samples (< −8‰) are sourced in the North Atlantic region. The back trajectory analysis and deuterium excess values, ranging from 0.4 to 18.4‰, further support our findings. To assess the isotopic variation across the island, water samples from eight caves were collected. The δ18O values range between −6.9 and −1.6‰. With one exception (Artà), the isotopic composition of waters in caves located along the coast (Drac, Vallgornera, Cala Varques, Tancada, and Son Sant Martí) indicates Mediterranean‐sourced moisture masses. By contrast, the drip water δ18O values for inland caves (Campanet, ses Rates Pinyades) or developed under a thick (>50 m) limestone cap (Artà) exhibit more negative values. A well‐homogenized aquifer supplied by rainwaters of both origins is clearly indicated by groundwater δ18O values, which show to be within 2.4‰ of the unweighted arithmetic mean of −7.4‰. Although limited, the isotopic data presented here constitute the baseline for future studies using speleothem δ18O records for western Mediterranean paleoclimate reconstructions. Copyright © 2016 John Wiley & Sons, Ltd.
Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in TP53‐driven non‐small cell lung cancer
Authors: Zhang Le‐Le , Kan Mengyuan , Zhang Man‐Man , Yu Sha‐Sha , Xie Hui‐Jun , Gu Zhao‐Hui , Wang Hai‐Ning , Zhao Shuang‐Xia , Zhou Guang‐Biao , Song Huai‐Dong , Zheng Cui‐Xia
Published: September 2016

Intratumor heterogeneity (ITH) in non‐small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The recognition of ITH helps identify high‐risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12‐paired normal‐tumor tissues were subjected to whole‐genome/whole‐exome sequencing. From these, 367 non‐silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non‐mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. In addition, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments.
Mutant formC115HofClostridium sporogenesmethionine γ‐lyase efficiently cleavesS‐Alk(en)yl‐l‐cysteine sulfoxides to antibacterial thiosulfinates
Authors: Kulikova Vitalia V. , Anufrieva Natalya V. , Revtovich Svetlana V. , Chernov Alexander S. , Telegin Georgii B. , Morozova Elena A. , Demidkina Tatyana V.
Published: September 2016

Pyridoxal 5'‐phosphate‐dependent methionine γ‐lyase (MGL) catalyzes the β‐elimination reaction of S‐alk(en)yl‐l‐cysteine sulfoxides to thiosulfinates, which possess antimicrobial activity. Partial inactivation of the enzyme in the course of the reaction occurs due to oxidation of active site cysteine 115 conserved in bacterial MGLs. In this work, the C115H mutant form ofClostridium sporogenesMGL was prepared and the steady‐state kinetic parameters of the enzyme were determined. The substitution results in an increase in the catalytic efficiency of the mutant form towards S‐substitutedl‐cysteine sulfoxides compared to the wild type enzyme. We used a sulfoxide/enzyme system to generate antibacterial activityin situ. Two‐component systems composed of the mutant enzyme and three S‐substitutedl‐cysteine sulfoxides were demonstrated to be effective against Gram‐positive and Gram‐negative bacteria and three clinical isolates from mice. © 2016 IUBMB Life, 68(10):830–835, 2016
Accelerated skin wound healing using electrospun nanofibrous mats blended with mussel adhesive protein and polycaprolactone
Authors: Kim Bum Jin , Cheong Hogyun , Choi Eun‐Som , Yun So‐Hee , Choi Bong‐Hyuk , Park Ki‐Soo , Kim Ick Soo , Park Dae‐Hwan , Cha Hyung Joon
Published: September 2016

Nanofibrous scaffolds have been assessed as one of many promising tissue engineering scaffolds to be utilized for wound‐healing applications. Previously, we reported multi‐functionalized electrospun nanofibrous scaffolds blended with mussel adhesive protein (MAP) and polycaprolactone (PCL), which provide durable mechanical strength, cell‐friendly environments, and a substantial ability to capture diverse bioactive molecules without any surface modifications. In the present work, we applied the blended nanofibrous mats of MAP and PCL for in vivo skin wound healing. The nanofibrous mats showed accelerated regeneration in a rat skin wound‐healing model, which might be attributed to a highly compatible environment for keratinocyte cell growth, an ability to capture inherent growth factors, and an efficient exudate absorption capacity. Thus, this work would suggest that adhesive property of scaffold could be a factor of successful application for wound healing. The MAP‐blended nanofibers could also be potentially exploited for diverse tissue regeneration applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 218–225, 2017.
Effect of amine content and chemistry on long‐term, three‐dimensional hepatocyte spheroid culture atop aminated elastin‐like polypeptide coatings
Authors: Weeks C. Andrew , Aden Bethany , Zhang Junlin , Singh Anisha , Hickey Raymond D. , Kilbey S. Michael , Nyberg Scott L. , Janorkar Amol V.
Published: September 2016

Culture conditions that induce hepatic spheroidal aggregates sustain liver cells with metabolism that mimics in vivo hepatocytes. Here we present an array of elastin‐like polypeptide conjugate coating materials (Aminated‐ELPs) that are biocompatible, have spheroid‐forming capacity, can be coated atop traditional culture surfaces, and maintain structural integrity while ensuring adherence of spheroids over long culture period. The Aminated‐ELPs were synthesized either by direct conjugation of ELP and various polyelectrolytes or by conjugating both ELP and various small electrolytes to the reactive polymer poly(2‐vinyl‐4,4‐dimethyl azlactone) (PVDMA). Spheroid morphology, cellular metabolic function, and liver‐specific gene expression over the long‐term, 20‐day culture period were assessed through optical microscopy, measurement of total protein content and albumin and urea production, and quantitative real‐time (qRT) PCR. We found that the amine content of the Aminated‐ELP coatings dictated the initial hepatocyte attachment, but not the subsequent hepatocyte spheroid formation and their continued attachment. A lower amine content was generally found to sustain higher albumin production by the spheroids. Out of the 19 Aminated‐ELP coatings tested, we found that the lysine‐containing substrates comprising ELP‐polylysine or ELP‐PVDMA‐butanediamine proved to consistently culture productive spheroidal hepatocytes. We suggest that the incorporation of lysine functional groups in Aminated‐ELP rendered more biocompatible surfaces, increasing spheroid attachment and leading to increased liver‐specific function. Taken together, the Aminated‐ELP array presented here has the potential to create in vitro hepatocyte culture models that mimic in vivo liver functionality and thus, lead to better understanding of liver pathophysiology and superior screening methods for drug efficacy and toxicity. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 377–388, 2017.
Outcome of Long-Term Bisphosphonate Therapy in McCune-Albright Syndrome and Polyostotic Fibrous Dysplasia
Authors: Majoor Bas CJ , Appelman-Dijkstra Natasha M , Fiocco Martha , van de Sande Michiel AJ , Dijkstra PD Sander , Hamdy Neveen AT
Published: September 2016

McCune-Albright syndrome (MAS) is a rare bone disorder characterized by fibrous dysplasia (FD), endocrinopathies, and café-au-lait patches. FD patients have been shown to respond favorably to treatment with bisphosphonates, but data are scarce in the more severe polyostotic form (PFD), including MAS, and factors determining treatment outcome are not known, particularly in the long-term. We evaluated the biochemical (bone turnover markers [BTMs]) and clinical (pain reduction) outcome of bisphosphonate therapy in 11 patients with MAS and 30 patients with PFD: median duration of treatment 6 years (range, 2 to 25 years). Prognostic factors for treatment outcome were identified in both groups. Patients with MAS were younger at diagnosis (p = 0.001), all had precocious puberty, and four (36%) had additional growth hormone (GH) excess associated with severe craniofacial FD. Extent of skeletal disease was more severe in MAS compared to PFD. MAS patients had higher serum alkaline phosphatase (ALP) concentrations (p = 0.005), higher skeletal burden scores (p < 0.001), and more fractures (p = 0.021). MAS patients had also higher levels of FGF-23 (p = 0.008) and higher prevalence of hypophosphatemia (p = 0.013). Twenty-four of 30 PFD patients (80%) demonstrated a complete clinical and biochemical response within a year of starting treatment (p = 0.015), compared to only four of 11 MAS patients (36%). There were no nonresponders. In the whole group, FGF-23, total ALP, P1NP, and CTX positively correlated with skeletal burden scores (all p ≤ 0.001), which was the only significant risk factor for an incomplete response to bisphosphonate therapy (p < 0.01). Our data suggest a beneficial and safe outcome of long-term bisphosphonate therapy in the majority of patients with PFD, although response to therapy was limited by the higher skeletal disease burden in MAS patients. In the PFD/MAS population studied, the only identified prognostic factor that influenced the outcome of bisphosphonate therapy was a high skeletal burden score. © 2016 American Society for Bone and Mineral Research.
Sylow Theory for Quasigroups II: Sectional Action
Authors: Kinyon Michael K. , Smith Jonathan D. H. , Vojtěchovský Petr
Published: September 2016

The first paper in this series initiated a study of Sylow theory for quasigroups and Latin squares based on orbits of the left multiplication group. The current paper is based on so‐called pseudo‐orbits, which are formed by the images of a subset under the set of left translations. The two approaches agree for groups, but differ in the general case. Subsets are described as sectional if the pseudo‐orbit that they generate actually partitions the quasigroup. Sectional subsets are especially well behaved in the newly identified class of conflatable quasigroups, which provides a unified treatment of Moufang, Bol, and conjugacy closure properties. Relationships between sectional and Lagrangean properties of subquasigroups are established. Structural implications of sectional properties in loops are investigated, and divisors of the order of a finite quasigroup are classified according to the behavior of sectional subsets and pseudo‐orbits. An upper bound is given on the size of a pseudo‐orbit. Various interactions of the Sylow theory with design theory are discussed. In particular, it is shown how Sylow theory yields readily computable isomorphism invariants with the resolving power to distinguish each of the 80 Steiner triple systems of order 15.
Associations among Serum Beta 2 Microglobulin, Malnutrition, Inflammation, and Advanced Cardiovascular Event in Patients with Chronic Kidney Disease
Authors: Wu Hung‐Chieh , Lee Lin‐Chien , Wang Wei‐Jie
Published: September 2016

Objectives: This study examines the associations among serum β2 microglobulin (B2M), malnutrition, inflammation, and atherosclerosis (MIA) in those with chronic kidney disease (CKD). Methods: CKD patients who were followed in Taoyuan General Hospital from 2009 to 2015 were enrolled. Demographic and biochemical data, including B2M and C‐reactive protein (CRP) were reviewed. The participants were stratified according to B2M tertiles. Adjusted hazard ratios (AHRs) and cumulative survival curves for death and MIA syndrome were evaluated by Cox hazard model and Kaplan–Meier method. We also calculated the area under the curve for the receiver operating characteristic curve (AUROC). Results: From a total of 312 CKD patients, mean follow‐up time was 39.7 months. Compared to those with lowest tertile of B2M, the highest tertile group had lower serum albumin, hemoglobin, and estimated glomerular filtration rate. After multivariate adjustment, the associations among tertiles of B2M, death or dialysis, cardiovascular events (CVEs), and MIA syndrome remained significant. The AHRs for the highest tertile group in death or dialysis, CVEs, and MIA syndrome were 25.91 and 65.84 and 152.50(all Ps <0.05).The AUROC for B2M in death or dialysis, CVEs, and MIA syndrome were greater than that for creatinine. The best cut‐off value of B2M for predicting death or dialysis, CVEs, and MIA syndrome were 5.39 mg/dL(sensitivity: 67.1%, specificity 62.5%), 4.21 mg/dL(sensitivity: 85.1%, specificity 52.1%), and 5.40 mg/dL(sensitivity: 79.7%, specificity 64.1%). Conclusions: In those with CKD, serum B2M was more sensitive than creatinine in predicting CVEs and MIA syndrome.