bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics, metabolism and safety of deuterated L‐DOPA (SD‐1077)/carbidopa compared to L‐DOPA/carbidopa following single oral dose administration in healthy subjects
Authors: Schneider Frank , Erisson Lavi , Beygi Hooman , Bradbury Margaret , Cohen‐Barak Orit , Grachev Igor D. , Guzy Serge , Loupe Pippa S. , Levi Micha , McDonald Mirna , Savola Juha‐Matti , Papapetropoulos Spyros , Tracewell William G. , Velinova Maria , Spiegelstein Ofer
Published: June 2018

Aims

SD‐1077, a selectively deuterated precursor of dopamine (DA) structurally related to L‐3,4‐dihydroxyphenylalanine (L‐DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD‐1077.

Methods

Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD‐1077 dose were compared to 150 mg L‐DOPA, each in combination with 37.5 mg carbidopa (CD) in a double‐blind, two‐period, crossover study in healthy volunteers (n = 16).

Results

Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD‐1077 vs. L‐DOPA for Cmax, AUC0–t, and AUC0–inf were 88.4 (75.9–103.1), 89.5 (84.1–95.3), and 89.6 (84.2–95.4), respectively. Systemic exposure to DA was significantly higher after SD‐1077/CD compared to that after L‐DOPA/CD, with GMRs (90% CI) of 1.8 (1.45–2.24; P = 0.0005) and 2.06 (1.68–2.52; P < 0.0001) for Cmax and AUC0–t and a concomitant reduction in the ratio of 3,4‐dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O‐methyltransferase (COMT) reaction, 3‐methoxytyramine (3‐MT) and 3‐O‐methyldopa (3‐OMD) with GMRs (90% CI) for SD‐1077/CD to L‐DOPA/CD for 3‐MT exposure of 1.33 (1.14–1.56; P = 0.0077) and 1.66 (1.42–1.93; P < 0.0001) for Cmax and AUC0–t, respectively and GMRs (90% CI) for 3‐OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for Cmax and AUC0–t. SD‐1077/CD exhibited comparable tolerability and safety to L‐DOPA/CD.

Conclusions

SD‐1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L‐DOPA/CD combination. A single dose of SD‐1077 is safe for further clinical development in Parkinson's disease patients.
Flavin‐Containing Monooxygenase 3 Polymorphic Variants Significantly Affect Clearance of Tamoxifen and Clomiphene
Authors: Catucci Gianluca , Bortolussi Stefania , Rampolla Giulia , Cusumano Debora , Gilardi Gianfranco , Sadeghi Sheila J.
Published: June 2018

Human flavin‐containing monooxygenase 3 (hFMO3) is a drug‐metabolising enzyme that oxygenates many drugs and xenobiotics in the liver. This enzyme is also known to exhibit single nucleotide polymorphisms (SNPs) that can alter the rates of monooxygenation of therapeutic agents. The purpose of this study was to investigate the effect of the three common polymorphic variants of hFMO3 (V257M, E158K and E308G) on the metabolism and clearance of three structurally similar compounds: tamoxifen (breast cancer medication), clomiphene (infertility medication) and GSK5182 (antidiabetic lead molecule). For GSK5182, none of the three variants showed any significant differences in its metabolism when compared to the wild‐type enzyme. In the case of clomiphene, two of the variants, V257M and E308G, exhibited a significant increase in all the kinetic parameters measured with nearly two times faster clearance. Finally, for tamoxifen, a mixed behaviour was observed; E158K variant showed a significantly higher clearance compared to the wild type, whereas V257M mutation had the opposite effect. Overall, the data obtained demonstrate that there is no direct correlation between the SNPs and the metabolism of these three hFMO3 substrates. The metabolic capacity is both variant‐dependent and substrate‐dependent and therefore when testing new drugs or administering already approved therapies, these differences should be taken into consideration.
Urine cytology is a feasible tool for assessing erythematous bladder lesions after bacille Calmette‐Guérin (BCG) treatment
Authors: Nurminen Pertti , Ettala Otto , Seppänen Marjo , Taimen Pekka , Boström Peter J. , Kaipia Antti
Published: June 2018

Objectives

To investigate the need to biopsy erythematous lesions of the bladder after bacille Calmette‐Guérin (BCG) treatment as well as the diagnostic value of voided urine cytology in the detection of recurrence.

Materials and Methods

Data on 206 consecutive patients with non‐muscle‐invasive bladder cancer treated with one or more BCG instillations in the period 2009–2015 at Satakunta Central Hospital and Turku University Hospital were reviewed. Biopsy histology was pooled according to lesion cystoscopy appearance regarding growth pattern and presence of erythema. Voided urine cytology grading before resection was reviewed. We correlated the cystoscopy findings with histology and calculated the sensitivity, specificity, and positive (PPV) and negative predictive value (NPV) for voided urine cytology.

Results

In total, 159 patients with a median follow‐up of 35 months were included in the study. Altogether, 367 biopsies were analysed. In the case of papillary or flat tumours, 76% of biopsies showed malignant histology and the diagnostic value of cytology was very limited (sensitivity 33%, specificity 84%). Erythematous lesions constituted 57% of all biopsy targets, with the majority being either chronic non‐specific inflammation or granulomatous inflammation; 10% of erythematous lesions were malignant at pathological examination. In contrast to papillary and flat tumours, cytology proved to be more accurate in the case of erythematous lesions with a sensitivity, specificity, PPV and NPV of 59%, 76%, 23% and 94%, respectively.

Conclusion

Bladder lesions after BCG instillations pose a challenge during follow‐up and the appropriate management strategy is not clear. Lesions should not be overlooked as being BCG‐induced irritation because they may harbour significant malignancies. The presence of papillary or flat tumour always warrants a biopsy or resection. In the case of erythematous lesions, our results suggest that biopsy may be avoided if voided urine cytology is negative.
Thrombin modifies growth, proliferation and apoptosis of human colon organoids: a protease‐activated receptor 1‐ and protease‐activated receptor 4‐dependent mechanism
Authors: Sébert Morgane , Denadai‐Souza Alexandre , Quaranta Muriel , Racaud‐Sultan Claire , Chabot Sophie , Lluel Philippe , Monjotin Nicolas , Alric Laurent , Portier Guillaume , Kirzin Sylvain , Bonnet Delphine , Ferrand Audrey , Vergnolle Nathalie
Published: June 2018

Background and Purpose

Thrombin is massively released upon tissue damage associated with bleeding or chronic inflammation. The effects of this thrombin on tissue regrowth and repair has been scarcely addressed and only in cancer cell lines. Hence, the purpose of the present study was to determine thrombin's pharmacological effects on human intestinal epithelium growth, proliferation and apoptosis, using three‐dimensional cultures of human colon organoids.

Experimental Approach

Crypts were isolated from human colonic resections and cultured for 6 days, forming human colon organoids. Cultured organoids were exposed to 10 and 50 mU·mL−1 of thrombin, in the presence or not of protease‐activated receptor (PAR) antagonists. Organoid morphology, metabolism, proliferation and apoptosis were followed.

Key Results

Thrombin favoured organoid maturation leading to a decreased number of immature cystic structures and a concomitant increased number of larger structures releasing cell debris and apoptotic cells. The size of budding structures, metabolic activity and proliferation were significantly reduced in organoid cultures exposed to thrombin, while apoptosis was dramatically increased. Both PAR1 and PAR4 antagonists inhibited apoptosis regardless of thrombin doses. Thrombin‐induced inhibition of proliferation and metabolic activity were reversed by PAR4 antagonist for thrombin's lowest dose and by PAR1 antagonist for thrombin's highest dose.

Conclusions and Implications

Overall, our data suggest that the presence of thrombin in the vicinity of human colon epithelial cells favours their maturation at the expense of their regenerative capacities. Our data point to thrombin and its two receptors PAR1 and PAR4 as potential molecular targets for epithelial repair therapies.
Resveratrol ameliorates Lewis lung carcinoma‐bearing mice development, decreases granulocytic myeloid‐derived suppressor cell accumulation and impairs its suppressive ability
Authors: Zhao Yilin , Shao Qi , Zhu Haitao , Xu Haiyuan , Long Wei , Yu Bin , Zhou Lining , Xu Huaxi , Wu Yan , Su Zhaoliang
Published: June 2018

Myeloid‐derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells which consist of 2 subsets: granulocytic MDSC (G‐MDSC) and monocytic MDSC (M‐MDSC). MDSC expand in tumor‐bearing hosts and contribute to immunotherapeutic resistance by remarkably blocking effector T‐cell activation via different mechanisms. Resveratrol (RSV) is a polyphenol and it has been widely used for its various health benefits. However, the underlying mechanism of its anti‐tumor properties remains unclear. In this study, a transplantable mouse model was used to investigate the effects of RSV on MDSC. The results showed that RSV ameliorated tumor development by decreasing G‐MDSC accumulation, impairing its suppressive ability on CD8+T cells and promoting M‐MDSC differentiation into CD11c+ and F4/80+ cells. Our results indicated that RSV should be considered as a modular of MDSC suppressive function and that RSV is a novel booster for tumor immunotherapy.
Phase II study of ceritinib in alectinib‐pretreated patients with anaplastic lymphoma kinase‐rearranged metastatic non‐small‐cell lung cancer in Japan: ASCEND‐9
Authors: Hida Toyoaki , Seto Takashi , Horinouchi Hidehito , Maemondo Makoto , Takeda Masayuki , Hotta Katsuyuki , Hirai Fumihiko , Kim Young Hak , Matsumoto Shingo , Ito Masayuki , Ayukawa Koichi , Tokushige Kota , Yonemura Masataka , Mitsudomi Testuya , Nishio Makoto
Published: June 2018

Clinical experience of ceritinib in patients who progressed on alectinib is limited. In this prospective phase II study, we evaluated the activity of ceritinib in alectinib‐pretreated patients with anaplastic lymphoma kinase (ALK)‐rearranged metastatic (stage IIIB/IV) non‐small‐cell lung cancer (NSCLC) in Japan. All patients were required to have ≥1 measurable lesion per RECIST, 1.1, and a World Health Organization Performance Status (WHO PS) of 0‐1. Prior crizotinib and/or up to 1 chemotherapy regimen was allowed. Primary endpoint was investigator‐assessed overall response rate (ORR) per RECIST 1.1. Ceritinib was given at a dose of 750 mg/day fasted. A total of 20 patients were enrolled from August 2015 to March 2017. All patients received prior alectinib (100%), 13 (65.0%) patients received prior platinum‐based chemotherapy, and 4 (20%) patients received prior crizotinib. Median duration of exposure and the follow‐up time with ceritinib were 3.7 months (range: 0.4‐15.1) and 11.6 months (range: 4.8‐23.0), respectively. Investigator‐assessed ORR was 25% (95% CI: 8.7‐49.1). Key secondary endpoints, all investigator assessed, included disease control rate (70.0%; 95% CI: 45.7‐88.1), time to response (median, 1.8 months; range: 1.8‐2.0), and duration of response (median, 6.3 months; 95% CI: 3.5‐9.2). Median progression‐free survival was 3.7 months (95% CI: 1.9‐5.3). The most common adverse events reported were diarrhea (85.0%), nausea (80.0%), and vomiting (65.0%). Based on our findings, ceritinib could be considered as one of the treatment options for patients with ALK‐positive NSCLC who progressed on alectinib. (Trial registration no. NCT02450903)
Children's Selective Trust in Promises
Authors: Isella Margherita , Kanngiesser Patricia , Tomasello Michael
Published: June 2018

There has been extensive research into the development of selective trust in testimony, but little is known about the development of selective trust in promises. The present research investigates children's (N = 264) selective trust in others' promises to help. In Study 1, 6‐year‐olds selectively trusted speakers who had previously kept a promise. In Study 2, 5‐year‐olds displayed selective trust for speakers who had previously kept a prosocial promise (promise to help). In Study 3, 5‐year‐olds trusted a speaker, who kept a prosocial promise, over a helper. These data suggest that from the age of 5 children show selective trust in others’ promises using prosociality, promise keeping, or both to inform their judgments.
Emotional Over‐ and Undereating in Children: A Longitudinal Analysis of Child and Contextual Predictors
Authors: Bjørklund Oda , Wichstrøm Lars , Llewellyn Clare H. , Steinsbekk Silje
Published: June 2018

Eating more or eating less in response to negative emotions, called emotional over‐ and undereating, is common in children, but research on the etiology of these behaviors is in its infancy. Drawing on a large, representative community sample of Norwegian children followed up on a biennial basis from 6 to 10 years of age (analysis sample: n = 802), child and contextual predictors (i.e., child temperament, depression symptoms, serious life events, family functioning, parental sensitivity and structuring) of change in emotional over‐ and undereating were examined. Results revealed that low (temperamental) soothability and less parental structuring at age 6 predicted increased emotional overeating at age 10 and that lower family functioning at age 6 predicted more emotional undereating during the same period.
Multiple sclerosis: severe exacerbation after stopping disease‐modifying drugs
Authors: Członkowska A. , Mirowska‐Guzel D.
Published: June 2018

Click here to view the accompanying paper in this volume.
Biological control of the prickly pear cochineal Dactylopius opuntiae Cockerell (Hemiptera: Dactylopiidae)
Authors: Bouharroud R. , Sbaghi M. , Boujghagh M. , El Bouhssini M.
Published: June 2018

The prickly pear cochineal Dactylopius opuntiae Cockerell (Hemiptera: Dactylopiidae) is a serious pest that causes severe damage to prickly pear cactus species of the genus Opuntia. Before its introduction to Morocco no control methods were available for use against this pest. The current paper presents the results of the use for the first time of the mealybug destroyer Cryptolaemus montrouzieri Mulsant (Coleoptera: Coccinellidae) and the biopesticide d‐limonene to control D. opuntiae. The efficacy of the biopesticide was evaluated under field conditions. Corrected female mortality rates were >82% 6 days after application of d‐limonene at 60 ppm. The greatest mortality rates 6 days after treatment were 98% and 99% at 120 and 150 ppm, respectively. The data analysis showed that there was no significant difference between the different doses 6 or 13 days after treatment. The LD50 recorded was 33 ppm. In terms of biological control, the use of Cryptolaemus montrouzieri significantly reduced the cochineal scale population by 92% 77 days after release. This effect was maintained until 99 days after release of C. montrouzieri, and then the rate of population reduction declined to the level observed 64 days after release (66%). These results suggest that C. montrouzieri has the potential to suppress D. opuntiae populations to an acceptable level and reduce the damage caused by this cochineal.
Citrus leafminer Phyllocnistis citrella and its parasitoids in Sargodha region of Pakistan
Authors: Arshad M. , Ullah M. I. , Afzal M.
Published: June 2018

In order to identify the parasitoids of Phyllocnistis citrella, an important pest of Citrus, the larvae and pupae of this pest were collected from Citrus reticulata Blanco orchards in the Sargodha region of Pakistan. The parasitoid species were identified, and their abundance was recorded. A total of two species were identified: Citrostichus phyllocnistoides (Narayan) (Hymenoptera: Eulophidae) and Cirrospilus ingenuus Gahan (Hymenoptera: Eulophidae). Out of a total of 409 P. citrella larvae and pupae collected, 73 C. phyllocnistoides and 39 C. ingenuus adults emerged. This paper documents the species and the abundance of the parasitoids associated with P. citrella in the Sargodha region of Pakistan.
C.B‐17SCIDmice develop epicardial calcinosis with unaltered cardiac function
Authors: Raghunathan Suchi , Reynolds Corey L. , Schwartz Robert J. , Stewart M. David , McConnell Bradley K.
Published: June 2018

Inbred mouse strains are the most widely used mammalian model organism in biomedical research owing to ease of genetic manipulation and short lifespan; however, each inbred strain possesses a unique repertoire of deleterious homozygous alleles that can make a specific strain more susceptible to a particular disease. In the current study, we report dystrophic cardiac calcinosis (DCC) in C.B‐17SCIDmale mice at 10 weeks of age with no significant change in cardiac function. Acquisition ofDCCwas characterized by myocardial injury, fibrosis, calcification, and necrosis of the tissue. At 10 weeks of age, 38% of the C.B‐17SCIDmice from two different commercial colonies exhibited significant calcinosis on the ventricular epicardium, predominantly on the right ventricle. The frequency of calcinosis was more than 50% for mice obtained from Taconic's Cambridge City colony and 25% for mice obtained from Taconic's German Town colony. Interestingly, theDCCphenotype did not affect cardiac function at 10 weeks of age. No differences in echocardiography or electrocardiography were observed between the calcinotic and non‐calcinotic mice from either colony. Our findings suggest that C.B‐17SCIDmice exhibitDCCas early as 10 weeks of age with no significant impact on cardiac function. This strain of mice should be cautiously considered for the study of cardiac physiology.
Threshold angle and valid fracture of the sectored flexural specimen
Authors: Oistad Brian A. , Wereszczak Andrew A. , Chen Branndon R. , Jadaan Osama M.
Published: June 2018

The sectored flexural specimen was developed over a decade ago to measure the strength of ceramic and glass tubes and cylinders in which flaws on a tube's or cylinder's outer surface are limiters of axial tensile failure stress. Using the specimen's geometry, the associated axial tensile failure stress can be analytically calculated from the failure force measured from simple uniaxial bending, and multiple specimens (and test data) can be harvested from a single tube or cylinder. The sector angles of specimens in previous studies were somewhat arbitrarily chosen and usually produced validly occurring fractures and data; however, if the angle used was too small (relative to the tube's or cylinder's geometry), then undesirable application‐irrelevant edge‐located failures resulted. To avoid such failures in specimen design, a threshold sector angle was identified to guide the selection of a minimum sector angle (and consequential cross section) for any arbitrary sector flexural specimen harvested from a tube or cylinder. If the sector angle of the specimen is larger than the threshold value, then fracture will not occur at a specimen's edge and the measured axial failure stress will be limited by surface‐located flaws on the tube's or cylinder's outer surface.
Reactive ion etching (CF4/Ar) and ion beam etching of various glasses for diffractive optical element fabrication
Authors: Schmitt Jana , Meier Andreas , Wallrabe Ulrike , Völklein Friedemann
Published: June 2018

The paper reports on the reactive ion etching (RIE) and ion beam etching (IBE) of commercially available glasses and their usability for the fabrication of diffractive optical elements as an alternative for expensive quartz glass. Fused quartz, borosilicate glasses BF33, BF40, D263, alkaline‐free aluminoborosilicate glasses AF45 and AF37, and alkaline‐alkaline‐earth silicate B270 were processed with RIE using CF4/Ar gas mixtures. EDX investigations displayed the dependence of the measured etch rates on nonvolatile reaction products. CF4/Ar flow rates influence the etch rates which show maximum values in the range 10‐20 sccm Ar flow. Etch rates as a function of etch depth were investigated as well. Variations in surface roughness are determined by AFM and SEM investigations. Etch rate, surface roughness, and structure shape depend on the alkaline and alkaline‐earth content of the various glass materials is displayed. The usability of the different glass types regarding optical performance was evaluated by comparison of simulated and measured diffraction efficiencies of IBE line gratings, since IBE provides comparable surface qualities. It offers a process alternative for the patterning of micro‐optical elements with high surface quality. Therefore, IBE etch rates were measured as well.
Significantly improved photoluminescence of the green‐emitting β‐sialon:Eu2+ phosphor via surface coating of TiO2
Authors: Zhang Chenning , Uchikoshi Tetsuo , Xie Rong‐Jun , Liu Lihong , Sakka Yoshio , Hirosaki Naoto
Published: June 2018

The β‐sialon:Eu2+ phosphor particles were successfully coated by TiO2 nanoparticles via the sol‐gel method. The TiO2‐coated β‐sialon:Eu2+ phosphor had a significantly improved photoluminescence (PL) performance under the 365 nm excitation, due to the localized surface plasmon resonance (LSPR) at the interface between the TiO2 coating layer and phosphor surface. The emission intensity of the TiO2‐coated β‐sialon:Eu2+ prepared with the titanium (IV) tetrabutoxide (Ti(OC4H9)4, TTBO):H2O = 1:0.5 volume ratio was dramatically increased by ~24%. When the preparation temperature was 500°C, it was responsible for superior PL intensity by considering the important domination factors of higher anatase content and spherical particle shape of the TiO2 coating layer to the LSPR effect. The coating around the phosphor surface by the TiO2 nanoparticles would be an effective technique to improve the PL efficiency of phosphor for the application in the white light‐emitting diodes (LEDs), by utilizing the LSPR effect of the semiconductor coating layer, instead of conventional metal plasmonic materials.
Thermochemical model on the carbothermal reduction of oxides during spark plasma sintering of zirconium diboride
Authors: Pham David , Dycus Joseph H. , LeBeau James M. , Manga Venkateswara R. , Muralidharan Krishna , Corral Erica L.
Published: June 2018

Carbon was used to reduce oxides in spark plasma sintered ZrB2 ultra‐high temperature ceramics. A thermodynamic model was used to evaluate the reducing reactions to remove B2O3 and ZrO2 from the powder. Powder oxygen content was measured and carbon additions of 0.5 and 0.75 wt% were used. A C–ZrO2 pseudo binary diagram, ZrO2–B2O3–C pseudo ternaries, and Zr–C–O potential phase diagrams were generated to show how the reactions can be related to an open system experiment in the tube furnace. Scanning transmission electron microscopy identified impurity phases composed of amorphous Zr–B–O with lamellar BN and a Zr–C–O ternary model was calculated under SPS sintering conditions at 1900°C and 6 Pa to understand how oxides can be retained in the microstructure.
Direct observation of Eu atoms in AlN lattice and the first‐principles simulations
Authors: Yin Liang‐Jun , Zhang Sheng‐Hui , Wang Hui , Jian Xian , Wang Xin , Xu Xin , Liu Ming‐Zhen , Fang Chang‐Ming
Published: June 2018

Rare‐earth metal (Eu)‐doped aluminum nitride has potential application as luminescence materials due to its unusual mechanical and physical properties, as well as high chemical stability. Here, we investigate the energetics, local structure and optical and electronic properties by means of a combination of experimental observations (XDR, SEM, HR‐TEM and XANES) and first‐principles simulations. Present study has revealed that Eu ions are likely to be co‐doped with O in the form of Eu–O pairs. Eu ions or Eu–O pairs favor participation at the surfaces of the AlN crystallites. Our analyses show dependences of the Eu valence and electronic/optical properties on the local chemical composition and structure. The obtained information helps us to realize tuning of the optical properties of the luminescent materials via composition and site occupation modification.
Structural complexity of hunting habitat and territoriality increase the reversed sexual size dimorphism in diurnal raptors
Authors: Pérez‐Camacho Lorenzo , Martínez‐Hesterkamp Sara , Rebollo Salvador , García‐Salgado Gonzalo , Morales‐Castilla Ignacio
Published: June 2018

Despite numerous efforts and many hypotheses to explain the selective pressures that may have favoured reversed sexual dimorphism (RSD) in raptors – i.e. that the female is larger than the male – some drivers of RSD are still unknown.

Here we analyse how much variation in RSD is explained by hunting habitat structure, territoriality or territory size. We do so using data on diurnal raptors from the New World and the Western Palearctic – i.e. Cathartidae, Pandionidae, Accipitridae and Falconidae, the largest bird group showing RSD – taking into account the phylogenetic relationships among species.

Our results identify the type of the main prey as a major factor explaining RSD in raptors. We also found RSD to increase with increasing structural complexity in the hunting habitat from open or semi‐open habitats to forest interior. RSD also increased with increasing degree of territoriality of the species (non‐territorial < facultative < territorial). Finally, for territorial species RSD increased with increasing size of nesting territory. A model comprising only three predictor variables (prey type, structural complexity of hunting habitat and territoriality) explained up to 50% of the variation in RSD of European and American diurnal raptor species, and up to 40% of the variation in RSD when only territorial species were considered.

Our results highlight the relevance of spatial facets of the niche – e.g. hunting habitat, territoriality and territory size – in exerting selective pressures on the body size of diurnal raptors. These selective pressures, joint with already known trophic factors – e.g. diet – are decisive for the evolution of the RSD, a key trait in the functional ecology of raptors. Our findings open up new perspectives in the study of sexual size divergence in birds.
Reliability of the hidradenitis suppurativa clinical response in the assessment of patients with hidradenitis suppurativa
Authors: Kimball A.B. , Ganguli A. , Fleischer A.
Published: June 2018

Background

Hidradenitis suppurativa clinical response (HiSCR) is a validated clinical end point for measuring response to treatment in patients with hidradenitis suppurativa (HS). Previous studies have reported on the validity, responsiveness and meaningfulness of the HiSCR.

Objective

To evaluate the HiSCR for inter‐ and intrarater reliability characteristics.

Methods

A stand‐alone, two‐site, prospective, non‐interventional observational study consisted of 22 patients, with self‐reported severity between mild, moderate and severe HS. The Patient Global Impression of Change (PGI‐C) scale was completed by patients at Timepoint 2. Descriptive statistics of Hurley Stage, total abscesses, total draining fistulas, total inflammatory nodules and total AN count (sum of inflammatory nodules and lesions) were reported at two timepoints. Inter‐rater reliability and intrarater reliability for the HS lesion count tool were evaluated at two timepoints (baseline and Day 7) using the HS lesion count tool. Intraclass correlation (ICC) coefficients of lesion counts were calculated to evaluate inter‐ and intrarater reliability of lesion counts between pairs of dermatologists.

Results

The majority of patients demonstrated either no change or minimally worse PGI‐C in HS scores. Descriptive statistics were similar between rater groups and timepoints assessed. Inter‐rater ICC coefficients for abscess count at Timepoints 1 and 2 were 0.38 and 0.67. The ICC coefficients for draining fistula and AN count were ≥0.61 at both timepoints. In an exploratory model, ICC coefficients were ≥0.68 for all evaluated lesion counts. The test–retest reliability using ICC coefficients was ≥0.70 for total abscess, draining fistula, inflammatory nodule and AN count.

Conclusion

The HS lesion count tool had an acceptable inter‐ and intrarater reliability, indicating that HiSCR has a strong degree of reproducibility and consistency in the evaluation of patients with HS.
Rosacea‐like demodicosis (but not primary demodicosis) and papulopustular rosacea may be two phenotypes of the same disease – a microbioma, therapeutic and diagnostic tools perspective
Authors: Tatu A.L. , Clatici V.G. , Nwabudike L.C.
Published: June 2018

Linked article: This article is commentary on by F. Forton et al., pp. e47–e48 in this issue. To view this article visit https://doi.org/10.1111/jdv.15162
Sphingolipids and neuronal degeneration in lysosomal storage disorders
Authors: Grassi Sara , Chiricozzi Elena , Mauri Laura , Sonnino Sandro , Prinetti Alessandro
Published: June 2018

Ceramide, sphingomyelin, and glycosphingolipids (both neutral and acidic) are characterized by the presence in the lipid moiety of an aliphatic base known as sphingosine. Altogether, they are called sphingolipids and are particularly abundant in neuronal plasma membranes, where, via interactions with the other membrane lipids and membrane proteins, they play a specific role in modulating the cell signaling processes. The metabolic pathways determining the plasma membrane sphingolipid composition are thus the key point for functional changes of the cell properties. Unnatural changes of the neuronal properties are observed in sphingolipidoses, lysosomal storage diseases occurring when a lysosomal sphingolipid hydrolase is not working, leading to the accumulation of the substrate and to its distribution to all the cell membranes interacting with lysosomes. Moreover, secondary accumulation of sphingolipids is a common trait of other lysosomal storage diseases.

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This article is part of the Special Issue “Lysosomal Storage Disorders”.
A motor neuron strategy to save time and energy in neurodegeneration: adaptive protein stoichiometry
Authors: Zucchi Elisabetta , Lu Ching‐Hua , Cho Yunju , Chang Rakwoo , Adiutori Rocco , Zubiri Irene , Ceroni Mauro , Cereda Cristina , Pansarasa Orietta , Greensmith Linda , Malaspina Andrea , Petzold Axel
Published: June 2018

Neurofilament proteins (Nf) are a biomarker of disease progression in amyotrophic lateral sclerosis (ALS). This study investigated whether there are major differences in expression from in vivo measurements of neurofilament isoforms, from the light chain, NfL (68 kDa), compared with larger proteins, the medium chain (NfM, 150 kDa) and the heavy (NfH, 200‐210 kDa) chains in ALS patients and healthy controls. New immunological methods were combined with Nf subunit stoichiometry calculations and Monte Carlo simulations of a coarse‐grained Nf brush model. Based on a physiological Nf subunit stoichiometry of 7 : 3 : 2 (NfL:NfM:NfH), we found an ‘adaptive’ Nf subunit stoichiometry of 24 : 2.4 : 1.6 in ALS. Adaptive Nf stoichiometry preserved NfL gyration radius in the Nf brush model. The energy and time requirements for Nf translation were 56 ± 27k ATP (5.6 h) in control subjects compared to 123 ± 102k (12.3 h) in ALS with ‘adaptive’ (24:2.4:1.6) Nf stoichiometry (not significant) and increased significantly to 355 ± 330k (35.5 h) with ‘luxury’ (7:3:2) Nf subunit stoichiometry (p < 0.0001 for each comparison). Longitudinal disease progression‐related energy consumption was highest with a ‘luxury’ (7:3:2) Nf stoichiometry. Therefore, an energy and time‐saving option for motor neurons is to shift protein expression from larger to smaller (cheaper) subunits, at little or no costs on a protein structural level, to compensate for increased energy demands.

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Using Classification Techniques for Assigning Work Descriptions to Task Groups on the Basis of Construction Vocabulary
Authors: Martínez‐Rojas María , Soto‐Hidalgo Jose Manuel , Marín Nicolás , Vila M. Amparo
Published: June 2018

Construction project management produces a huge amount of documents in a variety of formats. The efficient use of the data contained in these documents is crucial to enhance control and to improve performance. A central pillar throughout the project life cycle is the Bill of Quantities (BoQ) document. It provides economic information and details a collection of work descriptions describing the nature of the different works needed to be done to achieve the project goal. In this work, we focus on the problem of automatically classifying such work descriptions into a predefined task organization hierarchy, so that it can be possible to store them in a common data repository. We describe a methodology for preprocessing the text associated to work descriptions to build training and test data sets and carry out a complete experimentation with several well‐known machine learning algorithms.
Resource Leveling Based on Line of Balance and Constraint Programming
Authors: Tang Yuanjie , Sun Quanxin , Liu Rengkui , Wang Futian
Published: June 2018

This study investigated resource leveling problems concerning linear construction projects based on the line of balance (LOB) technique and constraint programming. In addition, an LOB‐based scheduling optimization model for resource leveling is proposed. This model retains the advantages of the conventional models, including multiple‐resource management and natural rhythm concept, and showcases new abilities: scheduling optimization without specifying a fixed schedule; scheduling optimization on more comprehensive optimization objects and variable values; maintaining continuity of resource while completely eliminating the occurrence of idle time; handling more comprehensive constraints after the addition of logical constraints and explicit expression of certain new constraints. The flexibility, practicality, and solution quality of the proposed model were enhanced accordingly. Further, a scheduling system was developed to assist in schedule optimization and visualization. Lastly, effectiveness of the proposed model was verified based on four case studies involving three case projects investigated in extant LOB‐based studies.
A genetic screen for plant mutants with altered nodulation phenotypes in response to rhizobial glycan mutants
Authors: Liu Huijun , Sandal Niels , Andersen Kasper R. , James Euan K. , Stougaard Jens , Kelly Simon , Kawaharada Yasuyuki
Published: June 2018

Nodule primordia induced by rhizobial glycan mutants often remain uninfected. To identify processes involved in infection and organogenesis we used forward genetics to identify plant genes involved in perception and responses to bacterial glycans.

To dissect the mechanisms underlying the negative plant responses to the Mesorhizobium loti R7AexoU and ML001cep mutants, a screen for genetic suppressors of the nodulation phenotypes was performed on a chemically mutagenized Lotus population.

Two mutant lines formed infected nitrogen‐fixing pink nodules, while five mutant lines developed uninfected large white nodules, presumably altered in processes controlling organogenesis. Genetic mapping identified a mutation in the cytokinin receptor Lhk1 resulting in an alanine to valine substitution adjacent to a coiled‐coil motif in the juxta‐membrane region of LHK1. This results in a spontaneous nodulation phenotype and increased ethylene production. The allele was renamed snf5, and segregation studies of snf5 together with complementation studies suggest that snf5 is a gain‐of‐function allele.

This forward genetic approach to investigate the role of glycans in the pathway synchronizing infection and organogenesis shows that a combination of plant and bacterial genetics opens new possibilities to study glycan responses in plants as well as identification of mutant alleles affecting nodule organogenesis.
MicroRNAs in Marchantia polymorpha
Authors: Lin Shih‐Shun , Bowman John L.
Published: June 2018

Contents

Summary
409

I.
Introduction
409

II.
RNA silencing machinery in Marchantia polymorpha
410

III.
miRNA prediction by integrating omics approach
410

IV.
miRNAs and their targets in Marchantia polymorpha
410

V.
Mpo‐miR390‐mediated MpTAS3 tasiRNA biogenesis and potential tasiARF target MpARF2
414

VI.
Artificial miRNA and CRISPR‐CAS9 edited MIR gene in Marchantia polymorpha
414

VII.
Conclusions
415

Acknowledgements
415

References
415

The liverwort Marchantia polymorpha occupies an important phylogenetic position for comparative studies of land plant gene regulation. Multiple gene regulatory pathways mediated by small RNAs, including microRNAs (miRNAs), trans‐acting short‐interfering RNAs, and heterochromatic siRNAs often associated with RNA‐dependent DNA methylation, have been characterized in flowering plants. Genes for essential components for all of these small RNA‐mediated gene silencing pathways are found in M. polymorpha as well as the moss Phsycomitrella patens, indicating that these pathways existed in the ancestral land plant. However, only seven miRNAs are conserved across land plants, with both ancestral and novel targets identified in M. polymorpha. There is little or no evidence that any of these conserved miRNAs are present in algae. As with other plants investigated, most miRNAs in M. polypmorpha exhibit lineage‐specific evolution. Application of artificial miRNA and CRISPR‐Cas9 technologies in genetic studies of M. polymorpha provide avenues to further investigate miRNA biology.
Epigenetic regulation of anthocyanin biosynthesis by an antagonistic interaction between H2A.Z and H3K4me3
Authors: Cai Hanyang , Zhang Man , Chai Mengnan , He Qing , Huang Xinyu , Zhao Lihua , Qin Yuan
Published: June 2018

The accumulation of anthocyanins in response to specific developmental cues or environmental conditions plays a vital role in plant development and protection against stresses. Extensive research has examined the regulation of anthocyanin biosynthetic genes at the transcriptional and post‐transcriptional levels, but the role of chromatin in this regulation remains unknown.

Chromatin immunoprecipitation and quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) analyses were performed. Genetic interactions between trimethylation of lysine 4 on histone H3 (H3K4me3) and the chromatin remodeling complex SWR1 in the control of anthocyanin biosynthesis were further studied.

In this study, we provide evidence that a conserved histone H2 variant, H2A.Z, negatively regulates anthocyanin accumulation through deposition at a set of anthocyanin biosynthetic genes and consequently represses their expression in Arabidopsis thaliana. Our data indicate that the accumulation of anthocyanin in H2A.Z deposition‐deficient mutants is associated with increased H3K4me3, which is required for promotion of the expression of anthocyanin biosynthetic genes. We further provide evidence that H3K4me3 in anthocyanin biosynthetic genes is negatively associated with the presence of H2A.Z.

Our results reveal an antagonistic relationship between H2A.Z and H3K4me3 in the regulation of the expression of anthocyanin biosynthesis genes, adding another layer of regulation to anthocyanin biosynthesis genes and highlighting the role of chromatin in gene regulation.
The value of wet leaves
Authors: Dawson Todd E. , Goldsmith Gregory R.
Published: June 2018

Contents

Summary
1156

I.
Introduction
1156

II.
How often are leaves wet?
1157

III.
The costs of leaf wetting
1157

IV.
The real and potential benefits of leaf wetting
1161

V.
Wet leaves: costs, benefits and tradeoffs in a changing world
1165

Acknowledgements
1166

References
1166

An often‐overlooked feature of all plants is that their leaf surfaces are wet for significant periods over their lifetimes. Leaf wetting has a number of direct and indirect effects on plant function from the scale of the leaf to that of the ecosystem. The costs of leaf wetting for plant function, such as the growth of pathogens and the leaching of nutrients, have long been recognized. However, an emerging body of research has also begun to demonstrate some very clear benefits. For instance, leaf wetting can improve plant–water relations and lead to increased photosynthesis. Leaf wetting may also lead to synergistic effects on plant function, such as when leaf water potential improvements lead to enhanced growth that does not occur when plant leaves are dry. We identify important reasons why leaf wetting can be critical for plant sciences to not only acknowledge, but also directly address, in future research. To do so, we provide a framework for the consideration of the relative balance of the various costs and benefits resulting from leaf wetting, as well as how this balance may be expected to change given projected scenarios of global climate change in the future.
Incidence and phenotypic variation in alewife alter the ontogenetic trajectory of young‐of‐the‐year largemouth bass
Authors: Boel Mikkel , Brodersen Jakob , Koed Anders , Baktoft Henrik , Post David M.
Published: June 2018

There is increasing evidence that phenotypic variation can strongly impact community structure and ecosystem functions. Alewife Alosa pseudoharengus is a planktivorous fish species that strongly impact lake ecosystems. It has previously been demonstrated that phenotypic variation related to differences in life history among landlocked and anadromous alewife populations alters the strength of interactions with other species, potentially modifying its role in the community. The migration between freshwater and marine ecosystems by anadromous alewife creates seasonal differences in alewife densities, which causes lake zooplankton communities to alternate between large‐body size and higher densities in the spring, and small‐body size and low densities in the summer and fall. In lakes with resident (landlocked) alewife, predation from alewife modifies the zooplankton community to having low zooplankton densities and mainly small‐bodied zooplankton year‐round. The strong effects of phenotypic variation in alewife on zooplankton may be important for coexisting species that rely on zooplankton as a resource. Here we use estimates of growth, and direct diet and stable isotope analyses to ask if the presence‐ and phenotypic variation of alewife alters the ontogenetic trajectory of young‐of‐the‐year (YOY) largemouth bass Micropterus salmoides, which depend on zooplankton in the early life stages. We found that both the presence‐ and phenotypic variation of alewife affects growth, trophic position, and diet of largemouth bass. YOY largemouth bass from lakes without alewife grew faster, switched to piscivory earlier, and reached higher trophic positions than in alewife lakes. In lakes with landlocked alewife largemouth bass grew slower and obtained a lower trophic position than those in lakes with anadromous alewife. These divergences can be explained by the strong effects of alewife on zooplankton community structure. Our results demonstrate how the strong effects of phenotypic variation can propagate through natural food webs to influence important life history transitions in other species.
Persistent sex disparities in implantable cardioverter‐defibrillator therapy
Authors: Johnson Amber E. , Adhikari Shubash , Althouse Andrew D. , Thoma Floyd , Marroquin Oscar C. , Koscumb Stephen , Hausmann Leslie R.M. , Myaskovsky Larissa , Saba Samir F.
Published: June 2018

Background

Clinical guidelines recommend cardioverter defibrillator implantation for patients with heart failure and reduced ejection fraction. Despite this, women and minorities have been less likely to receive implantable cardioverter‐defibrillator (ICD) therapy than white men. We examined race and sex differences in ICD implantation in a recent cohort.

Methods

Using cross‐sectional, retrospective analyses, we mined our health system's outpatient electronic medical records to assess age, race, sex, medications, and comorbidities for patients aged ≥18 years with ejection fraction ≤ 35% during 2014. While adjusting for confounding variables such as medications, age, and comorbidities, we conducted a multivariable logistic regression assessing whether racial and sex differences in ICD therapy persist.

Results

Among 5,156 outpatients with ejection fraction ≤35%, 1,681 (32.6%) patients had an ICD present at the time of their index outpatient visit in 2014. Women were less likely to have an ICD than men (25.0% vs 36.3%, P < 0.01), and black patients were less likely to have an ICD than white patients (28.0% vs 33.2%, P  =  0.02). In adjusted multivariable analyses, women were less like to have ICDs (adjusted odds ratio [OR]  =  0.68, 95% confidence interval [CI], 0.58–0.79, P < 0.01) but the race difference dissipated (adjusted OR for black race  =  0.86, 95% CI, 0.68–1.08, P  =  0.18).

Conclusions

In this large, outpatient cohort, we have shown that sex differences in ICD therapy continue to exist, but the difference in ICD prevalence by race was attenuated. Dedicated studies are required to fully understand the causes of persistent sex differences in ICD therapy.
Clavibacter michiganensis subsp. michiganensis strains from central Chile exhibit low genetic diversity and sequence types match strains in other parts of the world
Authors: Valenzuela M. , Besoain X. , Durand K. , Cesbron S. , Fuentes S. , Claverías F. , Jacques M. A. , Seeger M.
Published: June 2018

Bacterial canker caused by Clavibacter michiganensis subsp. michiganensis (Cmm) is one of the most important bacterial diseases of tomato. In order to understand the emergence and dissemination of this pathogen in Chile, Chilean Cmm strains isolated from different sites in central Chile were characterized and compared to a worldwide collection of strains. Multilocus sequence analysis and typing (MLSA‐MLST) based on five housekeeping genes, i.e. atpD, dnaK, gyrB, ppk and recA, and multilocus variable number of tandem repeats (VNTR) analysis (MLVA) based on eight VNTRs were used. Low diversity was found using MLSA‐MLST among the 25 Chilean strains, which clustered into three groups, each corresponding to a single sequence type (ST). Group I contained most strains (21/25), isolated over different years from Valparaíso and O'Higgins regions. Group II contained only one strain from Maule region that was isolated in 2005. These two groups belonged to the same genetic lineage. Group III contained three strains from Valparaíso region isolated in 2004, 2012 and 2013. MLVA also distributed the strains into the same three groups. Group III strains shared the same ST as strains from Algeria, Belgium, France, the Netherlands, Uruguay and the USA. Group II strains shared the same ST as strains from Brazil and Uruguay, while Group I strains shared the same ST as two strains of unknown origin. This study shows that Cmm strains from central Chile tend to be clonal and have similar genetic profiles to strains from other countries.