bluuebunny/crossref_metadata_2025 huggingface dataset:
Optical properties of truncated Au nanocages with different size and shape
Authors: Chen Qin , Qi Hong , Ren Ya-Tao , Sun Jian-Ping , Ruan Li-Ming
Published: June 2017

The hollow nanostructures are conducive to applications including drug delivery, energy storage and conversion, and catalysis. In the present work, a versatile type of Au nanoparticles, i.e. nanocage with hollow interior, was studied thoroughly. Simulation of the optical properties of nanocages with different sizes and shapes was presented, which is essential for tuning the localized surface plasmon resonance peak. The edge length, side length of triangle, and wall thickness were used as structural parameters of truncated Au nanocage. The dependence of absorption efficiency, resonant wavelength, and absorption quantum yield on the structural parameters were discussed. Meanwhile, the applications of absorption quantum yield in biomedical imaging and laser induced thermal therapy were investigated. It was found that the phenomenon of multipolar plasmon resonances exists on truncated Au nanocage. Furthermore, the electric field distribution at different resonant wavelengths was also investigated. It is found that the electromagnetic field corresponds to the dipolar mode in an individual nanocage is largely distributed at the corners. Whereas, the electromagnetic field corresponds to the multipolar region is mainly located in the internal corners and edges.
Intrinsic map dynamics exploration for uncharted effective free-energy landscapes
Authors: Chiavazzo Eliodoro , Covino Roberto , Coifman Ronald R. , Gear C. William , Georgiou Anastasia S. , Hummer Gerhard , Kevrekidis Ioannis G.
Published: June 2017

Significance

Direct simulations explore the dynamics of physical systems at their natural pace. Molecular dynamics (MD) simulations (e.g., of macromolecular folding) extensively revisit typical configurations until rare and interesting transition events occur. Biasing the simulator away from regions already explored can, therefore, drastically accelerate the discovery of features. We propose an enhanced sampling simulation framework, where MD and machine learning adaptively bootstrap each other. Machine learning guides the search for important configurations by processing information from previous explorations. This search proceeds iteratively in an algorithmically orchestrated fashion without advance knowledge of suitable collective variables. Applied to a molecular sensor of lipid saturation in membranes, a helix dissociation pathway not seen in millisecond simulations is discovered at the second iteration.
Redox-dependent interaction between thaumatin-like protein and β-glucan influences malting quality of barley
Authors: Singh Surinder , Tripathi Rajiv K. , Lemaux Peggy G. , Buchanan Bob B. , Singh Jaswinder
Published: June 2017

Significance

The process of malting in the making of beer is under fine biological regulation. Here, we report the dissection of a malting quality quantitative trait locus (QTL) known for its association with variation in the yield of β-glucan and malt extract. A key gene,
HvTLP8
, has been identified in the QTL2 region that is expressed differentially in barley malt and feed varieties, based on analyses of both mRNA and protein. The present finding that the affinity of recombinant HvTLP8 for insoluble barley β-glucan is redox-dependent suggests a key role for redox in the malting process. This discovery represents a significant step forward in understanding the biochemistry of malting.
Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP–ISD11 interactions
Authors: Cory Seth A. , Van Vranken Jonathan G. , Brignole Edward J. , Patra Shachin , Winge Dennis R. , Drennan Catherine L. , Rutter Jared , Barondeau David P.
Published: June 2017

Significance

Prokaryotic and eukaryotic organisms use analogous pathways to synthesize protein cofactors called iron–sulfur clusters. An unexplained difference between pathways is the functional requirements of the respective cysteine desulfurases. In eukaryotes, the cysteine desulfurase NFS1 requires additional accessory subunits for function. The lack of structural information has limited mechanistic insight into the role of these accessory proteins in mitochondrial Fe–S cluster biosynthesis. Here we determined crystallographic and electron microscopic structures of the NFS1–ISD11–ACP subcomplex. These results reveal an unexpected cysteine desulfurase architecture that reconciles mechanistic differences between the prokaryotic and eukaryotic systems, reveals the basis of control of iron–sulfur cluster assembly through fatty acid synthesis, and serves as a structural foundation for investigating human diseases related to iron–sulfur cluster assembly.
Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP-signaling modules in T cells
Authors: Beltejar Michael-Claude G. , Lau Ho-Tak , Golkowski Martin G. , Ong Shao-En , Beavo Joseph A.
Published: June 2017

Significance

We have coupled mass spectrometry-based phosphoproteomic analyses with treatment using various selective PDE inhibitors to characterize the PDE-regulated phosphoproteome of CD3/CD28-stimulated Jurkat cells. Predictive algorithms were used to identify likely upstream regulatory kinases, metabolic pathways, and biological processes that can be regulated by different PDEs. Here we compare the phosphoproteomes of different functional compartments subserved by combinations of individual PDE isozymes in a T-cell model. We observed unique phosphoproteomes associated with specific combinations of PDEs. These data allow one to prioritize future experiments to understand further how these pathways are regulated by specific PDEs. The results also have substantial implications for the design and use of selective PDE inhibitors in clinical practice.
Biosynthesis of isonitrile lipopeptides by conserved nonribosomal peptide synthetase gene clusters in Actinobacteria
Authors: Harris Nicholas C. , Sato Michio , Herman Nicolaus A. , Twigg Frederick , Cai Wenlong , Liu Joyce , Zhu Xuejun , Downey Jordan , Khalaf Ryan , Martin Joelle , Koshino Hiroyuki , Zhang Wenjun
Published: June 2017

Significance

Mycobacterium tuberculosis
is the leading causative agent of tuberculosis, from which millions die annually. A putative lipopeptide biosynthetic gene cluster has been shown to be essential for the survival of this pathogen in hosts, and homologous gene clusters have also been found in all pathogenic mycobacteria and other species of Actinobacteria. We have identified the function of these gene clusters in making a family of isonitrile lipopeptides. The biosynthesis has several unique features, including an unprecedented mechanism for isonitrile synthesis. Our results further suggest that these biosynthetic gene clusters play a role in metal transport and thus have shed light on a metal transport system that is crucial for virulence of pathogenic mycobacteria.
Lectin microarray analysis of isolated polysaccharides from Sasa veitchii
Authors: Yagi Hirokazu , Tateno Hiroaki , Hayashi Kyoko , Hayashi Toshimitsu , Takahashi Katsuhiko , Hirabayashi Jun , Kato Koichi , Tsuboi Masamichi
Published: June 2017

We report lectin microarray profile of the polysaccharide fraction derived from Sasa veitchii leaf that exhibits anti-influenza activity. This fraction showed higher reactivities with lectins known as binders to oligo-mannose, fucose, or galactose. Our findings along with previously reported monosaccharide components suggest that the polysaccharide can be cross-reactive with cell surface receptors involved in immune system, thereby exerting anti-influenza activity.
Cell cycle–dependent spatial segregation of telomerase from sites of DNA damage
Authors: Ouenzar Faissal , Lalonde Maxime , Laprade Hadrien , Morin Geneviève , Gallardo Franck , Tremblay-Belzile Samuel , Chartrand Pascal
Published: June 2017

Telomerase can generate a novel telomere at DNA double-strand breaks (DSBs), an event called de novo telomere addition. How this activity is suppressed remains unclear. Combining single-molecule imaging and deep sequencing, we show that the budding yeast telomerase RNA (TLC1 RNA) is spatially segregated to the nucleolus and excluded from sites of DNA repair in a cell cycle–dependent manner. Although TLC1 RNA accumulates in the nucleoplasm in G1/S, Pif1 activity promotes TLC1 RNA localization in the nucleolus in G2/M. In the presence of DSBs, TLC1 RNA remains nucleolar in most G2/M cells but accumulates in the nucleoplasm and colocalizes with DSBs in rad52Δ cells, leading to de novo telomere additions. Nucleoplasmic accumulation of TLC1 RNA depends on Cdc13 localization at DSBs and on the SUMO ligase Siz1, which is required for de novo telomere addition in rad52Δ cells. This study reveals novel roles for Pif1, Rad52, and Siz1-dependent sumoylation in the spatial exclusion of telomerase from sites of DNA repair.
F-actin prevents interaction between sperm DNA and the oocyte meiotic spindle in C. elegans
Authors: Panzica Michelle T. , Marin Harold C. , Reymann Anne-Cecile , McNally Francis J.
Published: June 2017

Fertilization occurs during female meiosis in most animals, which raises the question of what prevents the sperm DNA from interacting with the meiotic spindle. In this study, we find that Caenorhabditis elegans sperm DNA stays in a fixed position at the opposite end of the embryo from the meiotic spindle while yolk granules are transported throughout the embryo by kinesin-1. In the absence of F-actin, the sperm DNA, centrioles, and organelles were transported as a unit with the yolk granules, resulting in sperm DNA within 2 µm of the meiotic spindle. F-actin imaging revealed a cytoplasmic meshwork that might restrict transport in a size-dependent manner. However, increasing yolk granule size did not slow their velocity, and the F-actin moved with the yolk granules. Instead, sperm contents connect to the cortical F-actin to prevent interaction with the meiotic spindle.
Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD–induced myeloproliferation
Authors: Mead Adam J. , Neo Wen Hao , Barkas Nikolaos , Matsuoka Sahoko , Giustacchini Alice , Facchini Raffaella , Thongjuea Supat , Jamieson Lauren , Booth Christopher A.G. , Fordham Nicholas , Di Genua Cristina , Atkinson Deborah , Chowdhury Onima , Repapi Emmanouela , Gray Nicki , Kharazi Shabnam , Clark Sally-Ann , Bouriez Tiphaine , Woll Petter , Suda Toshio , Nerlov Claus , Jacobsen Sten Eirik W.
Published: June 2017

Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation found Flt3 mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between Flt3 and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment. Competitive transplantation experiments established that Flt3-ITD compromises HSCs through an extrinsically mediated mechanism of disrupting HSC-supporting bone marrow stromal cells, with reduced numbers of endothelial and mesenchymal stromal cells showing increased inflammation-associated gene expression. Tumor necrosis factor (TNF), a cell-extrinsic potent negative regulator of HSCs, was overexpressed in bone marrow niche cells from FLT3-ITD mice, and anti-TNF treatment partially rescued the HSC phenotype. These findings, which establish that Flt3-ITD–driven myeloproliferation results in cell-extrinsic suppression of the normal HSC reservoir, are of relevance for several aspects of acute myeloid leukemia biology.
Vaccination establishes clonal relatives of germinal center T cells in the blood of humans
Authors: Heit Antje , Schmitz Frank , Gerdts Sarah , Flach Britta , Moore Miranda S. , Perkins Jonathan A. , Robins Harlan S. , Aderem Alan , Spearman Paul , Tomaras Georgia D. , De Rosa Stephen C. , McElrath M. Juliana
Published: June 2017

Germinal center T follicular helper cells (GCTfh) in lymphatic tissue are critical for B cell differentiation and protective antibody induction, but whether GCTfh establish clonal derivatives as circulating memory T cells is less understood. Here, we used markers expressed on GCTfh, CXCR5, PD1, and ICOS, to identify potential circulating CXCR5+CD4+ Tfh-like cells (cTfh) in humans, and investigated their functional phenotypes, diversity, and ontogeny in paired donor blood and tonsils, and in blood after vaccination. Based on T cell receptor repertoire analysis, we found that PD-1–expressing cTfh and tonsillar GCTfh cells were clonally related. Furthermore, an activated, antigen-specific PD1+ICOS+ cTfh subset clonally expanded after booster immunization whose frequencies correlated with vaccine-specific serum IgG; these phenotypically resembled GCTfh, and were clonally related to a resting PD1+ICOS− CD4+ memory T cell subset. Thus, we postulate that vaccination establishes clonal relatives of GCTfh within the circulating memory CD4+CXCR5+PD1+ T cell pool that expand upon reencounter of their cognate antigen.
Low-Intensity Pulsed Ultrasound (LIPUS) Promotes BMP9-Induced Osteogenesis and Suppresses Inflammatory Responses in Human Periodontal Ligament-Derived Stem Cells
Authors: Kusuyama Joji , Nakamura Toshiaki , Ohnishi Tomokazu , Eiraku Nahoko , Noguchi Kazuyuki , Matsuguchi Tetsuya
Published: June 2017

Objective:

We previously reported that low intensity pulsed ultrasound (LIPUS) promotes marrow stromal cell (MSC) osteogenesis and suppresses the LPS-induced inflammatory response in osteoblasts. Here, we examined the effects of LIPUS on human periodontal ligament-derived stem cells (hPDLSCs) in chronic inflammatory bone disease, such as periodontitis.

Materials and Methods:

hPDLSCs were collected from 3 healthy third molars. hPDLSCs were induced to differentiate by either recombinant BMP2 or BMP9 with or without daily LIPUS treatment (20 min/d). hPDLSCs were also stimulated by Porphyromonas gingivalis-derived LPS (LPS-PG), IL-1beta, and TNF-alpha with or without LIPUS. Matrix mineralization was evaluated by alizarin red S staining. The expression of genes for osteogenic makers and for inflammatory cytokines were analyzed by real time RT-PCR.

Results:

LIPUS promoted BMP9-induced osteogenesis of hPDLSCs based on increases in both cell calcification and osteogenic marker expression. In contrast, LIPUS did not affect BMP2-induced osteogenic differentiation. LIPUS-induced Noggin expression was potentially involved in the differential response of the cells. Either LPS-PG, IL-1beta, or TNF-alpha-induced ERK phosphorylation and IL-8, CCL2, and RANKL expression were decreased in LIPUS-treated hPDLSCs. Moreover, the inhibitory effects of LPS-PG and IL-1beta on osteogenesis of hPDLSCs were significantly blocked by LIPUS.

Discussion:

LIPUS is an effective tool to promote osteogenic differentiation under inflammatory conditions.
Mistletoe fig (Ficus deltoidea Jack) leaf extract prevented postmenopausal osteoarthritis by attenuating inflammation and cartilage degradation in rat model
Authors: Che Ahmad Tantowi Nur Adeelah , Hussin Paisal , Lau Seng Fong , Mohamed Suhaila
Published: June 2017

Objective:

Ficus deltoidea Jack (mistletoe fig) is an ornamental plant found in various parts of the world and used as traditional herbal medicine in some countries. This study investigated the potential use of F deltoidea leaf extract to mitigate osteoarthritis (OA) in ovariectomized (estrogen-deficient postmenopausal model) rats and the mechanisms involved. Diclofenac was used for comparison.

Methods:

Sprague-Dawley female rats (12 weeks old) were divided randomly into five groups (n = 6): healthy; nontreated OA; OA + diclofenac (5 mg/kg); OA + extract (200 mg/kg); and OA + extract (400 mg/kg). Two weeks after bilaterally ovariectomy, OA was induced by intra-articular injection of monosodium iodoacetate into the right knee joints. After 28 days of treatment, the rats were evaluated for knee OA via physical (radiological and histological observations), biochemical, enzyme-linked immunosorbent assay, and gene expression analysis, for inflammation and cartilage degradation biomarkers.

Results:

The osteoarthritic rats treated with the extract, and diclofenac showed significant reduction of cartilage erosion (via radiological, macroscopic, and histological images) compared with untreated osteoarthritic rats. The elevated serum interleukin-1β, prostaglandin E2, and C-telopeptide type II collagen levels in osteoarthritic rats were significantly reduced by F deltoidea leaf extract comparable to diclofenac. The extract significantly down-regulated the interleukin-1β, prostaglandin E2 receptor, and matrix metalloproteinase-1 mRNA expressions in the osteoarthritic cartilages, similar to diclofenac.

Conclusions:

F deltoidea leaf extract mitigated postmenopausal osteoarthritic joint destruction by inhibiting inflammation and cartilage degradation enzymes, at an effective extract dose equivalent to about 60 mg/kg for humans. The main bioactive compounds are probably the antioxidative flavonoids vitexin and isovitexin.
Transcranial direct current stimulation effects on menopausal vasomotor symptoms
Authors: Bianchi Mônia Steigleder , Ferreira Charles Francisco , Fregni Felipe , Schestatsky Pedro , Caumo Wolnei , Wender Maria Celeste Osório
Published: June 2017

Objective:

To assess the effects of transcranial direct current stimulation (tDCS) compared with tDCS-sham on vasomotor symptoms of postmenopausal women.

Methods:

Postmenopausal women (N = 30), aged between 45 and 68 years, with at least four episodes of vasomotor symptoms per day, were recruited from a specialized outpatient clinic at a tertiary hospital in the south of Brazil and through a media call after inclusion and exclusion criteria were ensured. Active and tDCS-sham were administered over the motor cortex position (anode electrode) and contralateral supraorbital region (cathode electrode) for 10 consecutive days, except weekends. The number and intensity records of hot flashes were evaluated for 7 days before and along 30 days after the intervention. The Women's Health Questionnaire and the Hamilton Depression Rating Scale were applied to assess the quality of life and the depressive symptoms, respectively.

Results:

The frequencies of hot flashes per day happened in a similar way in both groups, with a reduction in the first 3 weeks after the intervention. There was a return in hot flash frequencies to baseline in the fourth week (week 0: 79.0 ± 6.2 and 75.8 ± 6.0, week 1: 61.6 ± 9.6 and 57.0 ± 7.8, week 2: 56.8 ± 8.9 and 55.9 ± 7.1, week 3: 56.8 ± 8.9 and 54.2 ± 7.2, week 4: 64.9 ± 10.7, 70.1 ± 8.9; tDCS-sham and tDCS groups, respectively). In the tDCS group, a trend towards a conversion of intensive hot flashes into mild ones was observed.

Conclusions:

Our results suggest that the tDCS technique showed small trends on postmenopausal vasomotor symptoms, justifying searches for more effective methods by which tDCS could reduce hot flashes.
The impact of Fiera, a women's personal care device, on genital engorgement as measured by thermography: a proof-of-principle study
Authors: Goldstein Irwin , Goldstein Sue , Millheiser Leah
Published: June 2017

Objective:

To determine the degree of vasoengorgement of the external genitalia caused by Fiera, a personal care device developed specifically to increase sexual arousal and interest. Time to onset of self-reported genital sexual arousal and development of responsive sexual desire were also measured.

Methods:

This nonblinded, prospective cohort, single-site study was conducted in women without sexual dysfunction between the ages of 18 and 70. Each participant underwent a single-visit procedure that established a baseline temperature of the external genitalia, followed by 15 minutes of Fiera use. A post-Fiera temperature assessment lasting 10 minutes was performed. Subjective measures assessed the development of genital arousal and responsive desire as a result of Fiera use.

Results:

Fourteen premenopausal and 12 postmenopausal participants completed the study. Mean time to reach genital arousal was 5.2 + 4.2 minutes in the premenopausal group, and 4.5 + 4.3 minutes in the postmenopausal group. Statistically significant increases in the temperature of the clitoris and vestibule were demonstrated in both groups up to 10 minutes after removal of Fiera. At the labia, temperature increase was significant up to 8 minutes in the premenopausal group and up to 2 minutes in the postmenopausal group. All of the participants experienced responsive sexual desire as a result of Fiera.

Conclusions:

Use of Fiera produced statistically significant increases in the temperature of the external genitalia, markers of vasoengorgement, in both the premenopausal and postmenopausal participants. The onset of genital sexual arousal was rapid in both groups, and responsive sexual desire was experienced by all of the participants.
Reduction in Diarrhea- and Rotavirus-related Healthcare Visits Among Children <5 Years of Age After National Rotavirus Vaccine Introduction in Zimbabwe
Authors: Mujuru Hilda A. , Yen Catherine , Nathoo Kusum J. , Gonah Nhamo A. , Ticklay Ismail , Mukaratirwa Arnold , Berejena Chipo , Tapfumanei Ottias , Chindedza Kenneth , Rupfutse Maxwell , Weldegebriel Goitom , Mwenda Jason M. , Burnett Eleanor , Tate Jacqueline E. , Parashar Umesh D. , Manangazira Portia
Published: June 2017

Background:

In Zimbabwe, rotavirus accounted for 41%–56% of acute diarrhea hospitalizations before rotavirus vaccine introduction in 2014. We evaluated rotavirus vaccination impact on acute diarrhea- and rotavirus-related healthcare visits in children.

Methods:

We examined monthly and annual acute diarrhea and rotavirus test-positive hospitalizations and Accident and Emergency Department visits among children <60 months of age at 3 active surveillance hospitals during 2012–2016; we compared prevaccine introduction (2012–2013) with postvaccine introduction (2015 and 2016) data for 2 of the hospitals. We examined monthly acute diarrhea hospitalizations by year and age group for 2013–2016 from surveillance hospital registers and monthly acute diarrhea outpatient visits reported to the Ministry of Health and Child Care during 2012–2016.

Results:

Active surveillance data showed winter seasonal peaks in diarrhea- and rotavirus-related visits among children <60 months of age during 2012–2014 that were substantially blunted in 2015 and 2016 after vaccine introduction; the percentage of rotavirus test-positive visits followed a similar seasonal pattern and decrease. Hospital register data showed similar pre-introduction seasonal variation and post-introduction declines in diarrhea hospitalizations among children 0–11 and 12–23 months of age. Monthly variation in outpatient diarrhea-related visits mirrored active surveillance data patterns. At 2 surveillance hospitals, the percentage of rotavirus-positive visits declined by 40% and 43% among children 0–11 months of age and by 21% and 33% among children 12–23 months of age in 2015 and 2016, respectively.

Conclusion:

Initial reductions in diarrheal illness among children <60 months of age, particularly among those 0–11 months of age, after vaccine introduction are encouraging. These early results provide evidence to support continued rotavirus vaccination and rotavirus surveillance in Zimbabwe.
Vitamin D Deficiency Is Not Associated With Growth or the Incidence of Common Morbidities Among Tanzanian Infants
Authors: Sudfeld Christopher R. , Manji Karim P. , Smith Emily R. , Aboud Said , Kisenge Rodrick , Fawzi Wafaie W. , Duggan Christopher P.
Published: June 2017

Objective:

The objective of this study was to examine risk factors for vitamin D deficiency and determine the association of vitamin D status with child growth and incidence of common morbidities among Tanzanian infants.

Methods:

A prospective cohort of 581 Tanzanian infants born to human immunodeficiency virus (HIV)‐uninfected mothers had serum 25‐hydroxyvitamin D assessed at 6 weeks and 6 months of age. Infants were seen at monthly clinic visits for growth monitoring until 18 months of age. Physicians examined infants every 3 months or when an illness was noted to document morbidities.

Results:

The prevalence of vitamin D deficiency (<20 ng/mL) declined from 76.4% at 6 weeks of age to 21.2% at 6 months. Infants who were exclusively breastfed at 6 weeks of age had 2.05 (95% confidence interval 1.11–3.79; P = 0.02) times the risk of vitamin D deficiency as compared formula‐fed infants. After multivariate adjustment, there was no association of vitamin D status at 6 weeks or 6 months with the incidence of stunting, wasting, or underweight. There was also no association of low vitamin D with the incidence of diarrhea, upper respiratory infection, acute lower respiratory tract infection, or malaria.

Conclusions:

Vitamin D deficiency is common during early infancy, particularly among exclusively breastfed infants; however, these observational data suggest it may not be an important contributor to morbidity and growth among the general population of Tanzanian infants. Future studies of vitamin D among high‐risk infants, including those with low birthweight and exposed to HIV, may be warranted.
European Society for Pediatric Gastroenterology Hepatology and Nutrition's Educational Offer and the Training Syllabus
Authors: Maglione Marco , Finizio Daniela , Veres Gabor , Pop Tudor L. , Continisio Grazia I. , Papadopoulou Alexandra , Guarino Alfredo
Published: June 2017

The basic knowledge necessary for a European pediatric gastroenterologist/hepatologist/nutritionist is set‐out in the training syllabus (TS) of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). We retrospectively compared the topics covered in ESPGHAN's training events between 2013 and 2016 with the basic knowledge TS items. Thirty‐six initiatives including e‐learning were identified. Twelve (33%) courses focused on gastroenterology, 9 (25%) on hepatology, and 10 (28%) on nutrition. Five (14%) courses covered >1 field and were classified “General.” The initiatives covered 12 of 57 (21%) TS items; 31 of 57 items (54%) were partially covered; and 14 of 57 (25%) not covered. Five of 9 e‐learning courses covered gastroenterology topics, whereas none covered hepatology topics. ESPGHAN's 3‐year educational offer partially met the training needs listed in the TS. A coordinated educational program covering all TS items would harmonize training within Europe and would provide trainees with a professional portfolio for employment purposes.
Prostate cancer immunotherapy: the path forward
Authors: Madan Ravi A. , Gulley James L.
Published: June 2017

Purpose of review

To provide an overview of current strategies being investigated in the development of immunotherapy in prostate cancer.

Recent findings

Development of immunotherapy in prostate cancer actually began in 2010 with FDA approval of sipuleucel-T. Given that immune checkpoint inhibitor trials have either been negative at the phase III level or underwhelming in smaller studies, it is likely that combination strategies will be required to further maximize the impact immune-based therapies on the clinical course of the disease. Emerging data suggests the presence of multiple checkpoint inhibitors in the prostate cancer tumor microenvironment highlighting the need for combination immunotherapy platforms that would potentially include androgen deprivation, chemotherapy, or radiation.

Preclinical and clinical data support immune-based combinations in prostate cancer and several trials are underway to better define the future of immunotherapy in prostate cancer.
The role of bone-targeted therapies for prostate cancer in 2017
Authors: Traboulsi Samer L. , Saad Fred
Published: June 2017

Purpose of review

Bone-targeted agents (BTAs), such as zoledronic acid and denosumab, delay the occurrence of skeletal-related events (SREs) in metastatic prostate cancer (PCa) patients. Recently, several agents, such as abiraterone acetate, enzalutamide and radium-223, were approved for the treatment of metastatic castration-resistant PCa (mCRPC). These agents resulted in improved overall survival (OS), pain control and had positive effects on bone health. Combining BTAs to the newly approved agents demonstrates additional benefits that warrant a review of available evidence looking at appropriate combination therapies and timing of BTAs for optimizing the management of advanced and metastatic PCa.

Recent findings

Post-hoc analyses of randomized trials demonstrated some benefits from combination therapy, such as increased OS when denosumab was used concurrently with radium-223 and when BTAs were used with abiraterone acetate. BTAs were not beneficial for the prevention of bone metastases.

There is a suggestion of synergy or additive effects between BTAs and new agents approved for the treatment of metastatic PCa, resulting in potential clinical benefits. Therefore, prospective randomized studies evaluating the safety and benefits of combination therapies to address gaps in the literature are needed to optimize treatment of mCRPC.
Experimental species removals impact the architecture of pollination networks
Authors: Brosi Berry J. , Niezgoda Kyle , Briggs Heather M.
Published: June 2017

Mutualistic networks are key for the creation and maintenance of biodiversity, yet are threatened by global environmental change. Most simulation models assume that network structure remains static after species losses, despite theoretical and empirical reasons to expect dynamic responses. We assessed the effects of experimental single bumblebee species removals on the structure of entire flower visitation networks. We hypothesized that network structure would change following processes linking interspecific competition with dietary niche breadth. We found that single pollinator species losses impact pollination network structure: resource complementarity decreased, while resource overlap increased. Despite marginally increased connectance, fewer plant species were visited after species removals. These changes may have negative functional impacts, as complementarity is important for maintaining biodiversity–ecological functioning relationships and visitation of rare plant species is critical for maintaining diverse plant communities.
On the occurrence of three non-native cichlid species including the first record of a feral population ofPelmatolapia(Tilapia)mariae(Boulenger, 1899) in Europe
Authors: Lukas Juliane A. Y. , Jourdan Jonas , Kalinkat Gregor , Emde Sebastian , Miesen Friedrich Wilhelm , Jüngling Hannah , Cocchiararo Berardino , Bierbach David
Published: June 2017

Thermally influenced freshwater systems provide suitable conditions for non-native species of tropical and subtropical origin to survive and form proliferating populations beyond their native ranges. In Germany, non-native convict cichlids (Amatitlania nigrofasciata) and tilapia (Oreochromissp.) have established populations in the Gillbach, a small stream that receives warm water discharge from a local power plant. Here, we report on the discovery of spotted tilapia (Pelmatolapia mariae) in the Gillbach, the first record of a reproducing population of this species in Europe. It has been hypothesized thatOreochromissp. in the Gillbach are descendants of aquaculture escapees and our mtDNA analysis found bothO. mossambicusandO. niloticusmaternal lineages, which are commonly used for hybrids in aquaculture. Convict cichlids and spotted tilapia were most probably introduced into the Gillbach by aquarium hobbyists. Despite their high invasiveness worldwide, we argue that all three cichlid species are unlikely to spread and persist permanently beyond the thermally influenced range of the Gillbach river system. However, convict cichlids from the Gillbach are known to host both native and non-native fish parasites and thus, non-native cichlids may constitute threats to the native fish fauna. We therefore strongly recommend continuous monitoring of the Gillbach and similar systems.
Energy-based analysis of biomolecular pathways
Authors: Gawthrop Peter J. , Crampin Edmund J.
Published: June 2017

Decomposition of biomolecular reaction networks into pathways is a powerful approach to the analysis of metabolic and signalling networks. Current approaches based on analysis of the stoichiometric matrix reveal information about steady-state mass flows (reaction rates) through the network. In this work, we show how pathway analysis of biomolecular networks can be extended using an energy-based approach to provide information about energy flows through the network. This energy-based approach is developed using the engineering-inspired bond graph methodology to represent biomolecular reaction networks. The approach is introduced using glycolysis as an exemplar; and is then applied to analyse the efficiency of free energy transduction in a biomolecular cycle model of a transporter protein [sodium-glucose transport protein 1 (SGLT1)]. The overall aim of our work is to present a framework for modelling and analysis of biomolecular reactions and processes which considers energy flows and losses as well as mass transport.
Neural Correlates of the Natural Observation of an Emotionally Loaded Video
Authors: Nanni Melanni , Martínez-Soto Joel , Gonzalez-Santos Leopoldo , Barrios Fernando A.
Published: June 2017

Studies based on a paradigm of free or natural viewing have revealed characteristics that allow us to know how the brain processes stimuli within a natural environment. This method has been little used to study brain function. With a connectivity approach, we examine the processing of emotions using an exploratory method to analyze functional magnetic resonance imaging (fMRI) data. This research describes our approach to modeling stress paradigms suitable for neuroimaging environments. We showed a short film (4.54 minutes) with high negative emotional valence and high arousal content to 24 healthy male subjects (36.42 years old; SD=12.14) during fMRI. Independent component analysis (ICA) was used to identify networks based on spatial statistical independence. Through this analysis we identified the sensorimotor system and its influence on the dorsal attention and default-mode networks, which in turn have reciprocal activity and modulate networks described as emotional.
Combining images and anatomical knowledge to improve automated vein segmentation in MRI
Authors: Ward Phillip G. D. , Ferris Nicholas J. , Raniga Parnesh , Dowe David L. , Ng Amanda C. L. , Barnes David G. , Egan Gary F.
Published: June 2017

Purpose

To improve the accuracy of automated vein segmentation by combining susceptibility-weighted images (SWI), quantitative susceptibility maps (QSM), and a vein atlas to produce a resultant image called a composite vein image (CV image).

Method

An atlas was constructed in common space from 1072 manually traced 2D-slices. The composite vein image was derived for each subject as a weighted sum of three inputs; a SWI image, a QSM image and the vein atlas. The weights for each input and each anatomical location, called template priors, were derived by assessing the accuracy of each input over an independent data set. The accuracy of venograms derived automatically from each of the CV image, SWI, and QSM image sets was assessed by comparison with manual tracings. Three different automated vein segmentation techniques were used, and ten performance metrics evaluated.

Results

Vein segmentations using the CV image were comprehensively better than those derived from SWI or QSM images (mean Cohen’s d = 1.1). Sixty permutations of performance metric and automated segmentation technique were evaluated. Vein identification improvements that were both large and significant (Cohen’s d>0.80, p<0.05) were found in 77% of the permutations, compared to no improvement in 5%.

Conclusion

The accuracy of automated venograms derived from the composite vein image was overwhelmingly superior to venograms derived from SWI or QSM alone.
Impact of fluorescent protein fusions on the bacterial flagellar motor
Authors: Heo M , Nord AL , Chamousset D , Rijn E van , Beaumont HJE , Pedaci F
Published: June 2017

Fluorescent fusion proteins open a direct and unique window onto protein function. However, they also introduce the risk of perturbation of the function of the native protein. Successful applications of fluorescent fusions therefore rely on a careful assessment and minimization of the side effects. Such insight, however, is still lacking for many applications of fluorescent fusions. This is particularly relevant in the study of the internal dynamics of motor protein complexes, where both the chemical and mechanical reaction coordinates can be affected. Fluorescent proteins fused to thestatorof the bacterial flagellar motor (BFM) complex have previously been used to successfully unveil the internal subunit dynamics of the motor. Here we report the effects of three different fluorescent proteins fused to the stator, all of which altered BFM behavior. The torque generated by individual stators was reduced while their stoichiometry in the complex remained unaffected. MotB fusions decreased the rotation-direction switching frequency of single motors and induced a novel BFM behavior: a bias-dependent asymmetry in the speed attained in the two rotation directions. All these effects could be mitigated by the insertion of a linker at the fusion point. These findings provide a quantitative account of the effects of fluorescent fusions on BFM dynamics and their alleviation—new insights that advance the use of fluorescent fusions to probe the dynamics of protein complexes.

Author summary

Much of what is known about the biology of proteins was discovered by fusing them to fluorescent proteins that allow detection of their location. But the label comes at a cost: the presence of the tag can alter the behavior of the protein of interest in unforeseen, yet biologically relevant ways. These side effects limit the depth to which fluorescent proteins can be used to probe protein function. One of the systems that has been successfully studied with fluorescent fusions for which these effects have not been addressed are dynamic protein complexes that carry out mechanical work. We examined how fluorescent proteins fused to a component of the bacterial flagellar motor complex impacts its function. Our findings show that the fusion proteins altered biologically relevant dynamical properties of the motor, including induction of a novel mechanical behavior, and demonstrate an approach to alleviate this. These results advance our ability to dissect the bacterial flagellar motor, and the internal dynamics of protein complexes in general, with fluorescent fusion proteins while causing minimal perturbation.
ORIGAMI: A Software Suite for Activated Ion Mobility Mass Spectrometry (aIM-MS) Applied To Multimeric Protein Assemblies
Authors: Migas Lukasz G. , France Aidan P. , Bellina Bruno , Barran Perdita E.
Published: June 2017

We present here a software suite (ORIGAMI) that facilitates the rapid acquisition and analysis of ion mobility data following collisional activation.ORIGAMIwas developed for use on Waters Synapt instruments where data acquisition is achieved by interfacing WREnS (Waters Research Enabled Software) and MassLynx. Two components are presented, the first isORIGAMIMSwhich enables activation of ions by sequential increase of collision voltages prior to ion mobility analysis. We demonstrate the use ofORIGAMIon the tetrameric assemblies formed by the proteins concanavalin A (103 kDa) and alcohol dehydrogenase (143 kDa). Activation is performed in the trap collision cell of the Synapt TriWave assembly, where the collision voltage can be ramped from 0-200 V. All of the acquired data is recorded in a single file which simplifies data acquisition. This substantially decreases the time needed to perform a typical activated IM-MS experiment on a single protein charge state from approx. 2 hours to ~25 minutes. Following data acquisition the data is analysed in the second component,ORIGAMIANALYSE, which allows the user to visualise the effect of activation on the mobility of the parent ion, as well as on any produced fragment ion. The user can export the data in the form of heat maps, waterfall or wire plots. In addition, tools implemented inORIGAMIenable easy data extraction from single or multiple MassLynx .raw files, in-depth interrogation of large datasets, statistical analysis and figure creation capabilities. We demonstrate the use ofORIGAMIon concanavalin A and alcohol dehydrogenase acquired using the traditional protocols and theORIGAMIMSmethod.

Highlights

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New methodology for faster acquisition and data analysis following activation of ions separated by ion mobility mass spectrometry

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Software package capable of simultaneous analysis of multiple MassLynx .raw files

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Visualization of the change in mobility of parent and fragment ions following activation

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Easy extraction, data processing and extensive plotting tools
The Diagnostic Potential & Interactive Dynamics of the Colorectal Cancer Virome
Authors: Hannigan Geoffrey D , Duhaime Melissa B , Ruffin Mack T , Koumpouras Charlie C , Schloss Patrick D
Published: June 2017

Human viruses (those that infect human cells) have been associated with many cancers, largely due to their mutagenic and functionally manipulative abilities. Despite this, cancer microbiome studies have almost exclusively focused on bacteria instead of viruses. We began evaluating the cancer virome by focusing on colorectal cancer, a primary cause of morbidity and mortality throughout the world, and a cancer linked to altered colonic bacterial community compositions but with an unknown association with the gut virome. We used 16S rRNA gene, whole shotgun metagenomic, and purified virus metagenomic sequencing of stool to evaluate the differences in human colorectal cancer virus and bacterial community composition. Through random forest modeling we identified differences in the healthy and colorectal cancer virome. The cancer-associated virome consisted primarily of temperate bacteriophages that were also predicted to be bacteria-virus community network hubs. These results provide foundational evidence that bacteriophage communities are associated with colorectal cancer and potentially impact cancer progression by altering the bacterial host communities.
Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA
Authors: Fell Stuart M. , Li Shuijie , Wallis Karin , Kock Anna , Surova Olga , Rraklli Vilma , Höfig Carolin S. , Li Wenyu , Mittag Jens , Henriksson Marie Arsenian , Kenchappa Rajappa S. , Holmberg Johan , Kogner Per , Schlisio Susanne
Published: June 2017

We recently identified pathogenic KIF1Bβ mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted KIF1Bβ in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bβ is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA. Moreover, pathogenic KIF1Bβ mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both KIF1Bβ-deficient mouse neuroblasts and human neuroblastomas that lack KIF1Bβ. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1Bβ independent of MYCN amplification and the loss of genes neighboring KIF1B on chromosome 1p36. Thus, defective precursor cell differentiation, a common trait of aggressive childhood malignancies, is a pathogenic effect of KIF1Bβ loss in neuroblastomas. Furthermore, neuropathy-associated KIF1Bβ mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration.
Is internal and external mechanism of governance enriching the performance of the banking sector of Pakistan?
Authors: Sohail Sundas , Rasul Farhat , Fatima Ummara
Published: June 2017

Purpose

The purpose of this study is to explore how governance mechanisms (internal and external) enhance the performance of the return on asset (ROA), return on equity (ROE), earning per share (EPS) and dividend payout ratios (DP) of the banks of Pakistan. The study incorporates not only the internal factors of governance (board size, out-ratio, annual general meeting, managerial ownership, institutional ownership, block holder stock ownership and financial transparency) but also the external factors (legal infrastructure and protection of minority shareholders, and the market for corporate control).

Design/methodology/approach

The sample size of the study consists of 30 banks (public, private and specialized) listed at the Pakistan Stock Exchange (PSE) for the period 2008-2014. The panel data techniques (fixed or random effect model) have been used for the empirical analysis after verification by Hausman (1978) test.

Findings

The results revealed that not only do the internal mechanisms of governance enhance the performance of the banking sector of Pakistan but external governance also plays a substantial role in enriching the performance. The findings conclude that for a good governance structure, both internal and external mechanisms are equally important, to accelerate the performance of the banking sector.

Research limitations/implications

Internal and external mechanisms of corporate governance can also be checked by adding some more variables (ownership i.e. foreign, female and family as internal and auditor as external), but they are not added in this work due to data unavailability.

Practical implications

The study contributes to the literature and could be useful for the policy makers who need to force banks to mandate codes of governance through which they can create an efficient board structure and augment the performance. The investments from different forms of ownership can be accelerated if they follow the codes properly.

Social implications

The study facilitates the bankers in incorporating sound codes of corporate governance to enhance the performance of the banks.

Originality/value

This work is unique as no one has explored the impact of external mechanism of governance on the performance of the banking sector of Pakistan.
A spherical element subdivision method for the numerical evaluation of nearly singular integrals in 3D BEM
Authors: Zhang Jianming , Wang Pan , Lu Chenjun , Dong Yunqiao
Published: June 2017

Purpose

The purpose of this paper is to preset a spherical element subdivision method for the numerical evaluation of nearly singular integrals in three-dimensional (3D) boundary element method (BEM).

Design/methodology/approach

In this method, the source point is first projected to the tangent plane of the element. Then two cases are considered: the projection point is either inside or outside the element. In both cases, the element is subdivided into a number of patches using a sequence of spheres with decreasing radius.

Findings

With the proposed method, the patches obtained are automatically refined as they approach the projection point and each patch of the integration element is “good” in shape and size for standard Gaussian quadrature. Therefore, all kinds of nearly singular boundary integrals on elements of any shape and size with arbitrary source point location related to the element can be evaluated accurately and efficiently.

Originality/value

Numerical examples for planar and slender elements with various relative location of the source point are presented. The results demonstrate that our method has much better accuracy, efficiency and stability than conventional methods.