bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise performance in young patients with complete atrioventricular block: the relevance of synchronous atrioventricular pacing
Authors: Gonzalez Corcia M. Cecilia , Remy Lorraine Saint , Marchandise Sebastien , Moniotte Stephane
Published: January 2016

At present, there are many pacing strategies for young patients with complete atrioventricular block. The most frequent policy is to attempt placing a dual-chamber system when possible; however, there is a group of patients that is functioning with a non-synchronous ventricular pacing, raising the question of the ideal timing to upgrade their systems. We investigated the exercise performance of a group of children and young adults with complete atrioventricular block and dual-chamber pacemakers in both single- and dual-chamber pacing modalities. A total of 15 patients performed maximal exercise stress testing after programming the VVIR or DDD modes with 2 hours of interval in a double-blind study protocol.

Compared with VVIR pacing, DDD pacing resulted in increase in the peak VO2, longer test duration, major increase in the heart rate achieved during peak exercise, decreased systemic non-invasive arterial blood pressure measured at maximal exercise, higher maximal workload, prolongation of the anaerobic threshold timing, and better self-rated performance perception in all the patients.

Synchronous atrioventricular pacing contributes to an increase in both the exercise performance and the performance perception in 100% of the patients. This difference contributes to create a sense of “fitness” with repercussions in the overall health, self-esteem, and life quality, as well as encourages youngster to practice sports. Our experience tends to favour upgrading patients’ systems to dual-chamber systems before reaching the adolescent years, even if the centre policy is to prolong as long as possible the epicardial site in order to avoid long years of right ventricular pacing.
The expression of spatial relationships in Turkish–Dutch bilinguals
Authors: INDEFREY PETER , ŞAHIN HÜLYA , GULLBERG MARIANNE
Published: January 2016

We investigated how two groups of Turkish–Dutch bilinguals and two groups of monolingual speakers of the two languages described static topological relations. The bilingual groups differed with respect to their first (L1) and second (L2) language proficiencies and a number of sociolinguistic factors. Using an elicitation tool that covers a wide range of topological relations, we first assessed the extensions of different spatial expressions (topological relation markers, TRMs) in the Turkish and Dutch spoken by monolingual speakers. We then assessed differences in the use of TRMs between the two bilingual groups and monolingual speakers.

In both bilingual groups, differences compared to monolingual speakers were mainly observed for Turkish. Dutch-dominant bilinguals showed enhanced congruence between translation-equivalent Turkish and Dutch TRMs. Turkish-dominant bilinguals extended the use of a topologically neutral locative marker.

Our results can be interpreted as showing different “bilingual optimization strategies” (Muysken, 2013) in bilingual speakers who live in the same environment but differ with respect to L2 onset, L2 proficiency, and perceived importance of the L1.
Conditioned to eat while watching television? Low-income caregivers’ perspectives on the role of snacking and television viewing among pre-schoolers
Authors: Blaine Rachel E , Fisher Jennifer Orlet , Blake Christine E , Orloski Alexandria , Younginer Nicholas , Bruton Yasmeen , Ganter Claudia , Rimm Eric B , Geller Alan C , Davison Kirsten K
Published: January 2016

Objective

Although television (TV) viewing is frequently paired with snacking among young children, little is known about the environment in which caregivers promote this behaviour. We describe low-income pre-schoolers’ snacking and TV viewing habits as reported by their primary caregivers, including social/physical snacking contexts, types of snacks and caregiver rationales for offering snacks. These findings may support the development of effective messages to promote healthy child snacking.

Design

Semi-structured interviews assessed caregiver conceptualizations of pre-schoolers’ snacks, purpose of snacks, snack context and snack frequency.

Setting

Interviews occurred in Boston, Massachusetts and Philadelphia, Pennsylvania, USA.

Subjects

Forty-seven low-income multi-ethnic primary caregivers of children aged 3–5 years (92 % female, 32 % Hispanic/Latino, 34 % African American) described their child’s snacking in the context of TV viewing.

Results

TV viewing and child snacking themes were described consistently across racial/ethnic groups. Caregivers described snacks offered during TV viewing as largely unhealthy. Labels for TV snacks indicated non-nutritive purposes, such as ‘time out’, ‘enjoyment’ or ‘quiet.’ Caregivers’ primary reasons for providing snacks included child’s expectations, behaviour management (e.g. to occupy child) and social time (e.g. family bonding). Some caregivers used TV to distract picky children to eat more food. Child snacking and TV viewing were contextually paired by providing child-sized furniture (‘TV table’) specifically for snacking.

Conclusions

Low-income caregivers facilitate pre-schoolers’ snacking and TV viewing, which are described as routine, positive and useful for non-nutritive purposes. Messages to caregivers should encourage ‘snack-free’ TV viewing, healthy snack options and guidance for managing children’s behaviour without snacks or TV.
Public perceptions of cooking and the implications for cooking behaviour in the USA
Authors: Wolfson Julia A , Smith Katherine Clegg , Frattaroli Shannon , Bleich Sara N
Published: January 2016

Objective

Despite the importance of cooking in modern life, public perceptions about what it means to cook are unknown. We aimed to examine perceptions of cooking and their association with cooking confidence, attitudes and behaviours in the USA.

Design

We designed and fielded a nationally representative survey among US adults (n 1112) in April 2015. We used factor analysis to identify perceptions about cooking and multivariate ordered logit and Poisson models to explore associations between those perceptions and cooking confidence, attitudes and behaviours.

Setting

Nationally representative web-based survey of US adults.

Subjects

US adults aged ≥18 years.

Results

Americans conceptualized cooking in three ways: the use of scratch ingredients, convenience foods and not using heat. Respondents who perceived cooking as including convenience foods were less confident in their ability to cook from scratch (OR=0·52, P<0·001) and less likely to enjoy cooking (OR=0·68, P=0·01) than those who did not. Although individuals who perceived cooking as including only scratch ingredients reported cooking dinner (4·31 times/week) and using packaged/boxed products (0·95 times/week) the least frequently, few notable differences in the frequency of cooking meals were observed.

Conclusions

Cooking frequency is similar among US adults regardless of how they perceive cooking, but cooking confidence and enjoyment are lowest among Americans who perceive cooking as including the use of convenience foods. These insights should inform the development of more specific measures of cooking behaviour as well as meaningful and targeted public health messages to encourage healthier cooking.
The meaning of occupation for patients in palliative care when in hospital
Authors: Eriksson Lina , Öster Inger , Lindberg Margareta
Published: January 2016

Objective:

The aim of this study was to describe how patients in palliative care relate to occupation during hospitalization and to define the meaning it has for them.

Method:

Eight inpatients in palliative care with various cancer diagnoses were interviewed one time. These interviews were transcribed and analyzed using qualitative content analysis.

Results:

Patients experience occupations as meaningful when in hospital during the last period of their lives. They would like to be able to handle their own needs as much as possible. Staff behavior, the design of the environment, the lack of accessible occupations, and the degree to which patients can decide whether to receive or decline visits affect the possibility to make their wishes a reality. Our results also revealed that patients experience a sense of loss of their role, as well as a lack of control and participation.

Significance of Results:

Our results confirm the importance of occupation and of patients having the option to and being given opportunities to take care of themselves when in palliative care. Further studies are needed to enable us to understand how organized occupations might influence patients' experience of being in a hospital during the final period of life.
Endocytosis and serpentine filopodia drive blebbishield-mediated resurrection of apoptotic cancer stem cells
Authors: Jinesh G G , Kamat A M
Published: January 2016

The blebbishield emergency program helps to resurrect apoptotic cancer stem cells (CSCs) themselves. Understanding the mechanisms behind this program is essential to block resurrection of CSCs during cancer therapy. Here we demonstrate that endocytosis drives serpentine filopodia to construct blebbishields from apoptotic bodies and that a VEGF-VEGFR2-endocytosis-p70S6K axis governs subsequent transformation. Disengagement of RalGDS from E-cadherin initiates endocytosis of RalGDS and its novel interaction partners cdc42, VEGFR2, cleaved β-catenin, and PKC-ζ as well as its known interaction partner K-Ras. We also report novel interactions of p45S6K (cleaved p70S6K) and PKM-ζ with PAK-1 filopodia-forming machinery specifically in blebbishields. Thus, a RalGDS-endocytosis-filopodia-VEGFR2-K-Ras-p70S6K axis drives the blebbishield emergency program, and therapeutic targeting of this axis might prevent resurrection of CSCs during cancer therapy.
Functional characterization of the ectopically expressed olfactory receptor 2AT4 in human myelogenous leukemia
Authors: Manteniotis S , Wojcik S , Brauhoff P , Möllmann M , Petersen L , Göthert JR , Schmiegel W , Dührsen U , Gisselmann G , Hatt H
Published: January 2016

The olfactory receptor (OR) family was found to be expressed mainly in the nasal epithelium. In the last two decades members of the OR family were detected to be functional expressed in different parts of the human body such as in liver, prostate or intestine cancer cells. Here, we detected the expression of several ORs in the human chronic myelogenous leukemia (CML) cell line K562 and in white blood cells of clinically diagnosed acute myeloid leukemia (AML) patients by RT-PCR and next-generation sequencing. With calcium-imaging, we characterized in greater detail the cell biological role of one OR (OR2AT4) in leukemia. In both cell systems, the OR2AT4 agonist Sandalore-evoked strong Ca2+ influx via the adenylate cyclase-cAMP-mediated pathway. The OR2AT4 antagonist Phenirat prevented the Sandalore-induced intracellular Ca2+ increase. Western blot and flow cytometric experiments revealed that stimulation of OR2AT4 reduced the proliferation by decreasing p38-MAPK phosphorylation and induced apoptosis via phosphorylation of p44/42-MAPK. Furthermore, Sandalore increased the number of hemoglobin-containing cells in culture. We described for the first time an OR-mediated pathway in CML and AML that can regulate proliferation, apoptosis and differentiation after activation. This mechanism offers novel therapeutic options for the treatment of AML.
Deciphering associations between dissolved organic molecules and bacterial communities in a pelagic marine system
Authors: Osterholz Helena , Singer Gabriel , Wemheuer Bernd , Daniel Rolf , Simon Meinhard , Niggemann Jutta , Dittmar Thorsten
Published: January 2016

Dissolved organic matter (DOM) is the main substrate and energy source for heterotrophic bacterioplankton. To understand the interactions between DOM and the bacterial community (BC), it is important to identify the key factors on both sides in detail, chemically distinct moieties in DOM and the various bacterial taxa. Next-generation sequencing facilitates the classification of millions of reads of environmental DNA and RNA amplicons and ultrahigh-resolution mass spectrometry yields up to 10 000 DOM molecular formulae in a marine water sample. Linking this detailed biological and chemical information is a crucial first step toward a mechanistic understanding of the role of microorganisms in the marine carbon cycle. In this study, we interpreted the complex microbiological and molecular information via a novel combination of multivariate statistics. We were able to reveal distinct relationships between the key factors of organic matter cycling along a latitudinal transect across the North Sea. Total BC and DOM composition were mainly driven by mixing of distinct water masses and presumably retain their respective terrigenous imprint on similar timescales on their way through the North Sea. The active microbial community, however, was rather influenced by local events and correlated with specific DOM molecular formulae indicative of compounds that are easily degradable. These trends were most pronounced on the highest resolved level, that is, operationally defined ‘species’, reflecting the functional diversity of microorganisms at high taxonomic resolution.
Niche partitioning and biogeography of high light adapted Prochlorococcus across taxonomic ranks in the North Pacific
Authors: Larkin Alyse A , Blinebry Sara K , Howes Caroline , Lin Yajuan , Loftus Sarah E , Schmaus Carrie A , Zinser Erik R , Johnson Zackary I
Published: January 2016

The distribution of major clades of Prochlorococcus tracks light, temperature and other environmental variables; yet, the drivers of genomic diversity within these ecotypes and the net effect on biodiversity of the larger community are poorly understood. We examined high light (HL) adapted Prochlorococcus communities across spatial and temporal environmental gradients in the Pacific Ocean to determine the ecological drivers of population structure and diversity across taxonomic ranks. We show that the Prochlorococcus community has the highest diversity at low latitudes, but seasonality driven by temperature, day length and nutrients adds complexity. At finer taxonomic resolution, some ‘sub-ecotype’ clades have unique, cohesive responses to environmental variables and distinct biogeographies, suggesting that presently defined ecotypes can be further partitioned into ecologically meaningful units. Intriguingly, biogeographies of the HL-I sub-ecotypes are driven by unique combinations of environmental traits, rather than through trait hierarchy, while the HL-II sub-ecotypes appear ecologically similar, thus demonstrating differences among these dominant HL ecotypes. Examining biodiversity across taxonomic ranks reveals high-resolution dynamics of Prochlorococcus evolution and ecology that are masked at phylogenetically coarse resolution. Spatial and seasonal trends of Prochlorococcus communities suggest that the future ocean may be comprised of different populations, with implications for ecosystem structure and function.
Comparative genomics reveals new evolutionary and ecological patterns of selenium utilization in bacteria
Authors: Peng Ting , Lin Jie , Xu Yin-Zhen , Zhang Yan
Published: January 2016

Selenium (Se) is an important micronutrient for many organisms, which is required for the biosynthesis of selenocysteine, selenouridine and Se-containing cofactor. Several key genes involved in different Se utilization traits have been characterized; however, systematic studies on the evolution and ecological niches of Se utilization are very limited. Here, we analyzed more than 5200 sequenced organisms to examine the occurrence patterns of all Se traits in bacteria. A global species map of all Se utilization pathways has been generated, which demonstrates the most detailed understanding of Se utilization in bacteria so far. In addition, the selenophosphate synthetase gene, which is used to define the overall Se utilization, was also detected in some organisms that do not have any of the known Se traits, implying the presence of a novel Se form in this domain. Phylogenetic analyses of components of different Se utilization traits revealed new horizontal gene transfer events for each of them. Moreover, by characterizing the selenoproteomes of all organisms, we found a new selenoprotein-rich phylum and additional selenoprotein-rich species. Finally, the relationship between ecological environments and Se utilization was investigated and further verified by metagenomic analysis of environmental samples, which indicates new macroevolutionary trends of each Se utilization trait in bacteria. Our data provide insights into the general features of Se utilization in bacteria and should be useful for a further understanding of the evolutionary dynamics of Se utilization in nature.
Unexpected seasonality in quantity and composition of Amazon rainforest air reactivity
Authors: Nölscher A. C. , Yañez-Serrano A. M. , Wolff S. , de Araujo A. Carioca , Lavrič J. V. , Kesselmeier J. , Williams J.
Published: January 2016

The hydroxyl radical (OH) removes most atmospheric pollutants from air. The loss frequency of OH radicals due to the combined effect of all gas-phase OH reactive species is a measureable quantity termed total OH reactivity. Here we present total OH reactivity observations in pristine Amazon rainforest air, as a function of season, time-of-day and height (0–80 m). Total OH reactivity is low during wet (10 s−1) and high during dry season (62 s−1). Comparison to individually measured trace gases reveals strong variation in unaccounted for OH reactivity, from 5 to 15% missing in wet-season afternoons to mostly unknown (average 79%) during dry season. During dry-season afternoons isoprene, considered the dominant reagent with OH in rainforests, only accounts for ∼20% of the total OH reactivity. Vertical profiles of OH reactivity are shaped by biogenic emissions, photochemistry and turbulent mixing. The rainforest floor was identified as a significant but poorly characterized source of OH reactivity.
Broadband single-molecule excitation spectroscopy
Authors: Piatkowski Lukasz , Gellings Esther , van Hulst Niek F.
Published: January 2016

Over the past 25 years, single-molecule spectroscopy has developed into a widely used tool in multiple disciplines of science. The diversity of routinely recorded emission spectra does underpin the strength of the single-molecule approach in resolving the heterogeneity and dynamics, otherwise hidden in the ensemble. In early cryogenic studies single molecules were identified by their distinct excitation spectra, yet measuring excitation spectra at room temperature remains challenging. Here we present a broadband Fourier approach that allows rapid recording of excitation spectra of individual molecules under ambient conditions and that is robust against blinking and bleaching. Applying the method we show that the excitation spectra of individual molecules exhibit an extreme distribution of solvatochromic shifts and distinct spectral shapes. Importantly, we demonstrate that the sensitivity and speed of the broadband technique is comparable to that of emission spectroscopy putting both techniques side-by-side in single-molecule spectroscopy.
Producing air-stable monolayers of phosphorene and their defect engineering
Authors: Pei Jiajie , Gai Xin , Yang Jiong , Wang Xibin , Yu Zongfu , Choi Duk-Yong , Luther-Davies Barry , Lu Yuerui
Published: January 2016

It has been a long-standing challenge to produce air-stable few- or monolayer samples of phosphorene because thin phosphorene films degrade rapidly in ambient conditions. Here we demonstrate a new highly controllable method for fabricating high quality, air-stable phosphorene films with a designated number of layers ranging from a few down to monolayer. Our approach involves the use of oxygen plasma dry etching to thin down thick-exfoliated phosphorene flakes, layer by layer with atomic precision. Moreover, in a stabilized phosphorene monolayer, we were able to precisely engineer defects for the first time, which led to efficient emission of photons at new frequencies in the near infrared at room temperature. In addition, we demonstrate the use of an electrostatic gate to tune the photon emission from the defects in a monolayer phosphorene. This could lead to new electronic and optoelectronic devices, such as electrically tunable, broadband near infrared lighting devices operating at room temperature.
Nanoscale manipulation of the Mott insulating state coupled to charge order in 1T-TaS2
Authors: Cho Doohee , Cheon Sangmo , Kim Ki-Seok , Lee Sung-Hoon , Cho Yong-Heum , Cheong Sang-Wook , Yeom Han Woong
Published: January 2016

The controllability over strongly correlated electronic states promises unique electronic devices. A recent example is an optically induced ultrafast switching device based on the transition between the correlated Mott insulating state and a metallic state of a transition metal dichalcogenide 1T-TaS2. However, the electronic switching has been challenging and the nature of the transition has been veiled. Here we demonstrate the nanoscale electronic manipulation of the Mott state of 1T-TaS2. The voltage pulse from a scanning tunnelling microscope switches the insulating phase locally into a metallic phase with irregularly textured domain walls in the charge density wave order inherent to this Mott state. The metallic state is revealed as a correlated phase, which is induced by the moderate reduction of electron correlation due to the charge density wave decoherence.
The lack of the Celf2a splicing factor converts a Duchenne genotype into a Becker phenotype
Authors: Martone J. , Briganti F. , Legnini I. , Morlando M. , Picillo E. , Sthandier O. , Politano L. , Bozzoni I.
Published: January 2016

Substitutions, deletions and duplications in the dystrophin gene lead to either the severe Duchenne muscular dystrophy (DMD) or mild Becker muscular dystrophy depending on whether out-of-frame or in-frame transcripts are produced. We identified a DMD case (GSΔ44) where the correlation between genotype and phenotype is not respected, even if carrying a typical Duchenne mutation (exon 44 deletion) a Becker-like phenotype was observed. Here we report that in this patient, partial restoration of an in-frame transcript occurs by natural skipping of exon 45 and that this is due to the lack of Celf2a, a splicing factor that interacts with exon 45 in the dystrophin pre-mRNA. Several experiments are presented that demonstrate the central role of Celf2a in controlling exon 45 splicing; our data point to this factor as a potential target for the improvement of those DMD therapeutic treatments, which requires exon 45 skipping.
A simple and novel way of maintaining constant wall temperature in microdevices
Authors: Duryodhan V. S. , Singh Abhimanyu , Singh Shiv Govind , Agrawal Amit
Published: January 2016

Constant wall temperature /homogeneity in wall temperature is the need of various lab-on-chip devices employed in biological and chemical investigations. However method to maintain this condition does not seem to be available. In this work, a novel and simple way of maintaining constant wall temperature is proposed. A diverging microchannel along with conjugate effects is utilized towards this end. Both measurements and three dimensional numerical simulations are undertaken to prove the design. The investigation has been carried out over a large parameter range (divergence angle: 1–8°; length: 10–30 mm; depth: 86–200 μm; solid-to-fluid thickness ratio: 1.5–4.0 and solid-to-fluid thermal conductivity ratio: 27–646) and input conditions (mass flow rate: 4.17 × 10−5 −9.17 × 10−5 kg/s, heat flux: 2.4–9.6 W/cm2) which helped in establishing the finding. It is observed that a nearly constant wall temperature condition can be achieved over a large parameter range investigated. A model to arrive at the design parameter values is also proposed. The method is further demonstrated for series of microchannels where we successfully maintain each station at different temperature within ±1 °C. The finding is therefore significant and can be employed in both single and multi-stage processes such as PCR requiring different constant wall temperature with a fine resolution.
Ratchet transport powered by chiral active particles
Authors: Ai Bao-quan
Published: January 2016

We numerically investigate the ratchet transport of mixtures of active and passive particles in a transversal asymmetric channel. A big passive particle is immersed in a ‘sea’ of active particles. Due to the chirality of active particles, the longitudinal directed transport is induced by the transversal asymmetry. For the active particles, the chirality completely determines the direction of the ratchet transport, the counterclockwise and clockwise particles move to the opposite directions and can be separated. However, for the passive particle, the transport behavior becomes complicated, the direction is determined by competitions among the chirality, the self-propulsion speed and the packing fraction. Interestingly, within certain parameters, the passive particle moves to the left, while active particles move to the right. In addition, there exist optimal parameters (the chirality, the height of the barrier, the self-propulsion speed and the packing fraction) at which the rectified efficiency takes its maximal value. Our findings could be used for the experimental pursuit of the ratchet transport powered by chiral active particles.
Controlling condensation and frost growth with chemical micropatterns
Authors: Boreyko Jonathan B. , Hansen Ryan R. , Murphy Kevin R. , Nath Saurabh , Retterer Scott T. , Collier C. Patrick
Published: January 2016

In-plane frost growth on chilled hydrophobic surfaces is an inter-droplet phenomenon, where frozen droplets harvest water from neighboring supercooled liquid droplets to grow ice bridges that propagate across the surface in a chain reaction. To date, no surface has been able to passively prevent the in-plane growth of ice bridges across the population of supercooled condensate. Here, we demonstrate that when the separation between adjacent nucleation sites for supercooled condensate is properly controlled with chemical micropatterns prior to freezing, inter-droplet ice bridging can be slowed and even halted entirely. Since the edge-to-edge separation between adjacent supercooled droplets decreases with growth time, deliberately triggering an early freezing event to minimize the size of nascent condensation was also necessary. These findings reveal that inter-droplet frost growth can be passively suppressed by designing surfaces to spatially control nucleation sites and by temporally controlling the onset of freezing events.
Correction: Corrigendum: Reduced grazing pressure delivers production and environmental benefits for the typical steppe of north China
Authors: Zhang Yingjun , Huang Ding , Badgery Warwick B. , Kemp David R. , Chen Wenqing , Wang Xiaoya , Liu Nan
Published: January 2016

Degradation by overgrazing is common in many areas of the world and optimising grassland functions depends upon finding suitable grazing tactics. This four-year study on the northern China steppe investigated combinations of rest, moderate or heavy grazing pressure early in the summer growing season, then moderate or heavy grazing in the mid and late season. Results showed that moderate grazing pressure (~550 sheep equivalent (SE) grazing days ha−1 year−1) gave the optimal balance between maintaining a productive and diverse grassland, a profitable livestock system, and greenhouse gas mitigation. Further analyses identified that more conservative stocking (~400 SE grazing days ha−1 year−1) maintained a desirable Leymus chinensis composition and achieved a higher live weight gain of sheep. Early summer rest best maintained a desirable grassland composition, but had few other benefits and reduced incomes. These findings demonstrate that reducing grazing pressure to half the current district stocking rates can deliver improved ecosystem services (lower greenhouse gases and improved grassland composition) while sustaining herder incomes.
An endometrial gene expression signature accurately predicts recurrent implantation failure after IVF
Authors: Koot Yvonne E. M. , van Hooff Sander R. , Boomsma Carolien M. , van Leenen Dik , Groot Koerkamp Marian J. A. , Goddijn Mariëtte , Eijkemans Marinus J. C. , Fauser Bart C. J. M. , Holstege Frank C. P. , Macklon Nick S.
Published: January 2016

The primary limiting factor for effective IVF treatment is successful embryo implantation. Recurrent implantation failure (RIF) is a condition whereby couples fail to achieve pregnancy despite consecutive embryo transfers. Here we describe the collection of gene expression profiles from mid-luteal phase endometrial biopsies (n = 115) from women experiencing RIF and healthy controls. Using a signature discovery set (n = 81) we identify a signature containing 303 genes predictive of RIF. Independent validation in 34 samples shows that the gene signature predicts RIF with 100% positive predictive value (PPV). The strength of the RIF associated expression signature also stratifies RIF patients into distinct groups with different subsequent implantation success rates. Exploration of the expression changes suggests that RIF is primarily associated with reduced cellular proliferation. The gene signature will be of value in counselling and guiding further treatment of women who fail to conceive upon IVF and suggests new avenues for developing intervention.
CRMAGE: CRISPR Optimized MAGE Recombineering
Authors: Ronda Carlotta , Pedersen Lasse Ebdrup , Sommer Morten O. A. , Nielsen Alex Toftgaard
Published: January 2016

A bottleneck in metabolic engineering and systems biology approaches is the lack of efficient genome engineering technologies. Here, we combine CRISPR/Cas9 and λ Red recombineering based MAGE technology (CRMAGE) to create a highly efficient and fast method for genome engineering of Escherichia coli. Using CRMAGE, the recombineering efficiency was between 96.5% and 99.7% for gene recoding of three genomic targets, compared to between 0.68% and 5.4% using traditional recombineering. For modulation of protein synthesis (small insertion/RBS substitution) the efficiency was increased from 6% to 70%. CRMAGE can be multiplexed and enables introduction of at least two mutations in a single round of recombineering with similar efficiencies. PAM-independent loci were targeted using degenerate codons, thereby making it possible to modify any site in the genome. CRMAGE is based on two plasmids that are assembled by a USER-cloning approach enabling quick and cost efficient gRNA replacement. CRMAGE furthermore utilizes CRISPR/Cas9 for efficient plasmid curing, thereby enabling multiple engineering rounds per day. To facilitate the design process, a web-based tool was developed to predict both the λ Red oligos and the gRNAs. The CRMAGE platform enables highly efficient and fast genome editing and may open up promising prospective for automation of genome-scale engineering.
Lactate Chemical Exchange Saturation Transfer (LATEST) Imaging in vivo: A Biomarker for LDH Activity
Authors: DeBrosse Catherine , Nanga Ravi Prakash Reddy , Bagga Puneet , Nath Kavindra , Haris Mohammad , Marincola Francesco , Schnall Mitchell D. , Hariharan Hari , Reddy Ravinder
Published: January 2016

Non-invasive imaging of lactate is of enormous significance in cancer and metabolic disorders where glycolysis dominates. Here, for the first time, we describe a chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) method (LATEST), based on the exchange between lactate hydroxyl proton and bulk water protons to image lactate with high spatial resolution. We demonstrate the feasibility of imaging lactate with LATEST in lactate phantoms under physiological conditions, in a mouse model of lymphoma tumors and in skeletal muscle of healthy human subjects pre- and post-exercise. The method is validated by measuring LATEST changes in lymphoma tumors pre- and post-infusion of pyruvate and correlating them with lactate determined from multiple quantum filtered proton magnetic resonance spectroscopy (SEL-MQC 1H-MRS). Similarly, dynamic LATEST changes in exercising human skeletal muscle are correlated with lactate determined from SEL-MQC 1H-MRS. The LATEST method does not involve injection of radioactive isotopes or labeled metabolites. It has over two orders of magnitude higher sensitivity compared to conventional 1H-MRS. It is anticipated that this technique will have a wide range of applications including diagnosis and evaluation of therapeutic response of cancer, diabetes, cardiac and musculoskeletal diseases. The advantages of LATEST over existing methods and its potential challenges are discussed.
Divergent targets of glycolysis and oxidative phosphorylation result in additive effects of metformin and starvation in colon and breast cancer
Authors: Marini Cecilia , Bianchi Giovanna , Buschiazzo Ambra , Ravera Silvia , Martella Roberto , Bottoni Gianluca , Petretto Andrea , Emionite Laura , Monteverde Elena , Capitanio Selene , Inglese Elvira , Fabbi Marina , Bongioanni Francesca , Garaboldi Lucia , Bruzzi Paolo , Orengo Anna Maria , Raffaghello Lizzia , Sambuceti Gianmario
Published: January 2016

Emerging evidence demonstrates that targeting energy metabolism is a promising strategy to fight cancer. Here we show that combining metformin and short-term starvation markedly impairs metabolism and growth of colon and breast cancer. The impairment in glycolytic flux caused by starvation is enhanced by metformin through its interference with hexokinase II activity, as documented by measurement of 18F-fluorodeoxyglycose uptake. Oxidative phosphorylation is additively compromised by combined treatment: metformin virtually abolishes Complex I function; starvation determines an uncoupled status of OXPHOS and amplifies the activity of respiratory Complexes II and IV thus combining a massive ATP depletion with a significant increase in reactive oxygen species. More importantly, the combined treatment profoundly impairs cancer glucose metabolism and virtually abolishes lesion growth in experimental models of breast and colon carcinoma. Our results strongly suggest that energy metabolism is a promising target to reduce cancer progression.
DNMT3L enables accumulation and inheritance of epimutations in transgenic Drosophila
Authors: Basu Amitava , Tomar Archana , Dasari Vasanthi , Mishra Rakesh Kumar , Khosla Sanjeev
Published: January 2016

DNMT3L is an important epigenetic regulator in mammals, integrating DNA methylation and histone modification based epigenetic circuits. Here we show DNMT3L to be a part of the machinery that enables inheritance of epigenetic modifications from one generation to the next. Ectopic expression of DNMT3L in Drosophila, which lacks DNMT3L and its normal interacting partners DNMT3A and DNMT3B, lead to nuclear reprogramming that was gradual and progressive, resulting in melanotic tumors that were observed only when these flies were maintained for five generations. This global gene expression misregulation was accompanied by aberrations in the levels of H3K4me3 and H3K36me3, globally as well as at specific gene promoters. The levels of these epigenetic aberrations (epimutations) also increased progressively across successive generations. The accumulation and inheritance of epimutations across multiple generations recapitulates the important role of DNMT3L in intergenerational epigenetic inheritance in mammals.
Tsc1 deficiency impairs mammary development in mice by suppression of AKT, nuclear ERα and cell-cycle-driving proteins
Authors: Qin Zhenqi , Zheng Hang , Zhou Ling , Ou Yanhua , Huang Bin , Yan Bo , Qin Zhenshu , Yang Cuilan , Su Yongchun , Bai Xiaochun , Guo Jiasong , Lin Jun
Published: January 2016

Loss of Tsc1/Tsc2 results in excess cell growth that eventually forms hamartoma in multiple organs. Our study using a mouse model with Tsc1 conditionally knockout in mammary epithelium showed that Tsc1 deficiency impaired mammary development. Phosphorylated S6 was up-regulated in Tsc1−/− mammary epithelium, which could be reversed by rapamycin, suggesting that mTORC1 was hyperactivated in Tsc1−/− mammary epithelium. The mTORC1 inhibitor rapamycin restored the development of Tsc1−/− mammary glands whereas suppressed the development of Tsc1wt/wt mammary glands, indicating that a modest activation of mTORC1 is critical for mammary development. Phosphorylated PDK1 and AKT, nuclear ERα, nuclear IRS-1, SGK3 and cell cycle regulators such as Cyclin D1, Cyclin E, CDK2, CDK4 and their target pRB were all apparently down-regulated in Tsc1−/− mammary glands, which could be reversed by rapamycin, suggesting that suppression of AKT by hyperactivation of mTORC1, inhibition on nuclear ERα signaling and down-regulation of cell-cycle-driving proteins play important roles in the retarded mammary development induced by Tsc1 deletion. This study demonstrated for the first time the in vivo role of Tsc1 in pubertal mammary development of mice and revealed that loss of Tsc1 does not necessarily lead to tissue hyperplasia.
Heme oxygenase-1 is dispensable for the anti-inflammatory activity of intravenous immunoglobulin
Authors: Galeotti Caroline , Hegde Pushpa , Das Mrinmoy , Stephen-Victor Emmanuel , Canale Fernando , Muñoz Marcos , Sharma Varun K. , Dimitrov Jordan D. , Kaveri Srini V. , Bayry Jagadeesh
Published: January 2016

Intravenous immunoglobulin G (IVIG) is used in the therapy of various autoimmune and inflammatory conditions. The mechanisms by which IVIG exerts anti-inflammatory effects are not completely understood. IVIG interacts with numerous components of the immune system including dendritic cells, macrophages, T and B cells and modulate their functions. Recent studies have reported that heme oxygenase-1 (HO-1) pathway plays an important role in the regulation of inflammatory response in several pathologies. Several therapeutic agents exert anti-inflammatory effects via induction of HO-1. Therefore, we aimed at exploring if anti-inflammatory effects of IVIG are mediated via HO-1 pathway. Confirming the previous reports, we report that IVIG exerts anti-inflammatory effects on innate cells as shown by the inhibitory effects on IL-6 and nitric oxide production and confers protection in experimental autoimmune encephalomyelitis (EAE) model. However, these effects were not associated with an induction of HO-1 either in innate cells such as monocytes, dendritic cells and macrophages or in the kidneys and liver of IVIG-treated EAE mice. Also, inhibition of endogenous HO-1 did not modify anti-inflammatory effects of IVIG. These results thus indicate that IVIG exerts anti-inflammatory effects independent of HO-1 pathway.
The frontline antibiotic vancomycin induces a zinc starvation response in bacteria by binding to Zn(II)
Authors: Zarkan Ashraf , Macklyne Heather-Rose , Truman Andrew W. , Hesketh Andrew R. , Hong Hee-Jeon
Published: January 2016

Vancomycin is a front-line antibiotic used for the treatment of nosocomial infections, particularly those caused by methicillin-resistantStaphylococcus aureus. Despite its clinical importance the global effects of vancomycin exposure on bacterial physiology are poorly understood. In a previous transcriptomic analysis we identified a number of Zur regulon genes which were highly but transiently up-regulated by vancomycin inStreptomyces coelicolor. Here, we show that vancomycin also induces similar zinc homeostasis systems in a range of other bacteria and demonstrate that vancomycin binds to Zn(II)in vitro. This implies that vancomycin treatment sequesters zinc from bacterial cells thereby triggering a Zur-dependent zinc starvation response. The Kd value of the binding between vancomycin and Zn(II) was calculated using a novel fluorometric assay and NMR was used to identify the binding site. These findings highlight a new biologically relevant aspect of the chemical property of vancomycin as a zinc chelator.
Two Genetic Variations in the IRF8 region are associated with Behçet’s disease in Han Chinese
Authors: Jiang Yanni , Wang Hong , Yu Hongsong , Li Lin , Xu Dengfeng , Hou Shengping , Kijlstra Aize , Yang Peizeng
Published: January 2016

Several modulatory factors in the TLR signaling pathway including IRF3, IRF7, IRF8, TRIM20, MYD88 and NF-κB1 have been associated with autoimmune disease. In this study, we investigated the association of 13 SNPs for these genes with Behçet’s disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Haplotype and linkage disequilibrium (LD) analysis were performed by Haploview4.2. IRF8 mRNA expression and cytokine production was tested by real-time PCR and ELISA. Two SNPs near IRF8 were associated with BD (for rs17445836 GG genotype, Pc = 9.56 × 10−8, OR = 2.044; for rs11642873 AA genotype, Pc = 9.24 × 10−7, OR = 1.776). No significant association was found for the 13 SNPs tested with VKH syndrome. Haplotype analysis of the two positive SNPs revealed that the AG haplotype was significantly increased in BD patients (Pc = 2.60 × 10−8, OR = 1.646). Functional studies revealed an increased mRNA expression of IRF8 and IFN-γ production and a decreased production of IL-10 in rs17445836 carriers with the GG genotype. Increased expression of IRF8 as well as IFN-γ production and a decreased production of IL-10 were found in individuals carrying the rs11642873/AA genotype. In conclusion, this study indicates that IRF8 may contribute to the genetic susceptibility of BD by regulating IRF8 expression and cytokine production.
Experience-independent sex differences in newborn macaques: Females are more social than males
Authors: Simpson Elizabeth A. , Nicolini Ylenia , Shetler Melissa , Suomi Stephen J. , Ferrari Pier F. , Paukner Annika
Published: January 2016

Human females exhibit greater social interest and skills relative to males, appearing in infancy, suggesting biological roots; however, male and female infants may be treated differently, potentially causing or amplifying sex differences. Here, we tested whether sex differences in social motivation emerge in infant monkeys (n = 48) reared in a controlled postnatal environment. Compared to males, females at 2–3 weeks looked more at conspecifics’ faces (d = 0.65), especially the eyes (d = 1.09) and at 4–5 weeks exhibited more affiliative behaviors (d = 0.64), including gesturing, looking and proximity to familiar and unfamiliar human caretakers. In sum, converging evidence from humans and monkeys suggests that female infants are more social than males in the first weeks of life and that such differences may arise independent of postnatal experience. Individual differences in social interest have wide-ranging developmental consequences, impacting infants’ social interaction quality and opportunities for learning. Understanding the evolution of sex differences and their developmental emergence is necessary to best support infants with varying levels of sociality.
detectMITE: A novel approach to detect miniature inverted repeat transposable elements in genomes
Authors: Ye Congting , Ji Guoli , Liang Chun
Published: January 2016

Miniature inverted repeat transposable elements (MITEs) are prevalent in eukaryotic genomes, including plants and animals. Classified as a type of non-autonomous DNA transposable elements, they play important roles in genome organization and evolution. Comprehensive and accurate genome-wide detection of MITEs in various eukaryotic genomes can improve our understanding of their origins, transposition processes, regulatory mechanisms and biological relevance with regard to gene structures, expression and regulation. In this paper, we present a new MATLAB-based program called detectMITE that employs a novel numeric calculation algorithm to replace conventional string matching algorithms in MITE detection, adopts the Lempel-Ziv complexity algorithm to filter out MITE candidates with low complexity and utilizes the powerful clustering program CD-HIT to cluster similar MITEs into MITE families. Using the rice genome as test data, we found that detectMITE can more accurately, comprehensively and efficiently detect MITEs on a genome-wide scale than other popular MITE detection tools. Through comparison with the potential MITEs annotated in Repbase, the widely used eukaryotic repeat database, detectMITE has been shown to find known and novel MITEs with a complete structure and full-length copies in the genome. detectMITE is an open source tool (https://sourceforge.net/projects/detectmite).
Association of toll-like receptor 3 polymorphism rs3775291 with age-related macular degeneration: a systematic review and meta-analysis
Authors: Ma Li , Tang Fang Yao , Chu Wai Kit , Young Alvin L. , Brelen Marten E. , Pang Chi Pui , Chen Li Jia
Published: January 2016

Association of a polymorphism rs3775291 in the toll-like receptor 3 (TLR3) gene with age-related macular degeneration (AMD) had been investigated intensively, with variable results across studies. Here we conducted a meta-analysis to verify the effect of rs3775291 on AMD. We searched for genetic association studies published in PubMed, EMBASE and Web of Science from start dates to March 10, 2015. Totally 235 reports were retrieved and 9 studies were included for meta-analysis, involving 7400 cases and 13579 controls. Summary odds ratios (ORs) with 95% confidence intervals (CIs) for alleles and genotypes were estimated. TLR3 rs3775291 was associated with both geographic atrophy (GA) and neovascular AMD (nAMD), with marginally significant pooled-P values. Stratification analysis by ethnicity indicated that rs3775291 was associated with all forms of AMD, GA and nAMD only in Caucasians (OR = 0.87, 0.78 and 0.77, respectively, for the TT genotype) but not in East Asians. However, the associations could not withstand Bonferroni correction. This meta-analysis has thus revealed suggestive evidence for TLR3 rs3775291 as an associated marker for AMD in Caucasians but not in Asians. This SNP may have only a small effect on AMD susceptibility. Further studies in larger samples are warranted to confirm its role.
Growing GaN LEDs on amorphous SiC buffer with variable C/Si compositions
Authors: Cheng Chih-Hsien , Tzou An-Jye , Chang Jung-Hung , Chi Yu-Chieh , Lin Yung-Hsiang , Shih Min-Hsiung , Lee Chao-Kuei , Wu Chih-I , Kuo Hao-Chung , Chang Chun-Yen , Lin Gong-Ru
Published: January 2016

The epitaxy of high-power gallium nitride (GaN) light-emitting diode (LED) on amorphous silicon carbide (a-SixC1−x) buffer is demonstrated. The a-SixC1−x buffers with different nonstoichiometric C/Si composition ratios are synthesized on SiO2/Si substrate by using a low-temperature plasma enhanced chemical vapor deposition. The GaN LEDs on different SixC1−x buffers exhibit different EL and C-V characteristics because of the extended strain induced interfacial defects. The EL power decays when increasing the Si content of SixC1−x buffer. The C-rich SixC1−x favors the GaN epitaxy and enables the strain relaxation to suppress the probability of Auger recombination. When the SixC1−x buffer changes from Si-rich to C-rich condition, the EL peak wavelengh shifts from 446 nm to 450 nm. Moreover, the uniform distribution contour of EL intensity spreads between the anode and the cathode because the traping density of the interfacial defect gradually reduces. In comparison with the GaN LED grown on Si-rich SixC1−x buffer, the device deposited on C-rich SixC1−x buffer shows a lower turn-on voltage, a higher output power, an external quantum efficiency and an efficiency droop of 2.48 V, 106 mW, 42.3% and 7%, respectively.