bluuebunny/crossref_metadata_2025 huggingface dataset:
Combining homogeneous groups of preclassified observations with application to international trade
Authors: Cerasa Andrea
Published: February 2016

This article proposes three methods for merging homogeneous clusters of observations that are grouped according to a pre‐existing (known) classification. This clusterwise regression problem is at the very least compelling in analyzing international trade data, where transaction prices can be grouped according to the corresponding origin–destination combination. A proper merging of these prices could simplify the analysis of the market without affecting the representativeness of the data and highlight commercial anomalies that may hide frauds. The three algorithms proposed are based on an iterative application of the F‐test and have the advantage of being extremely flexible, as they do not require to predetermine the number of final clusters, and their output depends only on a tuning parameter. Monte Carlo results show very good performances of all the procedures, whereas the application to a couple of empirical data sets proves the practical utility of the methods proposed for reducing the dimension of the market and isolating suspicious commercial behaviors.
Synthetic biology for production of natural and new‐to‐nature terpenoids in photosynthetic organisms
Authors: Arendt Philipp , Pollier Jacob , Callewaert Nico , Goossens Alain
Published: February 2016

With tens of thousands of characterized members, terpenoids constitute the largest class of natural compounds that are synthesized by all living organisms. Several terpenoids play primary roles in the maintenance of cell membrane fluidity, as pigments or as phytohormones, but most of them function as specialized metabolites that are involved in plant resistance to herbivores or plant–environment interactions. Terpenoids are an essential component of human nutrition, and many are economically important pharmaceuticals, aromatics and potential next‐generation biofuels. Because of the often low abundance in their natural source, as well as the demand for novel terpenoid structures with new or improved bioactivities, terpenoid biosynthesis has become a prime target for metabolic engineering and synthetic biology projects. In this review we focus on the creation of new‐to‐nature or tailor‐made plant‐derived terpenoids in photosynthetic organisms, in particular by means of combinatorial biosynthesis and the activation of silent metabolism. We reflect on the characteristics of different potential photosynthetic host organisms and recent advances in synthetic biology and discuss their utility for the (heterologous) production of (novel) terpenoids.
Role of reactive oxygen species in age‐related neuromuscular deficits
Authors: Jackson Malcolm J. , McArdle Anne
Published: February 2016

Although it is now clear that reactive oxygen species (ROS) are not the key determinants of longevity, a number of studies have highlighted the key role that these species play in age‐related diseases and more generally in determining individual health span. Age‐related loss of skeletal muscle mass and function is a key contributor to physical frailty in older individuals and our current understanding of the key areas in which ROS contribute to age‐related deficits in muscle is through defective redox signalling and key roles in maintenance of neuromuscular integrity. This topical review will describe how ROS stimulate adaptations to contractile activity in muscle that include up‐regulation of short‐term stress responses, an increase in mitochondrial biogenesis and an increase in some catabolic processes. These adaptations occur through stimulation of redox‐regulated processes that lead to the activation of transcription factors such as NF‐κB, AP‐1 and HSF1 which mediate changes in gene expression. They are attenuated during ageing and this appears to occur through an age‐related increase in mitochondrial hydrogen peroxide production. The potential for redox‐mediated cross‐talk between motor neurons and muscle is also described to illustrate how ROS released from muscle fibres during exercise may help maintain the integrity of axons and how the degenerative changes in neuromuscular structure that occur with ageing may contribute to mitochondrial ROS generation in skeletal muscle fibres.

image
Quantifying element incorporation in multispecies biofilms using nanoscale secondary ion mass spectrometry image analysis
Authors: Renslow Ryan S. , Lindemann Stephen R. , Cole Jessica K. , Zhu Zihua , Anderton Christopher R.
Published: February 2016

Elucidating nutrient exchange in microbial communities is an important step in understanding the relationships between microbial systems and global biogeochemical cycles, but these communities are complex and the interspecies interactions that occur within them are not well understood. Phototrophic consortia are useful and relevant experimental systems to investigate such interactions as they are not only prevalent in the environment, but some are cultivable in vitro and amenable to controlled scientific experimentation. Nanoscale secondary ion mass spectrometry (NanoSIMS) is a powerful, high spatial resolution tool capable of visualizing the metabolic activities of single cells within a biofilm, but quantitative analysis of the resulting data has typically been a manual process, resulting in a task that is both laborious and susceptible to human error. Here, the authors describe the creation and application of a semiautomated image-processing pipeline that can analyze NanoSIMS-generated data, applied to phototrophic biofilms as an example. The tool employs an image analysis process, which includes both elemental and morphological segmentation, producing a final segmented image that allows for discrimination between autotrophic and heterotrophic biomass, the detection of individual cyanobacterial filaments and heterotrophic cells, the quantification of isotopic incorporation of individual heterotrophic cells, and calculation of relevant population statistics. The authors demonstrate the functionality of the tool by using it to analyze the uptake of 15N provided as either nitrate or ammonium through the unicyanobacterial consortium UCC-O and imaged via NanoSIMS. The authors found that the degree of 15N incorporation by individual cells was highly variable when labeled with 15NH4+, but much more even when biofilms were labeled with 15NO3−. In the 15NH4+-amended biofilms, the heterotrophic distribution of 15N incorporation was highly skewed, with a large population showing moderate 15N incorporation and a small number of organisms displaying very high 15N uptake. The results showed that analysis of NanoSIMS data can be performed in a way that allows for quantitation of the elemental uptake of individual cells, a technique necessary for advancing research into the metabolic networks that exist within biofilms with statistical analyses that are supported by automated, user-friendly processes.
Spectral contrast enhancement improves speech intelligibility in noise for cochlear implants
Authors: Nogueira Waldo , Rode Thilo , Büchner Andreas
Published: February 2016

Spectral smearing causes, at least partially, that cochlear implant (CI) users require a higher signal-to-noise ratio to obtain the same speech intelligibility as normal hearing listeners. A spectral contrast enhancement (SCE) algorithm has been designed and evaluated as an additional feature for a standard CI strategy. The algorithm keeps the most prominent peaks within a speech signal constant while attenuating valleys in the spectrum. The goal is to partly compensate for the spectral smearing produced by the limited number of stimulation electrodes and the overlap of electrical fields produced in CIs. Twelve CI users were tested for their speech reception threshold (SRT) using the standard CI coding strategy with and without SCE. No significant differences in SRT were observed between conditions. However, an analysis of the electrical stimulation patterns shows a reduction in stimulation current when using SCE. In a second evaluation, 12 CI users were tested in a similar configuration of the SCE strategy with the stimulation being balanced between the SCE and the non-SCE variants such that the loudness perception delivered by the strategies was the same. Results show a significant improvement in SRT of 0.57 dB (p < 0.0005) for the SCE algorithm.
Assessment of the biomechanical stability of a dental implant with quantitative ultrasound: A three-dimensional finite element study
Authors: Vayron Romain , Nguyen Vu-Hieu , Bosc Romain , Naili Salah , Haïat Guillaume
Published: February 2016

Dental implant stability is an important determinant of the surgical success. Quantitative ultrasound (QUS) techniques can be used to assess such properties using the implant acting as a waveguide. However, the interaction between an ultrasonic wave and the implant remains poorly understood. The aim of this study is to investigate the sensitivity of the ultrasonic response to the quality and quantity of bone tissue in contact with the implant surface. The 10 MHz ultrasonic response of an implant used in clinical practice was simulated using an axisymmetric three-dimensional finite element model, which was validated experimentally. The amplitude of the echographic response of the implant increases when the depth of a liquid layer located at the implant interface increases. The results show the sensitivity of the QUS technique to the amount of bone in contact with the implant. The quality of bone tissue around the implant is varied by modifying the bone biomechanical properties by 20%. The amplitude of the implant echographic response decreases when bone quality increases, which corresponds to bone healing. In all cases, the amplitude of the implant response decreased when the dental implant stability increased, which is consistent with the experimental results.
Physical and Physiological Characteristics of Various-Sided Games in Elite Women’s Soccer
Authors: Mara Jocelyn K. , Thompson Kevin G. , Pumpa Kate L.
Published: February 2016

Purpose:

To investigate the physical and physiological response to different formats of various-sided games.

Methods:

Eighteen elite women’s soccer players wore 15-Hz global positioning system devices and heart-rate (HR) monitors during various-sided games (small, 4 vs 4 and 5 vs 5; medium, 6 vs 6 and 7 vs 7; large, 8 vs 8 and 9 vs 9).

Results:

Players covered more relative sprinting distance during large-sided games than in small-sided (P < .001, d = 0.69) and medium-sided (P < .001, d = 0.54) games. In addition, a greater proportion of total acceleration efforts that had a commencement velocity <1 m/s were observed in small-sided games (44.7% ± 5.5%) than in large-sided games (36.7% ± 10.6%) (P = .018, d = 0.94). This was accompanied by a greater proportion of acceleration efforts with a final velocity equivalent to the sprint threshold in large-sided games (15.4% ± 7.7%) than in small-sided games (5.2% ± 2.5%) (P < .001, d = 1.78). The proportion of time spent in HR zone 4 (>85% maximum HR) was greater during small-sided games (69.8% ± 2.5%) than in medium- (62.1% ± 2.8%, d = 2.90) and large-sided games (54.9% ± 3.1%) (P < .001, d = 5.29).

Conclusions:

The results from this study demonstrate that coaches can use small-sided games as an aerobic conditioning stimulus and to develop players’ explosiveness and repeat-sprint ability over short durations. Large-sided games can be used to maintain aerobic capacity and develop maximum speed over longer distances.
Cognitively Engaging Chronic Physical Activity, But Not Aerobic Exercise, Affects Executive Functions in Primary School Children: A Group-Randomized Controlled Trial
Authors: Schmidt Mirko , Jäger Katja , Egger Fabienne , Roebers Claudia M. , Conzelmann Achim
Published: February 2016

Although the positive effects of different kinds of physical activity (PA) on cognitive functioning have already been demonstrated in a variety of studies, the role of cognitive engagement in promoting children’s executive functions is still unclear. The aim of the current study was therefore to investigate the effects of two qualitatively different chronic PA interventions on executive functions in primary school children. Children (N = 181) aged between 10 and 12 years were assigned to either a 6-week physical education program with a high level of physical exertion and high cognitive engagement (team games), a physical education program with high physical exertion but low cognitive engagement (aerobic exercise), or to a physical education program with both low physical exertion and low cognitive engagement (control condition). Executive functions (updating, inhibition, shifting) and aerobic fitness (multistage 20-m shuttle run test) were measured before and after the respective condition. Results revealed that both interventions (team games and aerobic exercise) have a positive impact on children’s aerobic fitness (4–5% increase in estimated VO2max). Importantly, an improvement in shifting performance was found only in the team games and not in the aerobic exercise or control condition. Thus, the inclusion of cognitive engagement in PA seems to be the most promising type of chronic intervention to enhance executive functions in children, providing further evidence for the importance of the qualitative aspects of PA.
Differences in Attentional Focus Associated With Recovery From Sports Injury: Does Injury Induce an Internal Focus?
Authors: Gray Rob
Published: February 2016

Although it is commonly believed that focusing too much attention on the injured body area impairs recovery in sports, this has not been directly assessed. The present study investigated attentional focus following sports injury. Experienced baseball position players recovering from knee surgery (Expt 1) and baseball pitchers recovering from elbow surgery (Expt 2) performed simulated batting and pitching respectively. They also performed three different secondary tasks: leg angle judgments, arm angle judgments, and judgments about the ball leaving their bat/hand. Injured athletes were compared with expert and novice control groups. Performance on the secondary tasks indicated that the injured batters had an internal focus of attention localized on the area of the injury resulting in significantly poorer batting performance as compared with the expert controls. Injured pitchers had a diffuse, internal attentional focus similar to that of novices resulting in poorer pitching performance as compared with the expert controls.
Neandertal genes linked to modern diseases
Authors: Gibbons Ann
Published: February 2016

DNA inherited from our extinct cousins boosts risk of depression and other disorders.
After the accusation
Authors: Balter Michael
Published: February 2016

A complex case of alleged sexual misconduct rattles a field and signals a cultural shift.
Dynamics of epigenetic regulation at the single-cell level
Authors: Bintu Lacramioara , Yong John , Antebi Yaron E. , McCue Kayla , Kazuki Yasuhiro , Uno Narumi , Oshimura Mitsuo , Elowitz Michael B.
Published: February 2016

Quantitative analysis of epigenetic memory

To explore quantitative and dynamic properties of transcriptional regulation by epigenetic modifications, Bintu
et al.
monitored a transcriptional reporter gene carried on a human artificial chromosome in Chinese hamster ovary cells (see the Perspective by Keung and Khalil). They measured effects of DNA methylation and histone modifications by methylation or deacetylation in single cells using time-lapse microscopy. Silencing was an all-or-none, stochastic event, so graded adjustments to transcription occurred from changes in the proportion of cells that responded. Furthermore, the duration of recruitment of the chromatin regulators determined the fraction of cells that were silenced. Thus, distinct modifiers can produce different characteristics of epigenetic memory.

Science
, this issue p.
720
; see also p.
661
Valley-polarized exciton dynamics in a 2D semiconductor heterostructure
Authors: Rivera Pasqual , Seyler Kyle L. , Yu Hongyi , Schaibley John R. , Yan Jiaqiang , Mandrus David G. , Yao Wang , Xu Xiaodong
Published: February 2016

Stacking to prolong valley lifetime

In the material MoSe
2
, which, like graphene, has a two-dimensional honeycomb crystal lattice, the electronic structure has two “valleys.” Electrons can be distinguished by the valley they reside in, making them act as potential information carriers. However, electrons easily lose this information by scattering into the other valley. Rivera
et al.
placed single layers of MoSe
2
and WSe
2
on top of each other and shone circularly polarized light on the structure. The light caused excitons—pairs of electrons and holes—to form so that the hole and electron came from the same valley but different layers. The valley-specific character of such excitons persisted far longer than would be possible in a single layer of either material.

Science
, this issue p.
688
Negative local resistance caused by viscous electron backflow in graphene
Authors: Bandurin D. A. , Torre I. , Kumar R. Krishna , Ben Shalom M. , Tomadin A. , Principi A. , Auton G. H. , Khestanova E. , Novoselov K. S. , Grigorieva I. V. , Ponomarenko L. A. , Geim A. K. , Polini M.
Published: February 2016

Electrons that flow like a fluid

Electrons inside a conductor are often described as flowing in response to an electric field. This flow rarely resembles anything like the familiar flow of water through a pipe, but three groups describe counterexamples (see the Perspective by Zaanen). Moll
et al.
found that the viscosity of the electron fluid in thin wires of PdCoO
2
had a major effect on the flow, much like what happens in regular fluids. Bandurin
et al.
found evidence in graphene of electron whirlpools similar to those formed by viscous fluid flowing through a small opening. Finally, Crossno
et al.
observed a huge increase of thermal transport in graphene, a signature of so-called Dirac fluids.

Science
, this issue p.
1061
,
1055
,
1058
; see also p.
1026
Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion
Authors: Delong Thomas , Wiles Timothy A. , Baker Rocky L. , Bradley Brenda , Barbour Gene , Reisdorph Richard , Armstrong Michael , Powell Roger L. , Reisdorph Nichole , Kumar Nitesh , Elso Colleen M. , DeNicola Megan , Bottino Rita , Powers Alvin C. , Harlan David M. , Kent Sally C. , Mannering Stuart I. , Haskins Kathryn
Published: February 2016

T cells target peptide combos

One of the enduring mysteries of autoimmunity is the identity of the specific proteins targeted by autoimmune T cells. Delong
et al.
used mass spectrometry to elucidate the peptide targets of autoimmune T cells isolated from a mouse model of type 1 diabetes. T cells targeted hybrid peptides formed by the covalent linking of a peptide derived from pro-insulin to other peptides derived from proteins found in pancreatic beta cells. T cells isolated from the pancreatic islets of two individuals with type 1 diabetes also recognized such hybrid peptides, suggesting that they may play an important role in driving disease.

Science
, this issue p.
711
On-chip and freestanding elastic carbon films for micro-supercapacitors
Authors: Huang P. , Lethien C. , Pinaud S. , Brousse K. , Laloo R. , Turq V. , Respaud M. , Demortière A. , Daffos B. , Taberna P. L. , Chaudret B. , Gogotsi Y. , Simon P.
Published: February 2016

Flexible power for flexible electronics

A challenge for flexible electronics is to couple devices with power sources that are also flexible. Ideally, they could also be processed in a way that is compatible with current microfabrication technologies. Huang
et al.
deposited a relatively thick layer of TiC on top of an oxide-coated Si film. After chlorination, most, but importantly not all, of the TiC was converted into a porous carbon film that could be turned into an electrochemical capacitor. The carbon films were highly flexible, and the residual TiC acted as a stress buffer with the underlying Si film. The films could be separated from the Si to form free-floating films, with the TiC providing a support layer.

Science
, this issue p.
691
A unifying model of epigenetic regulation
Authors: Keung Albert J. , Khalil Ahmad S.
Published: February 2016

Single-cell tracking reveals a common “algorithm” of operation used by chromatin regulators

[Also see Report by

Bintu
et al.

]
Economics of public safety
Authors: McNutt Marcia
Published: February 2016

By now, the tragic saga of the lead-contaminated drinking water in Flint, Michigan, is well known. Unlike some disasters, this one was not inevitable, and there were many warning signs that could have halted it much sooner. In the developed world, citizens have come to trust that basic public services such as water, power, and sanitation will be provided, for a fee, safely and reliably. Therefore, Flint is not just a nightmare for its 100,000 residents, because it causes all citizens to question whether public officials, who are entrusted with providing essential services, have health and welfare in mind. With criminal investigation of the Flint crisis now under way, my focus is not on assigning blame but on how to prevent a tragedy like this from happening again.
Complete Genome Sequences of Dengue Virus Type 1 to 4 Strains Used for the Development of CBER/FDA RNA Reference Reagents and WHO International Standard Candidates for Nucleic Acid Testing
Authors: Añez Germán , Heisey Daniel A. , Volkova Evgeniya , Rios Maria
Published: February 2016

Dengue virus (DENV), a member of the
Flaviviridae
family, is the most common and clinically significant arbovirus in the world and is endemic in more than 100 countries. Here, we report the complete sequences of four DENV serotypes used in the development of the CBER/FDA RNA reference reagents and WHO International Standard candidates for nucleic acid testing.
Draft Genome Sequence of Desulfitobacterium hafniense Strain DH, a Sulfate-Reducing Bacterium Isolated from Paddy Soils
Authors: Zhang Xi , Li Guo-Xiang , Chen Song-Can , Jia Xiao-Yu , Wu Kun , Cao Chang-Li , Bao Peng
Published: February 2016

Desulfitobacterium hafniense
strain DH is a sulfate-reducing species. Here, we report the draft genome sequence of strain DH, with a size of 5,368,588 bp, average G+C content of 47.48%, and 5,296 predicted protein-coding sequences.
Draft Genome Sequence of a Versatile Hydrocarbon-Degrading Bacterium, Rhodococcus pyridinivorans Strain KG-16, Collected from Oil Fields in India
Authors: Aggarwal Ramesh K. , Dawar Chhavi , Phanindranath R. , Mutnuri Lakshmi , Dayal Anurodh M.
Published: February 2016

We describe here a 5.8-Mb draft genome sequence of
Rhodococcus pyridinivorans
strain KG-16, which was obtained from the soil samples collected from the oilfields of Krishna-Godavari basin in India. This genomic resource can provide insights into the pathways and mechanisms of hydrocarbon degradation and potentially aid in bioremediation applications.
Draft Genome Sequence of
Cylindrospermopsis
sp. Strain CR12 Extracted from the Minimetagenome of a Nonaxenic Unialgal Culture from a Tropical Freshwater Lake
Authors: Mohamed Nor Nur Hazimah , Tan Boon Fei , Te Shu Harn , Thompson Janelle R. , Gin Karina Yew-Hoong
Published: February 2016

Cylindrospermopsis
is known to be one of the major bloom-forming cyanobacterial genera in many freshwater environments. We report here the draft genome sequence of a tropical
Cylindrospermopsis
sp. strain, CR12, which is capable of producing the hepatotoxic cylindrospermopsin.
Sigmoid vaginoplasty in testicular feminising syndrome: surgical technique, outcome and review of the literature
Authors: Sinha Rahul Janak , Bhaskar Ved , Mehrotra Seema , Singh Vishwajeet
Published: February 2016

Vaginal agenesis occurs in approximately 1:5000 live female births. It results from failure of the sinovaginal bulbs to develop and form the vaginal plate. Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) is the most common cause of vaginal absence followed by complete or partial androgen insensitivity syndrome. Treatment of these patients encompasses a spectrum from simple non-operative dilation to the more complicated surgical creation of a neovagina. We present a case of a patient with testicular feminising syndrome who was reared as a female and underwent bilateral gonadal excision and sigmoid vaginoplasty.
Continuing reductions in HPV 16/18 in a population with high coverage of bivalent HPV vaccination in England: an ongoing cross-sectional study
Authors: Mesher David , Panwar Kavita , Thomas Sara L , Beddows Simon , Soldan Kate
Published: February 2016

Objectives

The human papillomavirus (HPV) immunisation programme in England was introduced in 2008. Monitoring changes in type-specific HPV prevalence allows assessment of the population impact of this vaccination programme.

Methods

Residual vulva-vaginal swab specimens were collected from young sexually active women (aged 16–24 years) attending for chlamydia screening across England. Specimens were collected between 2010 and 2013 for type-specific HPV-DNA testing. HPV prevalence was compared to a similar survey conducted in 2008 prior to the introduction of HPV vaccination.

Results

A total of 7321 specimens collected in the postvaccination period, and 2354 specimens from the prevaccination period were included in this analysis. Among the individuals aged 16–18 years, with an estimated vaccination coverage of 67%, the prevalence of HPV16/18 infection decreased from 17.6% in 2008 to 6.1% in the postvaccination period. Within the postvaccination period, there was a trend towards lower HPV16/18 prevalence with higher vaccination coverage and increasing time since vaccine introduction from 8.5% in the period 2–3 years postvaccination to 4.0% in the period 4–5 years postvaccination. The prevalence of HPV31 reduced from 3.7% in the prevaccination period to 0.9% after vaccine introduction, although this no longer reached statistical significance after additional consideration of the uncertainty due to the assay change. Smaller reductions were seen in the individuals aged 19–21 years with lower estimated vaccination coverage, but there was no evidence of a reduction in the older unvaccinated women. Some overall increase in non-vaccine types was seen in the youngest age groups (ORs (95% CI); 1.3 (1.0 to 1.7) and 1.5 (1.1 to 2.0) for individuals aged 16–18 and 19–21 years, respectively, when adjusted for known population changes and the change in assay) although this should be interpreted with caution given the potential unmasking effect.

Conclusions

These data demonstrate a reduction in the HPV vaccine types in the age group with the highest HPV vaccination coverage.
Population characteristics, mechanisms of primary care and premature mortality in England: a cross-sectional study
Authors: Baker Richard , Honeyford Kate , Levene Louis S , Mainous Arch G , Jones David R , Bankart M John , Stokes Tim
Published: February 2016

Objectives

Health systems with strong primary care tend to have better population outcomes, but in many countries demand for care is growing. We sought to identify mechanisms of primary care that influence premature mortality.

Design

We developed a conceptual model of the mechanisms by which primary care influences premature mortality, and undertook a cross-sectional study in which population and primary care variables reflecting the model were used to explain variations in mortality of those aged under 75 years. The premature standardised mortality ratios (SMRs) for each practice, available from the Department of Health, had been calculated from numbers of deaths in the 5 years from 2006 to 2010. A regression model was undertaken with explanatory variables for the year 2009/2010, and repeated to check stability using data for 2008/2009 and 2010/2011.

Setting

All general practices in England were eligible for inclusion and, of the total of 8290, complete data were available for 7858.

Results

Population variables, particularly deprivation, were the most powerful predictors of premature mortality, but the mechanisms of primary care depicted in our model also affected mortality. The number of GPs/1000 population and detection of hypertension were negatively associated with mortality. In less deprived practices, continuity of care was also negatively associated with mortality.

Conclusions

Greater supply of primary care is associated with lower premature mortality even in a health system that has strong primary care (England). Health systems need to sustain the capacity of primary care to deliver effective care, and should assist primary care providers in identifying and meeting the needs of socioeconomically deprived groups.
Lactobacillus acidophilusstimulates intestinal P-glycoprotein expression via a c-Fos/c-Jun-dependent mechanism in intestinal epithelial cells
Authors: Priyamvada Shubha , Anbazhagan Arivarasu N. , Kumar Anoop , Soni Vikas , Alrefai Waddah A. , Gill Ravinder K. , Dudeja Pradeep K. , Saksena Seema
Published: February 2016

Our previous studies showed that Lactobacillus acidophilus (LA) culture supernatant (CS) increased P-glycoprotein [Pgp/multidrug resistance 1 (MDR1)] function, expression, and promoter activity in Caco-2 cells. The current studies were designed to elucidate the molecular mechanisms mediating the stimulatory effects of LA CS on Pgp promoter activity. Deletion analysis indicated that the LA CS response element(s) is located in the −172/+428-bp region, and sequence analysis of this region revealed three potential binding sites for c-Fos or c-Jun: proximal activating protein (AP) 1a (−119/−98 bp), distal AP1b (−99/−78 bp), and AP1c (+175/+196 bp). LA CS (24 h) showed an approximately twofold increase in the protein expression of c-Fos and c-Jun in Caco-2 cells. Electrophoretic mobility shift assay showed that LA CS markedly increased the binding of Caco-2 nuclear proteins to AP1a and AP1b, but not AP1c. The DNA-protein complex was completely eliminated by c-Fos antibody, while c-Jun antibody partially eliminated the complex. Chromatin immunoprecipitation analysis also showed that LA CS enhanced the association of c-Fos and c-Jun (by ∼4- and 1.5-fold, respectively) with endogenous Pgp promoter in Caco-2 cells (p−172/+1). Interestingly, overexpression of c-Fos or c-Jun activated Pgp promoter by nearly twofold each. This increase was further enhanced (∼14-fold) when c-Fos and c-Jun were simultaneously overexpressed, suggesting that the presence of one of these transcription factors potentiates the effect of the other. These studies, for the first time, provide evidence for the involvement of c-Fos/c-Jun in stimulation of Pgp gene expression by LA CS in the human intestine.
High-phosphorus diet maximizes and low-dose calcitriol attenuates skeletal muscle changes in long-term uremic rats
Authors: Acevedo Luz M. , López Ignacio , Peralta-Ramírez Alan , Pineda Carmen , Chamizo Verónica E. , Rodríguez Mariano , Aguilera-Tejero Escolástico , Rivero José-Luis L.
Published: February 2016

Although disorders of mineral metabolism and skeletal muscle are common in chronic kidney disease (CKD), their potential relationship remains unexplored. Elevations in plasma phosphate, parathyroid hormone, and fibroblastic growth factor 23 together with decreased calcitriol levels are common features of CKD. High-phosphate intake is a major contributor to progression of CKD. This study was primarily aimed to determine the influence of high-phosphate intake on muscle and to investigate whether calcitriol supplementation counteracts negative skeletal muscle changes associated with long-term uremia. Proportions and metabolic and morphological features of myosin-based muscle fiber types were assessed in the slow-twitch soleus and the fast-twitch tibialis cranialis muscles of uremic rats (5/6 nephrectomy, Nx) and compared with sham-operated (So) controls. Three groups of Nx rats received either a standard diet (0.6% phosphorus, Nx-Sd), or a high-phosphorus diet (0.9% phosphorus, Nx-Pho), or a high-phosphorus diet plus calcitriol (10 ng/kg 3 day/wk ip, Nx-Pho + Cal) for 12 wk. Two groups of So rats received either a standard diet or a high-phosphorus diet (So-Pho) over the same period. A multivariate analysis encompassing all fiber-type characteristics indicated that Nx-Pho + Cal rats displayed skeletal muscle phenotypes intermediate between Nx-Pho and So-Pho rats and that uremia-induced skeletal muscle changes were of greater magnitude in Nx-Pho than in Nx-Sd rats. In uremic rats, treatment with calcitriol preserved fiber-type composition, cross-sectional size, myonuclear domain size, oxidative capacity, and capillarity of muscle fibers. These data demonstrate that a high-phosphorus diet potentiates and low-dose calcitriol attenuates adverse skeletal muscle changes in long-term uremic rats.
Advances in Adipose‐Derived Stem Cells Isolation, Characterization, and Application in Regenerative Tissue Engineering
Authors: Wankhade Umesh D. , Shen Michael , Kolhe Ravindra , Fulzele Sadanand
Published: February 2016

Obesity is a complex, multifactorial disease that has been extensively researched in recent times. Obesity is characterized by excess deposition of adipose tissue in response to surplus energy. Despite the negative connotations of adipose tissue (AT), it serves as a critical endocrine organ. Adipose tissue is a source of several adipokines and cytokines which have been deemed important for both normal metabolic function and disease formation. The discoveries of metabolically active brown AT in adult humans and adipose tissue derived stem cells (ADSC) have been key findings in the past decade with potential therapeutic implications. ADSCs represent an enticing pool of multipotent adult stem cells because of their noncontroversial nature, relative abundance, ease of isolation, and expandability. A decade and a half since the discovery of ADSCs, the scientific community is still working to uncover their therapeutic potential in a wide range of diseases. In this review, we provide an overview of the recent developments in the field of ADSCs and examine their potential use in transplantation and cell‐based therapies for the regeneration of diseased organs and systems. We also hope to provide perspective on how to best utilize this readily available, powerful pool of stem cells in the future.
Malignant Biliary Obstruction: Evidence for Best Practice
Authors: Pu Leonardo Zorrón Cheng Tao , Singh Rajvinder , Loong Cheong Kuan , de Moura Eduardo Guimarães Hourneaux
Published: February 2016

What should be done next? Is the stricture benign? Is it resectable? Should I place a stent? Which one? These are some of the questions one ponders when dealing with biliary strictures. In resectable cases, ongoing questions remain as to whether the biliary tree should be drained prior to surgery. In palliative cases, the relief of obstruction remains the main goal. Options for palliative therapy include surgical bypass, percutaneous drainage, and stenting or endoscopic stenting (transpapillary or via an endoscopic ultrasound approach). This review gathers scientific foundations behind these interventions. For operable cases, preoperative biliary drainage should not be performed unless there is evidence of cholangitis, there is delay in surgical intervention, or intense jaundice is present. For inoperable cases, transpapillary stenting after sphincterotomy is preferable over percutaneous drainage. The use of plastic stents (PS) has no benefit over Self-Expandable Metallic Stents (SEMS). In case transpapillary drainage is not possible, Endoscopic Ultrasonography- (EUS-) guided drainage is still an option over percutaneous means. There is no significant difference between the types of SEMS and its indication should be individualized.
A Current Review of the Meniscus Imaging: Proposition of a Useful Tool for Its Radiologic Analysis
Authors: Lefevre Nicolas , Naouri Jean Francois , Herman Serge , Gerometta Antoine , Klouche Shahnaz , Bohu Yoann
Published: February 2016

The main objective of this review was to present a synthesis of the current literature in order to provide a useful tool to clinician in radiologic analysis of the meniscus. All anatomical descriptions were clearly illustrated by MRI, arthroscopy, and/or drawings. The value of standard radiography is extremely limited for the assessment of meniscal injuries but may be indicated to obtain a differential diagnosis such as osteoarthritis. Ultrasound is rarely used as a diagnostic tool for meniscal pathologies and its accuracy is operator-dependent. CT arthrography with multiplanar reconstructions can detect meniscus tears that are not visible on MRI. This technique is also useful in case of MRI contraindications, in postoperative assessment of meniscal sutures and the condition of cartilage covering the articular surfaces. MRI is the most accurate and less invasive method for diagnosing meniscal lesions. MRI allows confirming and characterizing the meniscal lesion, the type, the extension, its association with a cyst, the meniscal extrusion, and assessing cartilage and subchondral bone. New 3D-MRI in three dimensions with isotropic resolution allows the creation of multiplanar reformatted images to obtain from an acquisition in one sectional plane reconstructions in other spatial planes. 3D MRI should further improve the diagnosis of meniscal tears.
SGK Kinase Activity in Multiple Myeloma Cells Protects against ER Stress Apoptosis via a SEK-Dependent Mechanism
Authors: Hoang Bao , Shi Yijiang , Frost Patrick J. , Mysore Veena , Bardeleben Carolyne , Lichtenstein Alan
Published: February 2016

To assess the role of the serum and glucocorticoid-regulated kinase (SGK) kinase in multiple myeloma, we ectopically expressed wild type or a phosphomimetic version of SGK into multiple myeloma cell lines. These cells were specifically resistant to the ER stress inducers tunicamycin, thapsigargin, and bortezomib. In contrast, there was no alteration of sensitivity to dexamethasone, serum starvation, or mTORC inhibitors. Mining of genomic data from a public database indicated that low baseline SGK expression in multiple myeloma patients correlated with enhanced ability to undergo a complete response to subsequent bortezomib treatment and a longer time to progression and overall survival following treatment. SGK overexpressing multiple myeloma cells were also relatively resistant to bortezomib in a murine xenograft model. Parental/control multiple myeloma cells demonstrated a rapid upregulation of SGK expression and activity (phosphorylation of NDRG-1) during exposure to bortezomib and an SGK inhibitor significantly enhanced bortezomib-induced apoptosis in cell lines and primary multiple myeloma cells. In addition, a multiple myeloma cell line selected for bortezomib resistance demonstrated enhanced SGK expression and SGK activity. Mechanistically, SGK overexpression constrained an ER stress–induced JNK proapoptotic pathway and experiments with a SEK mutant supported the notion that SGK's protection against bortezomib was mediated via its phosphorylation of SEK (MAP2K4) which abated SEK/JNK signaling. These data support a role for SGK inhibitors in the clinical setting for myeloma patients receiving treatment with ER stress inducers like bortezomib.

Implications: Enhanced SGK expression and activity in multiple myeloma cells contributes to resistance to ER stress, including bortezomib challenge. Mol Cancer Res; 14(4); 397–407. ©2016 AACR.
Three Cases of Intravascular Large B-Cell Lymphoma Detected in a Biopsy of Skin Lesions
Authors: Arai Takashi , Kato Yukihiko , Funaki Maki , Shimamura Sanae , Yokogawa Naoto , Sugii Syoji , Tsuboi Ryoji
Published: February 2016

Intravascular large B-cell lymphoma (IVL) is a rare subtype of extranodal malignant lymphoma. The proliferation of neoplastic B cells within small blood vessels causes eruptions and other symptoms in a variety of organs. The random skin biopsy is useful for diagnosing this condition in its early stages. In order to assess the diagnostic utility of this method, we examined 3 cases with the aim of comparing the occurrence of tumor cells in lesional and healthy-looking skin by performing a random skin biopsy of 32 separate sites. Our findings from the total of 32 biopsy specimens collected from the 3 cases indicated that 16 of the 17 sites on the lesional skin and 1 of the 15 sites on the healthy-looking skin were positive for neoplastic cells. This finding suggested that IVL cells occurred more frequently in the lesional skin than in the healthy-looking skin.
Migration of Ventriculoperitoneal Shunt into a Hernia Sac: An Unusual Complication of Ventriculoperitoneal Shunt Surgery in Children
Authors: Singh Sudhir , Pant Nitin , Kumar Piyush , Pandey Anand , Khan Tanvir Roshan , Gupta Archika , Rawat Jiledar
Published: February 2016

We report 2 cases of ventriculoperitoneal (VP) shunt migration into an inguinal hernia sac. In both cases hernia manifested itself on the right side in late infancy. We attempted to analyse the anatomical and mechanical factors leading to shunt migration as seen in the X-rays of our cases.
Phase II and UGT1A1 Polymorphism Study of Two Different Irinotecan Dosages Combined with Cisplatin as First-Line Therapy for Advanced Gastric Cancer
Authors: Wang Wenna , Huang Jing , Tao Yunxia , Lyu Xiao , Yang Lin , Wu Dawei , Tian Yantao
Published: February 2016

Background: We investigated the efficacy and safety of biweekly irinotecan and cisplatin (IP) as first-line treatment in advanced gastric cancer patients. Methods: Irinotecan 125 mg/m2 on day 1 and cisplatin 60 mg/m2 on day 2 were administrated every 14 days. UGT1A1*28/*6 and toxicities were analyzed. Results: Forty-one eligible patients were enrolled. Fifteen patients, who were defined as the high-dose group, received starting doses of irinotecan 125 mg/m2. Twenty-six patients, who were defined as the low-dose group, received starting doses of irinotecan 80 mg/m2 and cisplatin 50 mg/m2. The response rate was 53.3% in the irinotecan high-dose group and 53.8% in the irinotecan low-dose group. The most common grade 3/4 toxicity was neutropenia (68.3%). No significant difference in grade 3/4 neutropenia was found between patients with the wild-type genotype and those with variant genotypes for UGT1A1*28 or UGT1A1*6. Conclusions: The combination of biweekly irinotecan 80 mg/m2 and cisplatin 50 mg/m2 was active and tolerable. The role of the UGT1A1 genotype in clinical toxicity of an IP regimen requires further investigation.
Lithium Ameliorates LPS-Induced Astrocytes Activation Partly via Inhibition of Toll-Like Receptor 4 Expression
Authors: Li Nana , Zhang Xiang , Dong Hongquan , Zhang Susu , Sun Jie , Qian Yanning
Published: February 2016

Background/Aims: Astrocytes are critical for the development of postoperative cognitive dysfunction (POCD). In addition, astrocytes express toll-like receptors 4 (TLR4) and build up responses to innate immune triggers by releasing pro-inflammatory molecules. The pathogenesis of neurological disorders often involves the activation of astrocytes and associated inflammatory processes. Lithium, a primary drug for the treatment of bipolar disorder, has recently been suggested to have a role in neuroprotection during neurodegenerative diseases. In this study, we aimed to investigate whether lithium can ameliorate LPS-induced astrocytes activation via inhibition of TLR4 expression. Methods: Primary astrocytes cells were pretreated with lithium and stimulated with lipopolysaccharide (LPS). Cellular activation, cytokine production, and TLR4 expression, were assessed. Results: Lithium significantly inhibited LPS-induced astrocytes activation and pro-inflammatory cytokine production, as well as LPS-induced TLR4 expression. Conclusions: Lithium can inhibit LPS-induced TLR4 expression and astrocytes activation. These results indicate that lithium plays an important role in astrocytes activation and neuroinflammation-related diseases, which may open new avenues for neuroscience and biomedical research, and also offers new insight into the treatment of POCD.
Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept
Authors: Ranjbar Mahdy , Brinkmann Max Philipp , Zapf Dorinja , Miura Yoko , Rudolf Martin , Grisanti Salvatore
Published: February 2016

Background/Aims: VEGF-A is induced by oxidative stress, and functions as a survival factor for various cell types, including retinal pigment epithelial (RPE) cells. Anti-vascular endothelial growth factor (VEGF) drugs like aflibercept and bevacizumab have shown to be most effective in treating neovascular age-related macular degeneration (AMD), however uptake of the drugs might lead to interference with cell physiology. Herein, we evaluated the significance of the Fc receptor (FcR) within this context and moreover explored the impact of VEGF inhibition under normal conditions as well as under oxidative stress, in terms of potential adverse effects. Methods: ARPE-19 (human RPE) cells were treated with aflibercept and bevacizumab in presence or absence of H2O2 as oxidative stress stimulus. After 24h cells were evaluated for drug uptake, VEGF-A expression and secretion, levels of intracellular reactive oxygen species (ROS) as well as cell proliferation. Experiments were repeated with cells being pre-incubated with an FcR inhibitor prior to drug application. Results: Both drugs inhibited extracellular levels of VEGF-A and were taken up into the RPE, resulting in significantly reduced intracellular levels of VEGF-A. When oxidative stress was applied, intracellular ROS levels in cells treated with both drugs rose, and cell proliferation was reduced. Prior incubation with the FcR inhibitor lessened the uptake of bevacizumab, but not aflibercept into RPE cells, and simultaneously enhanced cell survival under oxidative stress conditions. Conclusions: Our results indicate that uptake and accumulation of aflibercept and bevacizumab within RPE cells affect the intracellular VEGF-A metabolism negatively, leading to a biologically relevant reduced cell survival under oxidative stress. The FcR plays a substantial role in the uptake of bevacizumab, but not aflibercept, which allows an enhanced RPE cell survival through FcR blockage in an environment dominated by oxidative stress, as clinically significant for various inflammatory retinal disorders.
MiR-214 Attenuates Osteogenic Differentiation of Mesenchymal Stem Cells via Targeting FGFR1
Authors: Yang Lei , Ge Dawei , Cao Xiaojian , Ge Yingbin , Chen Hongtao , Wang Weiwei , Zhang Hongxiu
Published: February 2016

Background/Aims: Postmenopausal osteoporosis is closely associated with reduction in the differentiation of mesenchymal stem cells (MSCs) into osteoblasts. Previous studies have demonstrated that miR-214 plays an important role in the genesis and development of postmenopausal osteoporosis. Here, we performed this study to investigate the potential mechanism by which miR-214 regulates osteoblast differentiation of MSCs. Methods: First, we explored the expression of miR-214 in MSCs of osteoporotic mice. Next, we examined the change of miR-214 during osteoblast differentiation of MSCs. Then, MSCs were infected with lentiviral vectors expressing miR-214 or miR-214 sponge to investigate the effect of miR-214 on osteoblast differentiation of MSCs. Further, bioinformatics analysis and luciferase reporter assay were performed to identify and validate the target gene of miR-214. Results: MiR-214 was up-regulated in MSCs of osteoporotic mice and down-regulated during osteoblast differentiation of MSCs. Furthermore, overexpression of miR-214 inhibited osteoblast differentiation of MSCs in vitro, whereas inhibition of miR-214 function promoted this process, evidenced by increased expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Bioinformatics, Western blot analysis and luciferase reporter assay demonstrated that FGFR1 is a direct target of miR-214. Conclusions: MiR-214 attenuates osteogenesis by inhibiting the FGFR1/FGF signaling pathway. Our findings suggest that targeting miR-214 promises to be a potential therapy in treatment of postmenopausal osteoporosis.