bluuebunny/crossref_metadata_2025 huggingface dataset:
A unique ferredoxin acts as a player in the low-iron response of photosynthetic organisms
Authors: Schorsch Michael , Kramer Manuela , Goss Tatjana , Eisenhut Marion , Robinson Nigel , Osman Deenah , Wilde Annegret , Sadaf Shamaila , Brückler Hendrik , Walder Lorenz , Scheibe Renate , Hase Toshiharu , Hanke Guy T.
Published: December 2018

Significance

Iron limits the growth of photosynthetic organisms, especially in marine environments. Understanding the response of photosynthetic organisms to changing iron concentrations is therefore important for agriculture and biotechnology. We have identified a protein that is essential for the correct response to changing iron concentrations in photosynthetic bacteria (cyanobacteria). This protein was previously annotated as an electron transfer component of photosynthesis, called Fed2, and contains an iron−sulfur cluster. We tested Fed2, and found that it cannot act in photosynthetic electron transport. The corresponding gene is essential, and is highly conserved between cyanobacteria, algae, and higher plants. By specifically perturbing its function, we could show that it is essential for the low-iron response at the posttranscriptional level.
Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis
Authors: Andersson Karin M. E. , Wasén Caroline , Juzokaite Lina , Leifsdottir Lovisa , Erlandsson Malin C. , Silfverswärd Sofia T. , Stokowska Anna , Pekna Marcela , Pekny Milos , Olmarker Kjell , Heckemann Rolf A. , Kalm Marie , Bokarewa Maria I.
Published: December 2018

Significance

Aberrant insulin-like growth factor 1 receptor (IGF1R)/insulin receptor signaling in brain has recently been linked to neurodegeneration in diabetes mellitus and in Alzheimer’s disease. In this study, we demonstrate that functional disability and pain in patients with rheumatoid arthritis (RA) and in experimental RA are associated with hippocampal inflammation and inhibition of IGF1R/insulin receptor substrate 1 (IRS1) signal, reproducing an IGF1/insulin-resistant state. This restricts formation of new neurons in the hippocampus, reduces hippocampal volume, and predisposes RA patients to develop neurological symptoms. Improving IRS1 function through down-regulation of IGF1R disinhibits neurogenesis and can potentially ameliorate neurological symptoms. This opens perspectives for drugs that revert IGF1/insulin resistance as an essential complement to the antirheumatic and antiinflammatory arsenal.
Constitutive boost of a K
+
channel via inherent bilayer tension and a unique tension-dependent modality
Authors: Iwamoto Masayuki , Oiki Shigetoshi
Published: December 2018

Significance

Proteins embedded in the cell membrane are subjected to the membrane’s chemical and physical modifications. Here, we report that cholesterol and other sterols attenuated single-channel activities of a prototypical potassium channel KcsA. Inherent lipid bilayer tension was measured high compared with cell membrane tension, and all tested sterols decreased bilayer tension. Reducing tension by mechanical means also attenuated channel activity. Thus, channel activity was regulated by bilayer tension changes under chemical and physical perturbations. Unlike conventional stretch activation, bilayer tension activated the channel only when the channel was stimulated by intracellular acidic pH. Overall, acidic pH is necessary for activation, but channel opening is fine-tuned by membrane tension in what constitutes a doubly regulated activation modality.
Structure and activity of lipid bilayer within a membrane-protein transporter
Authors: Qiu Weihua , Fu Ziao , Xu Guoyan G. , Grassucci Robert A. , Zhang Yan , Frank Joachim , Hendrickson Wayne A. , Guo Youzhong
Published: December 2018

Membrane proteins function in native cell membranes, but extraction into isolated particles is needed for many biochemical and structural analyses. Commonly used detergent-extraction methods destroy naturally associated lipid bilayers. Here, we devised a detergent-free method for preparing cell-membrane nanoparticles to study the multidrug exporter AcrB, by cryo-EM at 3.2-Å resolution. We discovered a remarkably well-organized lipid-bilayer structure associated with transmembrane domains of the AcrB trimer. This bilayer patch comprises 24 lipid molecules; inner leaflet chains are packed in a hexagonal array, whereas the outer leaflet has highly irregular but ordered packing. Protein side chains interact with both leaflets and participate in the hexagonal pattern. We suggest that the lipid bilayer supports and harmonizes peristaltic motions through AcrB trimers. In AcrB D407A, a putative proton-relay mutant, lipid bilayer buttresses protein interactions lost in crystal structures after detergent-solubilization. Our detergent-free system preserves lipid–protein interactions for visualization and should be broadly applicable.
Oxygenated Mesoproterozoic lake revealed through magnetic mineralogy
Authors: Slotznick Sarah P. , Swanson-Hysell Nicholas L. , Sperling Erik A.
Published: December 2018

Terrestrial environments have been suggested as an oxic haven for eukaryotic life and diversification during portions of the Proterozoic Eon when the ocean was dominantly anoxic. However, iron speciation and Fe/Al data from the ca. 1.1-billion-year-old Nonesuch Formation, deposited in a large lake and bearing a diverse assemblage of early eukaryotes, are interpreted to indicate persistently anoxic conditions. To shed light on these distinct hypotheses, we analyzed two drill cores spanning the transgression into the lake and its subsequent shallowing. While the proportion of highly reactive to total iron (FeHR/FeT) is consistent through the sediments and typically in the range taken to be equivocal between anoxic and oxic conditions, magnetic experiments and petrographic data reveal that iron exists in three distinct mineral assemblages resulting from an oxycline. In the deepest waters, reductive dissolution of iron oxides records an anoxic environment. However, the remainder of the sedimentary succession has iron oxide assemblages indicative of an oxygenated environment. At intermediate water depths, a mixed-phase facies with hematite and magnetite indicates low oxygen conditions. In the shallowest waters of the lake, nearly every iron oxide has been oxidized to its most oxidized form, hematite. Combining magnetics and textural analyses results in a more nuanced understanding of ambiguous geochemical signals and indicates that for much of its temporal duration, and throughout much of its water column, there was oxygen in the waters of Paleolake Nonesuch.
Microtubule-directed transport of purine metabolons drives their cytosolic transit to mitochondria
Authors: Chan Chung Yu , Pedley Anthony M. , Kim Doory , Xia Chenglong , Zhuang Xiaowei , Benkovic Stephen J.
Published: December 2018

Significance

This study draws on the power of superresolution microscopy to investigate how metabolons behave near different subcellular components. We revealed an interdependent relationship among purinosomes, mitochondria, and microtubules. This further suggests a role for each in maximizing purine production in times of high intracellular demand. With the increasing number of reported metabolons, this study has uncovered a potential general strategy for how metabolons use subcellular networks to facilitate metabolic trade between themselves and other cellular organelles.
Seneca Valley virus attachment and uncoating mediated by its receptor anthrax toxin receptor 1
Authors: Cao Lin , Zhang Ran , Liu Tingting , Sun Zixian , Hu Mingxu , Sun Yuna , Cheng Lingpeng , Guo Yu , Fu Sheng , Hu Junjie , Li Xiangmin , Yu Chengqi , Wang Hanyang , Chen Huanchun , Li Xueming , Fry Elizabeth E. , Stuart David I. , Qian Ping , Lou Zhiyong , Rao Zihe
Published: December 2018

Seneca Valley virus (SVV) is an oncolytic picornavirus with selective tropism for neuroendocrine cancers. SVV mediates cell entry by attachment to the receptor anthrax toxin receptor 1 (ANTXR1). Here we determine atomic structures of mature SVV particles alone and in complex with ANTXR1 in both neutral and acidic conditions, as well as empty “spent” particles in complex with ANTXR1 in acidic conditions by cryoelectron microscopy. SVV engages ANTXR1 mainly by the VP2 DF and VP1 CD loops, leading to structural changes in the VP1 GH loop and VP3 GH loop, which attenuate interprotomer interactions and destabilize the capsid assembly. Despite lying on the edge of the attachment site, VP2 D146 interacts with the metal ion in ANTXR1 and is required for cell entry. Though the individual substitution of most interacting residues abolishes receptor binding and virus propagation, a serine-to-alanine mutation at VP2 S177 significantly increases SVV proliferation. Acidification of the SVV–ANTXR1 complex results in a major reconfiguration of the pentameric capsid assemblies, which rotate ∼20° around the icosahedral fivefold axes to form a previously uncharacterized spent particle resembling a potential uncoating intermediate with remarkable perforations at both two- and threefold axes. These structures provide high-resolution snapshots of SVV entry, highlighting opportunities for anticancer therapeutic optimization.
A neural data structure for novelty detection
Authors: Dasgupta Sanjoy , Sheehan Timothy C. , Stevens Charles F. , Navlakha Saket
Published: December 2018

Significance

This work is significant for two reasons. First, considering fly olfaction in the context of a computational algorithm emphasizes features of olfactory processing that might otherwise be less apparent. For example, comparison of prior approaches for novelty detection makes clear that different odors are not just novel vs. familiar, but rather can have various degrees of novelty depending on the similarities between odors. Second, understanding how the fruit fly olfactory circuit detects novel odors can inspire new methods for similar problems in machine learning. In this way, both computer science and neuroscience benefit from the comparison of these two systems.
Mother–child transmission of epigenetic information by tunable polymorphic imprinting
Authors: Carpenter Brittany L. , Zhou Wanding , Madaj Zachary , DeWitt Ashley K. , Ross Jason P. , Grønbæk Kirsten , Liang Gangning , Clark Susan J. , Molloy Peter L. , Jones Peter A.
Published: December 2018

Significance

First, our work provides critical biological interpretation of intermediate DNA methylation readouts at the
nc886
differentially methylated region (DMR).
nc886
was identified in multiple large-scale epigenome-wide association studies (EWAS) that did not recognize that this region acts as a contiguous DMR imposed by genomic imprinting, highlighting the need to reexamine several 450k data sets. Second, strict control of genomic imprinting was thought to be required for organismal viability. Reports of polymorphic imprinting are limited to specific tissue types such as placenta and brain. In blood and somatic tissues, we show
nc886
imprinting is mosaic in the population and influenced by maternal environment.
Noninvasive diagnostic imaging using machine-learning analysis of nanoresolution images of cell surfaces: Detection of bladder cancer
Authors: Sokolov I. , Dokukin M. E. , Kalaparthi V. , Miljkovic M. , Wang A. , Seigne J. D. , Grivas P. , Demidenko E.
Published: December 2018

Significance

New noninvasive and accurate diagnostic tests of cancer are important. Here we describe such a test, which is applied to the detection of bladder cancer, one of the most common cancers and cause of cancer-related deaths. This method can also be applied for the detection of other cancers, in which cells or body fluid are available for analysis without the need for invasive biopsy, e.g., upper urinary tract, urethra, colorectal and other gastrointestinal, cervical, aerodigestive cancers, etc. Furthermore, the described approach can be extended to detect cell abnormalities beyond cancer as well as to monitor cell reaction to various drugs (nanopharmacology). Thus, this approach may suggest a whole new direction of diagnostic imaging.
Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection
Authors: Yu Tai-Yuan , Kimble Michael T. , Symington Lorraine S.
Published: December 2018

Significance

Chromosomal double-strand breaks (DSBs) are cytotoxic forms of DNA damage that must be accurately repaired to maintain genome integrity. The conserved Mre11-Rad50-Xrs2
NBS1
complex plays an important role in repair by functioning as a damage sensor and by regulating DNA end processing to ensure repair by the most appropriate mechanism. Yeast Sae2 is known to activate the Mre11 endonuclease to process DNA ends, and previous studies suggest an additional role to dampen checkpoint signaling. Here, we show Sae2 functions independently of the Mre11 nuclease to prevent Rad9 accumulation at DSBs. Excessive Rad9 binding inhibits DNA end processing by the Dna2-Sgs1 and Exo1 nucleases causing sensitivity of Sae2-deficient cells to DNA damaging agents.
A perspective review on the bonding mechanisms in cold gas dynamic spray
Authors: Viscusi Antonio , Astarita Antonello , Gatta Roberta Della , Rubino Felice
Published: December 2018

The Cold Gas Dynamic Spray technology, generally referred as Cold Spray, is a relatively new additive manufacturing technique able to produce fully dense coatings through the deposition of particles on a substrate. Fine powders are accelerated to high velocity and projected onto a substrate, upon impact with the target surface, conversion of kinetic energy to plastic deformation occurs and the solid particles deform and bond together. During the cold spray deposition process, the particles remain in a solid state during the deposition, resulting in high-quality coatings with low residual stresses and oxide inclusions. The relative lower process temperatures allow the cold spray to manufacture coatings on high temperature-sensitive materials. It could also be a valid method for deposition of a wide variety of materials, from metallic alloys up to ceramics and composites. Depending on the materials employed as substrate and coating, different bonding mechanisms can occur during the deposition. The present review aims to summarise the main bonding theories proposed up to now for the cold spray, focusing on both the particle deformation behaviour during the contact with the surface and the interfacial bonding mechanisms. The available theories for different substrate/coating configurations will be discussed and compared. The effects of deposition parameters, the substrate's surface and microstructure of feedstock powders on the bonding mechanism will also be discussed.
Ecology of algal blooms in the Bay of Quinte: composition, diversity and dynamics
Authors: Munawar M. , Fitzpatrick M. , Niblock H. , Rozon R. , Lorimer J. , Kling H.
Published: December 2018

A total of 25 algal blooms were observed during three separate surveys of the Bay of Quinte, Lake Ontario, conducted during August 2010, September 2010 and September 2011. Here we define algal blooms based on the direct measurement of phytoplankton biomass (>3 g m−3) and not proxy measures such as chlorophyll a. In this chronically eutrophic embayment, we observed 8 diatom blooms (Aulacoseira spp.), 7 cyanobacteria blooms (Dolichospermum, Gloeotrichia, Microcystis, etc.) and 10 more that were mixtures of both taxa. At the cyano-bloom sites, ≈50% or more of the total biomass was composed of species known to be toxigenic. High rates of primary production (40 – 160 mg C m−3 h−1) by the larger algal size classes (>20 μm and 2–20 μm) indicated that there were few constraints on photosynthesis during bloom events (both diatom and cyanobacteria). Productivity to biomass quotients were considerably higher for filamentous algal forms (>9 for both diatoms and cyanobacteria) compared to colonial cyanobacteria (<5) suggesting that filamentous algae are more photosynthetically efficient. Our findings showed the observed algal blooms to be diverse and dynamic entities; management strategies need to recognize the unique characteristics of individual bloom events. Moreover, long term research and monitoring programs are necessary for the application of adaptive management strategies in order to address persistent ecosystem stressors like eutrophication.
Gender, the workplace and the limits of the law: a reply to Cramer and Cote Hampson
Authors: McNulty Stephanie
Published: December 2018

This reply discusses two articles that explore the limits of legal initiatives that attempt to rectify gender imbalances. The two articles tackle different issue areas (birthing and parental policies), yet come to similar conclusions: legal initiatives cannot necessarily change deeply entrenched cultural norms about women's bodies and choices. The articles also point to the problematic conclusion that policies meant to improve women's experience and expand their choices are ultimately restricted by societal norms about a woman's imagined role in the home and workplace. The articles push the boundaries of debates about gender empowerment and the law, and suggest a series of questions that remain to be answered.
Demand for Household Food Waste
Authors: Landry Craig E , Smith Travis A
Published: December 2018

We estimate the demand for food waste within the household using observational data of food stock usage and meal consumption, the net of which forms a proxy for unconsumed food. We find that food waste is a luxury good with an expenditure elasticity ranging from 1.1 to 1.4. The wasting of food is also rather responsive to price: our own‐price elasticity estimates range from ‐1.9 to ‐1.3. We further find differences in the demand for food waste related to household membership structure, human capital, joint preparation of meals within the household, and geographic location.
BIOLITMAP: a web-based geolocated, temporal and thematic visualization of the evolution of bioinformatics publications
Authors: Bazaga Adrián , Valencia Alfonso , JoséRementeria María-
Published: December 2018

Motivation

The fast growth of bioinformatics adds a significant difficulty to assess the contribution, geographical and thematic distribution of the research publications.

Results

To help researchers, grant agencies and general public to assess the progress in bioinformatics, we have developed BIOLITMAP, a web-based geolocation system that allows an easy and sensible exploration of the publications by institution, year and topic.

Availability and implementation

BIOLITMAP is available at http://socialanalytics.bsc.es/biolitmap and the sources have been deposited at https://github.com/inab/BIOLITMAP.

Supplementary information

Supplementary data are available at Bioinformatics online.
ARGDIT: a validation and integration toolkit for Antimicrobial Resistance Gene Databases
Authors: Chiu Jimmy Ka Ho , Ong Rick Twee-Hee
Published: December 2018

Motivation

Antimicrobial resistance is currently one of the main challenges in public health due to the excessive use of antimicrobials in medical treatments and agriculture. The advancements in high-throughput next-generation sequencing and development of bioinformatics tools allow simultaneous detection and identification of antimicrobial resistance genes (ARGs) from clinical, food and environment samples, to monitor the prevalence and track the dissemination of these ARGs. Such analyses are however reliant on a comprehensive database of ARGs with accurate sequence content and annotation. Most of the current ARG databases are therefore manually curated, but this is a time-consuming process and the resulting curation errors could be hard to detect. Several secondary ARG databases consolidate contents from different source ARG databases, and hence modifications in the primary databases might not be propagated and updated promptly in the secondary ARG databases.

Results

To address these problems, a validation and integration toolkit called ARGDIT was developed to validate ARG database fidelity, and merge multiple primary ARG databases into a single consolidated secondary ARG database with optional automated sequence re-annotation. Experimental results demonstrated the effectiveness of this toolkit in identifying errors such as sequence annotation typos in current ARG databases and generating an integrated non-redundant ARG database with structured annotation. A toolkit-oriented workflow is also proposed to minimize the efforts in validating, curating and merging multiple ARG protein or coding sequence databases. Database developers therefore benefit from faster update cycles and lower costs for database maintenance, while ARG pipeline users can easily evaluate the reference ARG database quality.

Availability and implementation

ARGDIT is available at https://github.com/phglab/ARGDIT.

Supplementary information

Supplementary data are available at Bioinformatics online.
Impact of De-escalation on Prognosis of Patients With Bacteremia due to Enterobacteriaceae: A Post Hoc Analysis From a Multicenter Prospective Cohort
Authors: Palacios-Baena Zaira R , Delgado-Valverde Mercedes , Valiente Méndez Adoración , Almirante Benito , Gómez-Zorrilla Silvia , Borrell Núria , Corzo Juan E , Gurguí Mercedes , De la Calle Cristina , García-Álvarez Lara , Ramos Lucía , Gozalo Mónica , Morosini María Isabel , Molina José , Causse Manuel , Pascual Álvaro , Rodríguez-Baño Jesús ,   REIPI/GEIRAS-SEIMC Bacteraemia-MIC Group, de Cueto M , Planes Reig A M , Tubau Quintano F , Peña C , Galán Otalora M E , Ruíz de Alegría C , Cantón R , Lepe J A , Cisneros J M , Torre-Cisneros J , Lara R
Published: December 2018

Background

More data are needed about the safety of antibiotic de-escalation in specific clinical situations as a strategy to reduce exposure to broad-spectrum antibiotics. The aims of this study were to investigate predictors of de-escalation and its impact on the outcome of patients with bloodstream infection due to Enterobacteriaceae (BSI-E).

Methods

A post hoc analysis was performed on a prospective, multicenter cohort of patients with BSI-E initially treated with ertapenem or antipseudomonal β-lactams. Logistic regression was used to analyze factors associated with early de-escalation (EDE) and Cox regression for the impact of EDE and late de-escalation (LDE) on 30-day all-cause mortality. A propensity score (PS) for EDE vs no de-escalation (NDE) was calculated. Failure at end of treatment and length of hospital stay were also analyzed.

Results

Overall, 516 patients were included. EDE was performed in 241 patients (46%), LDE in 95 (18%), and NDE in 180 (35%). Variables independently associated with a lower probability of EDE were multidrug-resistant isolates (odds ratio [OR], 0.50 [95% confidence interval {CI}, .30–.83]) and nosocomial infection empirically treated with imipenem or meropenem (OR, 0.35 [95% CI, .14–.87]). After controlling for confounders, EDE was not associated with increased risk of mortality; hazard ratios (HR) (95% CIs) were as follows: general model, 0.58 (.25–1.31); model with PS, 0.69 (.29–1.65); and PS-based matched pairs, 0.98 (.76–1.26). LDE was not associated with mortality. De-escalation was not associated with clinical failure or length of hospital stay.

Conclusions

De-escalation in patients with monomicrobial bacteremia due to Enterobacteriaceae was not associated with a detrimental impact on clinical outcome.
Identifying the anti-inflammatory response to lipid lowering therapy: a position paper from the working group on atherosclerosis and vascular biology of the European Society of Cardiology
Authors: Tuñón José , Badimón Lina , Bochaton-Piallat Marie-Luce , Cariou Bertrand , Daemen Mat J , Egido Jesus , Evans Paul C , Hoefer Imo E , Ketelhuth Daniel F J , Lutgens Esther , Matter Christian M , Monaco Claudia , Steffens Sabine , Stroes Erik , Vindis Cécile , Weber Christian , Bäck Magnus
Published: December 2018

Dysregulated lipid metabolism induces an inflammatory and immune response leading to atherosclerosis. Conversely, inflammation may alter lipid metabolism. Recent treatment strategies in secondary prevention of atherosclerosis support beneficial effects of both anti-inflammatory and lipid-lowering therapies beyond current targets. There is a controversy about the possibility that anti-inflammatory effects of lipid-lowering therapy may be either independent or not of a decrease in low-density lipoprotein cholesterol. In this Position Paper, we critically interpret and integrate the results obtained in both experimental and clinical studies on anti-inflammatory actions of lipid-lowering therapy and the mechanisms involved. We highlight that: (i) besides decreasing cholesterol through different mechanisms, most lipid-lowering therapies share anti-inflammatory and immunomodulatory properties, and the anti-inflammatory response to lipid-lowering may be relevant to predict the effect of treatment, (ii) using surrogates for both lipid metabolism and inflammation as biomarkers or vascular inflammation imaging in future studies may contribute to a better understanding of the relative importance of different mechanisms of action, and (iii) comparative studies of further lipid lowering, anti-inflammation and a combination of both are crucial to identify effects that are specific or shared for each treatment strategy.
Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment
Authors: Stiekema Lotte C A , Stroes Erik S G , Verweij Simone L , Kassahun Helina , Chen Lisa , Wasserman Scott M , Sabatine Marc S , Mani Venkatesh , Fayad Zahi A
Published: December 2018

Aims

Subjects with lipoprotein(a) [Lp(a)] elevation have increased arterial wall inflammation and cardiovascular risk. In patients at increased cardiovascular risk, arterial wall inflammation is reduced following lipid-lowering therapy by statin treatment or lipoprotein apheresis. However, it is unknown whether lipid-lowering treatment in elevated Lp(a) subjects alters arterial wall inflammation. We evaluated whether evolocumab, which lowers both low-density lipoprotein cholesterol (LDL-C) and Lp(a), attenuates arterial wall inflammation in patients with elevated Lp(a).

Methods and results

In this multicentre, randomized, double-blind, placebo-controlled study, 129 patients {median [interquartile range (IQR)]: age 60.0 [54.0–67.0] years, Lp(a) 200.0 [155.5–301.5] nmol/L [80.0 (62.5–121.0) mg/dL]; mean [standard deviation (SD)] LDL-C 3.7 [1.0] mmol/L [144.0 (39.7) mg/dL]; National Cholesterol Education Program high risk, 25.6%} were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-C by 60.7% [95% confidence interval (CI) 65.8–55.5] and Lp(a) by 13.9% (95% CI 19.3–8.5). Among evolocumab-treated patients, the Week 16 mean (SD) LDL-C level was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL], and the median (IQR) Lp(a) level was 188.0 (140.0–268.0) nmol/L [75.2 (56.0–107.2) mg/dL]. Arterial wall inflammation [most diseased segment target-to-background ratio (MDS TBR)] in the index vessel (left carotid, right carotid, or thoracic aorta) was assessed by 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography. Week 16 index vessel MDS TBR was not significantly altered with evolocumab (−8.3%) vs. placebo (−5.3%) [treatment difference −3.0% (95% CI −7.4% to 1.4%); P = 0.18].

Conclusion

Evolocumab treatment in patients with median baseline Lp(a) 200.0 nmol/L led to a large reduction in LDL-C and a small reduction in Lp(a), resulting in persistent elevated Lp(a) levels. The latter may have contributed to the unaltered arterial wall inflammation.
Numerical solution of fractional elliptic stochastic PDEs with spatial white noise
Authors: Bolin David , Kirchner Kristin , Kovács Mihály
Published: December 2018

The numerical approximation of solutions to stochastic partial differential equations with additive spatial white noise on bounded domains in $\mathbb{R}^d$ is considered. The differential operator is given by the fractional power $L^\beta $, $\beta \in (0,1)$ of an integer-order elliptic differential operator $L$ and is therefore nonlocal. Its inverse $L^{-\beta }$ is represented by a Bochner integral from the Dunford–Taylor functional calculus. By applying a quadrature formula to this integral representation the inverse fractional-order operator $L^{-\beta }$ is approximated by a weighted sum of nonfractional resolvents $( I + \exp(2 y_\ell) \, L )^{-1}$ at certain quadrature nodes $t_j> 0$. The resolvents are then discretized in space by a standard finite element method. This approach is combined with an approximation of the white noise, which is based only on the mass matrix of the finite element discretization. In this way an efficient numerical algorithm for computing samples of the approximate solution is obtained. For the resulting approximation the strong mean-square error is analyzed and an explicit rate of convergence is derived. Numerical experiments for $L=\kappa ^2-\Delta $, $\kappa> 0$ with homogeneous Dirichlet boundary conditions on the unit cube $(0,1)^d$ in $d=1,2,3$ spatial dimensions for varying $\beta \in (0,1)$ attest to the theoretical results.
SOX2 in cancer stemness: tumor malignancy and therapeutic potentials
Authors: Mamun Mahfuz Al , Mannoor Kaiissar , Cao Jun , Qadri Firdausi , Song Xiaoyuan
Published: December 2018

Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition, ATP-binding cassette drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance. Gaining a better insight and comprehensive interrogation into the mechanistic basis of SOX2-mediated generation of CSCs and treatment failure might therefore lead to new therapeutic targets involving CSC-specific anti-cancer strategies.
Dipeptidyl peptidase-4 inhibitor teneligliptin accelerates recovery from cisplatin-induced acute kidney injury by attenuating inflammation and promoting tubular regeneration
Authors: Iwakura Takamasa , Zhao Zhibo , Marschner Julian A , Devarapu Satish Kumar , Yasuda Hideo , Anders Hans Joachim
Published: December 2018

Background

Cisplatin is an effective chemotherapeutic agent. However, acute kidney injury (AKI) and subsequent kidney function decline limits its use. Dipeptidyl peptidase-4 (DPP-4) inhibitor has been reported to attenuate kidney injury in some in vivo models, but the mechanisms-of-action in tubule recovery upon AKI remain speculative. We hypothesized that DPP-4 inhibitor teneligliptin (TG) can facilitate kidney recovery after cisplatin-induced AKI.

Methods

In in vivo experiment, AKI was induced in rats by injecting 5 mg/kg of cisplatin intravenously. Oral administration of 10 mg/kg of TG, once a day, was started just before injecting cisplatin or from Day 5 after cisplatin injection. In an in vitro experiment, proliferation of isolated murine tubular cells was evaluated with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and cell counting. Cell viability was analysed by MTT assay or lactate dehydrogenase (LDH) assay.

Results

In in vivo experiments, we found that TG attenuates cisplatin-induced AKI and accelerates kidney recovery after the injury by promoting the proliferation of surviving epithelial cells of the proximal tubule. TG also suppressed intrarenal tumour necrosis factor-α expression, and induced macrophage polarization towards the anti-inflammatory M2 phenotype, both indirectly endorsing tubule recovery upon cisplatin injury. In in vitro experiments, TG directly accelerated the proliferation of primary tubular epithelial cells. Systematic screening of the DPP-4 substrate chemokines in vitro identified CXC chemokine ligand (CXCL)-12 as a promoted mitogenic factor. CXCL12 not only accelerated proliferation but also inhibited cell death of primary tubular epithelial cells after cisplatin exposure. CXC chemokine receptor (CXCR)-4 antagonism abolished the proliferative effect of TG.

Conclusions

The DPP-4 inhibitor TG can accelerate tubule regeneration and functional recovery from toxic AKI via an anti-inflammatory effect and probably via inhibition of CXCL12 breakdown. Hence, DPP-4 inhibitors may limit cisplatin-induced nephrotoxicity and improve kidney function in cancer patients.
Image-Guided Navigation and Robotics in Spine Surgery
Authors: Kochanski Ryan B , Lombardi Joseph M , Laratta Joseph L , Lehman Ronald A , O’Toole John E
Published: December 2018

Image guidance (IG) and robotics systems are becoming more widespread in their utilization and can be invaluable intraoperative adjuncts during spine surgery. Both are highly reliant upon stereotaxy and either pre- or intraoperative radiographic imaging. While user-operated IG systems have been commercially available longer and subsequently are more widely utilized across centers, robotics systems provide unique theoretical advantages over freehand and IG techniques for placing instrumentation within the spine. While there is a growing plethora of data showing that IG and robotic systems decrease the incidence of malpositioned screws, less is known about their impact on clinical outcomes. Both robotics and IG may be of particular value in cases of substantial deformity or complex anatomy. Indications for the use of these systems continue to expand with an increasing body of literature justifying their use in not only guiding thoracolumbar pedicle screw placement, but also in cases of cervical and pelvic instrumentation as well as spinal tumor resection. Both techniques also offer the potential benefit of reducing occupational exposures to ionizing radiation for the operating room staff, the surgeon, and the patient. As the use of IG and robotics in spine surgery continues to expand, these systems’ value in improving surgical accuracy and clinical outcomes must be weighed against concerns over cost and workflow. As newer systems incorporating both real-time IG and robotics become more utilized, further research is necessary to better elucidate situations where these systems may be particularly beneficial in spine surgery.
Novel Strategy of Ventral Dural Repair for Idiopathic Thoracic Spinal Cord Herniation: Report of Outcomes and Review of Techniques
Authors: Herring Eric Z , Shin John H , Nagel Sean J , Krishnaney Ajit A
Published: December 2018

BACKGROUND

Idiopathic ventral thoracic spinal cord herniation is a rare condition that usually presents with progressive myelopathy or Brown-Séquard syndrome. More than 100 cases have been reported with significant variance in surgical treatment strategies and likewise, significant variance in patient outcomes. Although laminectomy has often been used, to date, there is no consensus regarding the optimal surgical approach or strategy for ventral dural repair.

OBJECTIVE

To report and illustrate a novel approach to repair the ventral dural defect with more than 2 yr of clinical follow-up. The specific approach and graft used are both detailed.

METHODS

A retrospective chart review of all known cases of idiopathic spinal cord herniation at the Cleveland Clinic over the last 15 yr was performed. Postoperative outcome scores (including the Japanese Orthopedic Association score, European Myelopathy score, and Nurick) were calculated preoperatively and postoperatively.

RESULTS

A total of 5 patients were identified. Four of five patients improved clinically after surgery and 1 patient remained unchanged at last follow-up (average 23.2 mo, range 12-60 mo). There were no complications. All patients had postoperative magnetic resonance imaging demonstrating realignment of the spinal cord and no recurrence of tethering.

CONCLUSION

A unilateral dorsolateral, transpedicular approach combined with laminectomy provides excellent exposure for ventral or ventrolateral dural defects associated with idiopathic spinal cord herniation and minimizes spinal cord manipulation. A collagen matrix graft used as an onlay between the spinal cord and ventral dural defect is a safe and effective option for ventral dural repair.
A Critical Appraisal of Predatory Journals in Pathology
Authors: AlAhmad Yaman M , Abdelhafez Ibrahim , Cyprian Farhan S , Skenderi Faruk , Akhtar Saghir , Vranic Semir
Published: December 2018

Predatory or pseudo journals have recently come into focus due to their massive internet expansion and extensive spam email soliciting. Recent studies explored this urging problem in several biomedical disciplines. In the present study, we identified 69 potential predatory (pseudo) pathology journals that were contrasted to 89 legitimate pathology journals obtained from the major bibliographic databases. All potential predatory journals in pathology shared at least one of the features proposed by previous studies (e.g. a poor web-site integrity, submissions via email, unclear or ambiguous peer-review process, missing names of the editorial board members, missing or pending the journal ISSN). Twenty-one (30%) of the potential predatory pathology journals had misleading titles mimicking those of legitimate journals. Only one of the identified journals was listed in the Directory of Open Access journals whereas none (0%) was indexed in PubMed/MEDLINE or Web of Science, listed in the Committee on Publication Ethics nor have they had a legitimate impact factor in the Journal Citation Reports.
Beyond a single patch: local and regional processes explain diversity patterns in a seagrass epifaunal metacommunity
Authors: Stark Keila A , Thompson Patrick L , Yakimishyn Jennifer , Lee Lynn , Adamczyk Emily M , Hessing-Lewis Margot , O’Connor Mary I
Published: December 2018

Ecological communities are jointly structured by dispersal, density-independent responses to environmental conditions and density-dependent biotic interactions. Metacommunity ecology provides a framework for understanding how these processes combine to determine community composition among local sites that are regionally connected through dispersal. In 17 temperate seagrass meadows along the British Columbia coast, we tested the hypothesis that eelgrass (Zostera marinaL.) epifaunal invertebrate assemblages are influenced by local environmental conditions, but that high dispersal rates at larger spatial scales dampen effects of environmental differences. We used hierarchical joint species distribution modelling to understand the contribution of environmental conditions, spatial distance between meadows, and species co-occurrences to epifaunal invertebrate abundance and distribution across the region. We found that patterns of taxonomic compositional similarity among meadows were inconsistent with dispersal limitation and meadows in the same region were often no more similar to each other than meadows over 1000 km away. Abiotic environmental conditions (temperature, dissolved oxygen) explained a small fraction of variation in taxonomic abundances patterns across the region. We found novel co-occurrence patterns among taxa that could not be explained by shared responses to environmental gradients, suggesting the possibility that interspecific interactions influence seagrass invertebrate abundance and distribution. Our results add to mounting evidence that suggests that the biodiversity and ecosystem functions provided by seagrass meadows reflect ecological processes occurring both within meadows and across seascapes, and suggest that management of eelgrass habitat for biodiversity may be most effective when both local and regional processes are considered.
Dispersal syndromes can impact ecosystem functioning in spatially structured freshwater populations
Authors: Little Chelsea J. , Fronhofer Emanuel A. , Altermatt Florian
Published: December 2018

Dispersal can strongly influence ecological and evolutionary dynamics. Besides the direct contribution of dispersal to population dynamics, dispersers often differ in their phenotypic attributes from non-dispersers, which leads to dispersal syndromes. The consequences of such dispersal syndromes have been widely explored at the population and community level, however, to date, ecosystem-level effects remain unclear. Here, we examine whether dispersing and resident individuals of two different aquatic keystone invertebrate species have different contributions to detrital processing, a key function in freshwater ecosystems. Using experimental two-patch systems, we found no difference in leaf consumption rates with dispersal status of the common native species Gammarus fossarum. In Dikerogammarus villosus, however, a Ponto-Caspian species now expanding throughout Europe, dispersers consumed leaf litter at roughly three times the rate of non-dispersers. Furthermore, this put the contribution of dispersing D. villosus to leaf litter processing on par with native G. fossarum, after adjusting for differences in organismal size. Given that leaf litter decomposition is a key function in aquatic ecosystems, and the rapid species turnover in freshwater habitats with range expansions of non-native species, this finding suggests that dispersal syndromes may have important consequences for ecosystem functioning.
Dye-free retinal angiography using blood-oxygenation modulation
Authors: MacKenzie Lewis E , Choudhary Tushar R , Fernandez Ramos Javier , Benjamin Nigel , Delles Christian , Harvey Andrew R
Published: December 2018

Fluorescence angiography (FA) is widely used for studying and diagnosing abnormalities in the retinal blood circulation, but has associated risks of nausea, skin irritation, and even death. We describe a new non-invasive angiography technique: Blood Oxygenation Modulation Angiography, in which multispectral imaging of a transient perturbation in blood-oxygen saturation, yields angiography sequences similar to FA, including key features such as sequential filling of choroidal and retinal-vessels, which underpin assessment of circulation health. This is the first non-invasive angiography technique capable of visualizing these circulation features.
Dynamical structure of cortical taste responses revealed by precisely-timed optogenetic perturbation
Authors: Mukherjee Narendra , Wachukta Joseph , Katz Donald B
Published: December 2018

The purpose of perception is driving action. During tasting, for instance, every stimulus must be either swallowed or rejected (the latter via a behavior known as “gaping”). Taste responses in the rodent primary gustatory cortex (GC) span this sensorimotor divide, progressing through a series of firing epochs that culminate in the emergence of action-related firing. Population analyses reveal this emergence to be a sudden, coherent ensemble transition that, despite varying in latency between trials, precedes gaping onset by 0.2-0.3s. Here, we tested whether this transition drives gaping, delivering 0.5s GC perturbations at various time-points in tasting trials. Perturbations significantly delayed gaping, but only when they preceded the action-related transition - thus, the same perturbation might have an impact or not, depending on the transition latency in that particular trial. Our results suggest a distributed attractor network model of taste processing, and a dynamical role for cortex in driving motor behavior.
Transcranial ultrasound selectively biases decision-making in primates
Authors: Kubanek Jan , Brown Julian , Ye Patrick , Pauly Kim Butts , Moore Tirin , Newsome William
Published: December 2018

Transcranial focused ultrasound has the promise to evolve into a transformative noninvasive way to modulate activity of neuronal circuits deep in the brain. The approach may enable systematic and causal mapping of how individual brain circuits are involved in specific behaviors and behavioral disorders. Previous studies demonstrated neuromodulatory potential, but the effect polarity, size, and spatial specificity have been difficult to assess. Here, we engaged non-human primates (macaca mulatta) in an established task that provides a well defined framework to characterize the neuromodulatory effects. In this task, subjects decide whether to look at a right or a left target, guided by one the targets appearing first. Previous studies showed that excitation/inhibition of oculomotor circuits leads to contralateral/ipsilateral biases in this choice behavior. We found that brief, low-intensity ultrasound stimuli (300 ms, 0.6 MPa, 270 kHz) delivered to the animals’ left/right frontal eye fields bias the animals’ decisions to the right/left visual hemifield. The effect was modest, about on the order of that produced when injecting moderate amounts of potent neuromodulatory drugs into the same regions in this task. The polarity of the effects suggested a neuronal excitation within the stimulated regions. No effects were observed when we applied the same stimuli to control brain regions not involved in oculomotor target selection. Together, using an established paradigm, we found that transcranial ultrasound is capable of modulating neurons to the extent of biasing choice behavior of non-human primates. A demonstration of tangible, brain-region-specific effects on behavior of primates constitutes a critical step toward applying this noninvasive neuromodulation method in investigations of how specific neural circuits are involved in specific behaviors or disease signs.
Does pixel/voxel-size limit the measurement of distances in CBCT-tomography?
Authors: Köberle Roland , Spavieri Deusdedit Lineu , Bianchi Jonas , Ignácio Jaquelilne , Gonçalves João Roberto
Published: December 2018

The necessity to obtain relevant structural information from tomographic
images is an all-pervasive step in a host of clinical and research-areas.
Cone Beam Computed Tomography (CBCT) is the imaging modality often used
among the many available.

Currently approaches to extract structural
properties from raw CBCT-images, involve some manual intervention by experts to measure their properties, such as size and displacements of their geometrical structures.
Regarding the factors limiting the precision of these measurements, such as voxel-size and image contrast, we find conflicting statements in the literature.
It is therefore useful to provide accurate data under well-defined experimental conditions.

Here we present a method and associated software to measure displacements of geometrical structures. We also determined the minimum measureable displacement and minimum detectable defect in terms of voxel size.
We select as our geometrical structure a sample of bovine bone and to provide a set of defects, we drilled a pattern of holes into it.
We determined the hole's three-dimensional structures using confocal spectroscopy.

In order to obtain the minimum measurable displacement, we acquired CBCT-radiographies containing a stationary reference and micro-metrically cnc controlled displacements of the sample. We then process these images with our software to extract the distances and compare them with the cnc displacements. All our processing includes a computational interpolation from the voxel-size of $0.35$ mm corresponding to our CBCT-radiographies, down to $0.05$ mm.
We find that sample-displacements can be measured with a precision of $\sim 20 \mu$, 17 times smaller than the voxel-size of $0.35$ mm.

To measure the size of the holes using our CBCT-radiographies, we first register the holes onto a hole-free region of the sample with our software, then overlay the result with the three-dimensional structure obtained from confocal spectroscopy. We find the minimum detectable hole-size to be $0.7$ mm, twice the voxel-size.