bluuebunny/crossref_metadata_2025 huggingface dataset:
KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients
Authors: Quinti Luisa , Dayalan Naidu Sharadha , Träger Ulrike , Chen Xiqun , Kegel-Gleason Kimberly , Llères David , Connolly Colúm , Chopra Vanita , Low Cho , Moniot Sébastien , Sapp Ellen , Tousley Adelaide R. , Vodicka Petr , Van Kanegan Michael J. , Kaltenbach Linda S. , Crawford Lisa A. , Fuszard Matthew , Higgins Maureen , Miller James R. C. , Farmer Ruth E. , Potluri Vijay , Samajdar Susanta , Meisel Lisa , Zhang Ningzhe , Snyder Andrew , Stein Ross , Hersch Steven M. , Ellerby Lisa M. , Weerapana Eranthie , Schwarzschild Michael A. , Steegborn Clemens , Leavitt Blair R. , Degterev Alexei , Tabrizi Sarah J. , Lo Donald C. , DiFiglia Marian , Thompson Leslie M. , Dinkova-Kostova Albena T. , Kazantsev Aleksey G.
Published: May 2017

Significance

Chronic neuroinflammation and oxidative stress are likely complicit in driving disease progression in Huntington's disease (HD). Here, we describe the mechanism of action of a unique chemical scaffold that is highly selective for activation of NRF2, the master transcriptional regulator of cellular antiinflammatory and antioxidant defense genes. The use of this scaffold revealed that NRF2 activation responses were muted in HD patient-derived neural stem cells, suggesting increased susceptibility of this critical renewable cell population to oxidative stress in HD brain. However, pharmacological activation of NRF2 was able to repress inflammatory responses in mouse microglia and astrocytes, the principal cellular mediators of neuroinflammation, and in blood monocytes from HD patients. Our results suggest multiple protective benefits of NRF2 activation for HD patients.
Pyrite sulfur isotopes reveal glacial−interglacial environmental changes
Authors: Pasquier Virgil , Sansjofre Pierre , Rabineau Marina , Revillon Sidonie , Houghton Jennifer , Fike David A.
Published: May 2017

Significance

Changes in sulfur isotope ratios (
34
S/
32
S) of marine sulfur phases are often attributed to global biogeochemical perturbations. Sediments collected on the shelf of the Gulf of Lion revealed remarkable sulfur isotopic fluctuations in sedimentary pyrite over the last 500,000 years, ranging between −44.0‰ and 32.3‰. We suggest this pattern is related to changes in the local environmental deposition, specifically, sedimentation modulating connectivity with the overlying water column and resulting microbial activity. Besides providing new understanding of an important and poorly constrained aspect of past glacial−interglacial transitions, our results are critically important because they question the degree to which changes in sulfur isotopes in pyrite reflect global biogeochemical processes versus local depositional conditions.
Integrative modeling of gene and genome evolution roots the archaeal tree of life
Authors: Williams Tom A. , Szöllősi Gergely J. , Spang Anja , Foster Peter G. , Heaps Sarah E. , Boussau Bastien , Ettema Thijs J. G. , Embley T. Martin
Published: May 2017

Significance

The Archaea represent a primary domain of cellular life, play major roles in modern-day biogeochemical cycles, and are central to debates about the origin of eukaryotic cells. However, understanding their origins and evolutionary history is challenging because of the immense time spans involved. Here we apply a new approach that harnesses the information in patterns of gene family evolution to find the root of the archaeal tree and to resolve the metabolism of the earliest archaeal cells. Our approach robustly distinguishes between published rooting hypotheses, suggests that the first Archaea were anaerobes that may have fixed carbon via the Wood–Ljungdahl pathway, and quantifies the cumulative impact of horizontal transfer on archaeal genome evolution.
Prediction of disease activity in models of multiple sclerosis by molecular magnetic resonance imaging of P-selectin
Authors: Fournier Antoine Philippe , Quenault Aurélien , Martinez de Lizarrondo Sara , Gauberti Maxime , Defer Gilles , Vivien Denis , Docagne Fabian , Macrez Richard
Published: May 2017

Significance

Multiple sclerosis is a brain and spinal cord disease. In the most common forms, the disease unfolds by switching between periods of relapses, during which symptoms rise, and remissions, during which symptoms decline. However, it is not yet possible to predict the occurrence of relapses and remissions. Today, the diagnosis of multiple sclerosis is based on clinical criteria and on the use of magnetic resonance imaging (MRI). Here, we developed an MRI method that helps predict relapses and remissions in a classical model of multiple sclerosis in the mouse.
Learned response sequences in cerebellar Purkinje cells
Authors: Jirenhed Dan-Anders , Rasmussen Anders , Johansson Fredrik , Hesslow Germund
Published: May 2017

Significance

Learning is thought to rely on the strengthening or weakening of synapses. However, we have previously shown that a neuron can also learn when to time its response so that the timing reflects the interval between two stimuli, without any temporal information in the input signal. Here, we report that a neuron can even learn a sequence of at least two, and probably more, accurately timed responses. A single cell is in a sense “programmable,” and can encode a temporal response pattern. This means that the nature of what a cell can learn is very different from the traditional view, and that the information storage capacity may be far greater.
CCR8+FOXp3+Tregcells as master drivers of immune regulation
Authors: Barsheshet Yiftah , Wildbaum Gizi , Levy Eran , Vitenshtein Alon , Akinseye Chika , Griggs Jeremy , Lira Sergio A. , Karin Nathan
Published: May 2017

Significance

The current study identifies CCR8+regulatory T cells (Tregcells) as drivers of immunosuppression and provides compelling evidence of a self-feeding mechanism by which, at an autoimmune site, CCL1 produced by FOXp3+Tregcells upregulates the expression of its own receptor, CCR8, on these cells, and potentiates their in vivo proliferation and suppressive activities as driver Tregcells. The suppression of ongoing autoimmunity by a stabilized version of the chemokine (CCL1–Ig) highlights the translational potential of these findings.
Insect pathogenic fungus interacts with the gut microbiota to accelerate mosquito mortality
Authors: Wei Ge , Lai Yiling , Wang Guandong , Chen Huan , Li Fang , Wang Sibao
Published: May 2017

Significance

As insecticide resistance is rapidly spreading, alternative tools for mosquito control are urgently needed.
Beauveria bassiana
is equally effective at killing insecticide-resistant and insecticide-susceptible mosquitoes. Better understanding of fungus–mosquito interactions is critical for improvement of its efficacy. Here we discover a contributory role for the gut microbiota in promoting fungal killing of mosquitoes via down-regulation of antimicrobial peptides and dual oxidase in the midgut. Fungal infection results in dysbiosis of mosquito gut microbiota by significantly increasing gut bacterial loads and decreasing bacterial diversity. In particular, fungal infection causes overgrowth and translocation of the opportunistic pathogen
Serratia marcescens
from the gut to the hemocoel, thus promoting mosquito death. Our study may lead to new strategies for biological control of mosquitoes.
Mechanism of H
2
S-mediated protection against oxidative stress in
Escherichia coli
Authors: Mironov Alexander , Seregina Tatyana , Nagornykh Maxim , Luhachack Lyly G. , Korolkova Natalya , Lopes Liubov Errais , Kotova Vera , Zavilgelsky Gennady , Shakulov Rustem , Shatalin Konstantin , Nudler Evgeny
Published: May 2017

Significance

Hydrogen sulfide (H
2
S) is a highly toxic gas that interferes with cellular respiration; however, at low physiological amounts, it plays an important role in cell signaling. Remarkably, in bacteria, endogenously produced H
2
S has been recently recognized as a general protective molecule, which renders multiple bacterial species highly resistant to oxidative stress and various classes of antibiotics. The mechanism of this phenomenon remains poorly understood. In this paper, we use
Escherichia coli
as a model system to elucidate its major enzymatic source of H
2
S and establish the principle biochemical pathways that account for H
2
S-mediated protection against reactive oxygen species. Understanding those mechanisms has far-reaching implications in preventing bacterial resistance and designing effective antimicrobial therapies.
Changes in conformational equilibria regulate the activity of the Dcp2 decapping enzyme
Authors: Wurm Jan Philip , Holdermann Iris , Overbeck Jan H. , Mayer Philipp H. O. , Sprangers Remco
Published: May 2017

Significance

The Dcp2 decapping enzyme targets mRNA for degradation and thereby plays a role in the regulation of gene expression. Despite numerous static crystal structures of the enzyme, it remained unclear how its catalytic activity correlates with the relative domain orientation in Dcp2. Here we used solution-state NMR spectroscopic methods and find that the active state of Dcp2 is only stably formed in the presence of the Dcp1 and Edc1 activator proteins and the mRNA cap. Importantly, our solution data provide a conclusive view of how the Dcp2 structure changes during the catalytic cycle and provide a unique example of the importance of integrated structural biology approaches to unravel the mechanism behind complex molecular machines.
The pentameric complex drives immunologically covert cell–cell transmission of wild-type human cytomegalovirus
Authors: Murrell Isa , Bedford Carmen , Ladell Kristin , Miners Kelly L. , Price David A. , Tomasec Peter , Wilkinson Gavin W. G. , Stanton Richard J.
Published: May 2017

Significance

Strains of human cytomegalovirus (HCMV) that have been passaged in the laboratory fail to recapitulate the phenotypic characteristics of ex vivo isolates due to the rapid acquisition of genetic mutations. In particular, clinical viruses spread via direct cell–cell contact, whereas passaged strains spread via diffusion of cell-free virions. We developed a method that enables in vitro propagation of genetically intact HCMV. Using this system, we report that cell–cell transmission of wild-type HCMV not only is highly efficient, but also enables the virus to overcome key innate and adaptive immune defenses. These findings inform our understanding of viral persistence and validate a new approach to experimentation that may facilitate the design of improved prophylactic and therapeutic interventions against HCMV.
Phosphorylated Presenilin 1 decreases β-amyloid by facilitating autophagosome–lysosome fusion
Authors: Bustos Victor , Pulina Maria V. , Bispo Ashley , Lam Alison , Flajolet Marc , Gorelick Fred S. , Greengard Paul
Published: May 2017

Significance

Autophagy is a catabolic process involving the formation of double-membrane–bound organelles called autophagosomes, which participate in the degradation of intracellular material through fusion with lysosomes. We have found a level of regulation of autophagosomal–lysosomal fusion where Presenilin 1 (PS1) phosphorylated at Ser367 specifically binds Annexin A2, which, through successive binding steps, facilitates this fusion. Lack of phosphorylation on PS1 1 Ser367 causes accumulation of partially fused autophagosomes and lysosomes in mouse brain and reduced autophagic flux. This inhibition of autophagy leads to decreased βCTF degradation and accumulation of toxic Aβ-peptide in the brain. This signaling pathway offers new potential drug targets for Alzheimer’s disease.
Matching Watershed and Otolith Chemistry to Establish Natal Origin of an Endangered Desert Lake Sucker
Authors: Strohm Deanna D. , Budy Phaedra , Crowl Todd A.
Published: May 2017

Stream habitat restoration and supplemental stocking of hatchery‐reared fish have increasingly become key components of recovery plans for imperiled freshwater fish; however, determining when to discontinue stocking efforts, prioritizing restoration areas, and evaluating restoration success present a conservation challenge. In this study, we demonstrate that otolith microchemistry is an effective tool for establishing natal origin of the June Sucker Chasmistes liorus, an imperiled potamodromous fish. This approach allows us to determine whether a fish is of wild or hatchery origin in order to assess whether habitat restoration enhances recruitment and to further identify areas of critical habitat. Our specific objectives were to (1) quantify and characterize chemical variation among three main spawning tributaries; (2) understand the relationship between otolith microchemistry and tributary chemistry; and (3) develop and validate a classification model to identify stream origin using otolith microchemistry data. We quantified molar ratios of Sr:Ca, Ba:Ca, and Mg:Ca for water and otolith chemistry from three main tributaries to Utah Lake, Utah, during the summer of 2013. Water chemistry (loge transformed Sr:Ca, Ba:Ca, and Mg:Ca ratios) differed significantly across all three spawning tributaries. We determined that Ba:Ca and Sr:Ca ratios were the most important variables driving our classification models, and we observed a strong linear relationship between water and otolith values for Sr:Ca and Ba:Ca but not for Mg:Ca. Classification models derived from otolith element : Ca signatures accurately sorted individuals to their experimental tributary of origin (classification tree: 89% accuracy; random forest model: 91% accuracy) and determined wild versus hatchery origin with 100% accuracy. Overall, this study aids in evaluating the effectiveness of restoration, tracking progress toward recovery, and prioritizing future restoration plans for fishes of conservation concern. Our results have further application, such as identifying subpopulations that provide the greatest reproductive contribution to a metapopulation or finding the reproductive area and origin of invasive fishes.

Received August 27, 2016; accepted February 28, 2017 Published online May 22, 2017
Bacillus cereus-type polyhydroxyalkanoate biosynthetic gene cluster contains R-specific enoyl-CoA hydratase gene
Authors: Kihara Takahiro , Hiroe Ayaka , Ishii-Hyakutake Manami , Mizuno Kouhei , Tsuge Takeharu
Published: May 2017

Bacillus cereus and Bacillus megaterium both accumulate polyhydroxyalkanoate (PHA) but their PHA biosynthetic gene (pha) clusters that code for proteins involved in PHA biosynthesis are different. Namely, a gene encoding MaoC-like protein exists in the B. cereus-type pha cluster but not in the B. megaterium-type pha cluster. MaoC-like protein has an R-specific enoyl-CoA hydratase (R-hydratase) activity and is referred to as PhaJ when involved in PHA metabolism. In this study, the pha cluster of B. cereus YB-4 was characterized in terms of PhaJ’s function. In an in vitro assay, PhaJ from B. cereus YB-4 (PhaJYB4) exhibited hydration activity toward crotonyl-CoA. In an in vivo assay using Escherichia coli as a host for PHA accumulation, the recombinant strain expressing PhaJYB4 and PHA synthase led to increased PHA accumulation, suggesting that PhaJYB4 functioned as a monomer supplier. The monomer composition of the accumulated PHA reflected the substrate specificity of PhaJYB4, which appeared to prefer short chain-length substrates. The pha cluster from B. cereus YB-4 functioned to accumulate PHA in E. coli; however, it did not function when the phaJYB4 gene was deleted. The B. cereus-type pha cluster represents a new example of a pha cluster that contains the gene encoding PhaJ.
Effects of microstructural asymmetries across friction stir welded AA2024 joints on mechanical properties
Authors: Niu Pengliang , Li Wenya , Yang Xiawei , Vairis Achillefs
Published: May 2017

The effect of offset of the centre of a tensile specimen to the weldline on global tensile properties of friction stir welded AA2024 joints was investigated using experiments and numerical analysis. The size and geometry of these discrete zones, such as the central low hardness zone, the low hardness zone-I near the thermo-mechanically affected zone, the low hardness zone-II near the base metal and the base metal, were determined from a cross-sectional hardness map. Results show that tensile specimens with different area of the joint placed in the centre of the specimen do not affect the tensile strength and fracture path of a joint, strain is affected. Predictions based on local tensile properties follow well the measured global tensile behaviour.
Demonstration of a Novel Control Strategy for Prymnesium parvum Management in Fish Hatcheries
Authors: Yeager Armstead Mindy , Wilson Mandee , Parsons-White Amy
Published: May 2017

Prymnesium parvum blooms result in fish kills around the world and are devastating to fish hatcheries, where few management tools are available. Current control strategies include algaecides, nutrient management, and flocculation, which are moderately effective at best and can be toxic to nontarget organisms. A relatively new type of medium, registered by the U.S. Environmental Protection Agency for the control of fecal coliforms in storm water runoff, was evaluated as a possible P. parvum control tool. The medium, called Smart Sponge, was designed to absorb petroleum hydrocarbons; a variant, Smart Sponge Plus, is enhanced with antimicrobial properties. It is these antimicrobial properties that we investigated for possible use in algal bloom management. Our objective was to evaluate the efficacy of this type of medium on the eradication of P. parvum and its associated toxins, with a view toward advancing toxic algae control strategies. Prymnesium parvum was passed through columns of the filter medium. Algal cell counts and visual observations were used to assess mortality; fish bioassays were conducted to assess toxicity. Smart Sponge Plus successfully killed the algae, although toxins were released during filtration. After filtration, 87–100% algal removal was achieved, with the variability potentially being related to cell density at the initiation of the test. Smart Sponge was also successful in reducing associated the toxicity of P. parvum, as was a charcoal medium. Smart Sponge Plus shows promise for use in the management of golden algal blooms by reducing cell density and should be further evaluated in hatchery and field settings.
An Accurate Method for Measuring Triploidy of Larval Fish Spawns
Authors: Jenkins Jill A , Draugelis-Dale Rassa O , Glennon Robert P , Kelly Anita M , Brown Bonnie L , Morrison John R
Published: May 2017

A standard flow cytometric protocol was developed for estimating triploid induction in batches of larval fish. Polyploid induction treatments are not guaranteed to be 100% efficient, thus the ability to quantify the proportion of triploid larvae generated by a particular treatment helps managers to stock high-percentage spawns and researchers to select treatments for efficient triploid induction. At 3 d posthatch, individual Grass Carp Ctenopharyngodon idella were mechanically dissociated into single-cell suspensions; nuclear DNA was stained with propidium iodide then analyzed by flow cytometry. Following ploidy identification of individuals, aliquots of diploid and triploid cell suspensions were mixed to generate 15 levels (0–100%) of known triploidy (n = 10). Using either 20 or 50 larvae per level, the observed triploid percentages were lower than the known, actual values. Using nonlinear regression analyses, quadratic equations solved for triploid proportions in mixed samples and corresponding estimation reference plots allowed for predicting triploidy. Thus, an accurate prediction of the proportion of triploids in a spawn can be made by following a standard larval processing and analysis protocol with either 20 or 50 larvae from a single spawn, coupled with applying the quadratic equations or reference plots to observed flow cytometry results. Due to the universality of triploid DNA content being 1.5 times the diploid level and because triploid fish consist of fewer cells than diploids, this method should be applicable to other produced triploid fish species, and it may be adapted for use with bivalves or other species where batch analysis is appropriate.
The effect of cold ambient temperatures on climbing‐specific finger flexor performance
Authors: Phillips Kevin , Noh Byungjoo , Gage Matthew , Yoon Tejin
Published: May 2017

Different ambient temperatures are known to affect muscular performance based on the type of contraction. The effect of cold (10°C) and thermoneutral (TN) (24°C) ambient temperatures on finger flexor performance was examined in 12 rock climbers. After 30 min of seated rest in the designated temperature condition, participants completed maximal voluntary contractions (MVC) on a climbing‐specific finger flexor assessment device equipped with a crimp grip hold. Participants then completed an intermittent fatiguing task until failure. The fatiguing task consisted of 10‐s contractions at 40% MVC followed by a 3‐s of rest. MVC recovery was assessed immediately, 5, 10, and 15 min post‐task failure. Estimated muscle temperature and subjective thermal ratings were significantly lower throughout testing in the cold condition (P < .001). Finger flexor MVC strength was similar between conditions at baseline and throughout recovery. Time to task failure was significantly longer (364 ± 135 vs. 251 ± 97 s, P = .003) and force time integral was greater (53,715 ± 19,988 vs. 40,243 ± 15,360 Ns, P = .001) during the cold condition. No significant differences were found between conditions for force variability or electromyography (EMG) at the start and end of the fatiguing task. However, the rate of increase in EMG for the TN condition was significantly faster (P = .03). These results suggest important implications for researchers when examining climbing performance, especially in outdoor settings where temperatures may vary from day to day. Inconsistencies in testing temperatures might significantly affect muscular endurance.
A social–ecological study of stock structure and fleet dynamics in the Newfoundland herring fishery
Authors: Paterson Barbara , Neis Barbara , Stephenson Robert L
Published: May 2017

Successful management of small pelagic fisheries is critical in integrated ecosystem based approaches and requires understanding of how the ecological dynamics of pelagic stocks mesh with the economic and social dynamics of commercial fisheries and the larger systems within which they operate. Combining insights from stock assessments with those from local fishers, scientists, and managers, can help identify knowledge gaps that could jeopardize stock resilience. This article presents results from a social-ecological, mixed-methods study that combines insights from science and from interviews with fishermen, scientists, and managers of small pelagic fisheries in western Newfoundland, Canada (NAFO division 4R) and in NAFO division 4X. Different approaches to herring management are used in the two areas. In area 4R fishing for herring (Clupea harengus) is part of a complex multi-species, multi-gear fishery; most harvesters who target herring also target Atlantic mackerel (Scomber scombrus). Harvester interviews indicate herring in 4R, like herring in 4X and elsewhere, have substantial within-species stock structure, but that it is not well-documented in science and not well protected under the current management system. Further, fishing strategies in the competitive mackerel fishery in which the herring vessels are involved may contribute to the risk of over-fishing on some herring populations.
X-rays from Green Pea analogues
Authors: Brorby M. , Kaaret P.
Published: May 2017

X-ray observations of two metal-deficient luminous compact galaxies (LCG; SHOC 486 and SDSS J084220.94+115000.2) with properties similar to the so-called Green Pea galaxies were obtained using the Chandra X-ray Observatory. Green Pea galaxies are relatively small, compact (a few kpc across) galaxies that get their green colour from strong [O iii] λ5007 Å emission, an indicator of intense, recent star formation. These two galaxies were predicted to have the highest observed count rates, using the X-ray luminosity–star formation rate (LX–SFR) relation for X-ray binaries, from a statistically complete sample drawn from optical criteria. We determine the X-ray luminosity relative to SFR and metallicity for these two galaxies. Neither exhibits any evidence of active galactic nuclei, and we suspect that the X-ray emission originates from unresolved populations of high-mass X-ray binaries. We discuss the LX–SFR–metallicity plane for star-forming galaxies and show that the two LCGs are consistent with the prediction of this relation. This is the first detection of Green Pea analogues in X-rays.
Subaru High-z Exploration of Low-Luminosity Quasars (SHELLQs). II. Discovery of 32 quasars and luminous galaxies at 5.7 < z ≤ 6.8
Authors: Matsuoka Yoshiki , Onoue Masafusa , Kashikawa Nobunari , Iwasawa Kazushi , Strauss Michael A , Nagao Tohru , Imanishi Masatoshi , Lee Chien-Hsiu , Akiyama Masayuki , Asami Naoko , Bosch James , Foucaud Sébastien , Furusawa Hisanori , Goto Tomotsugu , Gunn James E , Harikane Yuichi , Ikeda Hiroyuki , Izumi Takuma , Kawaguchi Toshihiro , Kikuta Satoshi , Kohno Kotaro , Komiyama Yutaka , Lupton Robert H , Minezaki Takeo , Miyazaki Satoshi , Morokuma Tomoki , Murayama Hitoshi , Niida Mana , Nishizawa Atsushi J , Oguri Masamune , Ono Yoshiaki , Ouchi Masami , Price Paul A , Sameshima Hiroaki , Schulze Andreas , Shirakata Hikari , Silverman John D , Sugiyama Naoshi , Tait Philip J , Takada Masahiro , Takata Tadafumi , Tanaka Masayuki , Tang Ji-Jia , Toba Yoshiki , Utsumi Yousuke , Wang Shiang-Yu
Published: May 2017

We present spectroscopic identification of 32 new quasars and luminous galaxies discovered at 5.7 < z ≤ 6.8. This is the second in a series of papers presenting the results of the Subaru High-z Exploration of Low-Luminosity Quasars (SHELLQs) project, which exploits the deep multi-band imaging data produced by the Hyper Suprime-Cam (HSC) Subaru Strategic Program survey. The photometric candidates were selected by a Bayesian probabilistic algorithm, and then observed with spectrographs on the Gran Telescopio Canarias and the Subaru Telescope. Combined with the sample presented in the previous paper of this series, we have now identified 64 HSC sources over about 430 deg2, which include 33 high-z quasars, 14 high-z luminous galaxies, two [O iii] emitters at z ∼ 0.8, and 15 Galactic brown dwarfs. The new quasars have considerably lower luminosity (M1450 ∼ −25 to −22 mag) than most of the previously known high-z quasars. Several of these quasars have luminous (>1043 erg s−1) and narrow (< 500 km s−1) Lyα lines, and also a possible mini broad-absorption-line system of N v λ1240 in the composite spectrum, which clearly separate them from typical quasars. On the other hand, the high-z galaxies have extremely high luminosities (M1450 ∼ −24 to −22 mag) compared to other galaxies found at similar redshifts. With the discovery of these new classes of objects, we are opening up new parameter spaces in the high-z Universe. Further survey observations and follow-up studies of the identified objects, including the construction of the quasar luminosity function at z ∼ 6, are ongoing.
The Tomato Kinase Pti1 Contributes to Production of Reactive Oxygen Species in Response to Two Flagellin-Derived Peptides and Promotes Resistance to Pseudomonas syringae Infection
Authors: Schwizer Simon , Kraus Christine M. , Dunham Diane M. , Zheng Yi , Fernandez-Pozo Noé , Pombo Marina A. , Fei Zhangjun , Chakravarthy Suma , Martin Gregory B.
Published: May 2017

The Pti1 kinase was identified from a reverse genetic screen as contributing to pattern-triggered immunity (PTI) against Pseudomonas syringae pv. tomato (Pst). The tomato genome has two Pti1 genes, referred to as Pti1a and Pti1b. A hairpin-Pti1 (hpPti1) construct was developed and was used to generate two independent stable transgenic tomato lines that had reduced transcript abundance of both genes. In response to P. syringae pv. tomato inoculation, these hpPti1 plants developed more severe disease symptoms, supported higher bacterial populations, and had reduced transcript accumulation of PTI-associated genes, as compared with wild-type plants. In response to two flagellin-derived peptides, the hpPti1 plants produced lesser amounts of reactive oxygen species (ROS) but showed no difference in mitogen-activated protein kinase (MAPK). Synthetic Pti1a and Pti1b genes designed to avoid silencing were transiently expressed in the hpPti1 plants and restored the ability of the plants to produce wild-type levels of ROS. Our results identify a new component of PTI in tomato that, because it affects ROS production but not MAPK signaling, appears to act early in the immune response.
Drought Stress Enhances Up-Regulation of Anthocyanin Biosynthesis inGrapevine leafroll-associated virus 3-Infected in vitro Grapevine (Vitis vinifera) Leaves
Authors: Cui Zhen-Hua , Bi Wen-Lu , Hao Xin-Yi , Li Peng-Min , Duan Ying , Walker M. Andrew , Xu Yan , Wang Qiao-Chun
Published: May 2017

Reddish-purple coloration on the leaf blades and downward rolling of leaf margins are typical symptoms of grapevine leafroll disease (GLD) in red-fruited grapevine cultivars. These typical symptoms are attributed to the expression of genes encoding enzymes for anthocyanins synthesis, and the accumulation of flavonoids in diseased leaves. Drought has been proven to accelerate development of GLD symptoms in virus-infected leaves of grapevine. However, it is not known how drought affects GLD expression nor how anthocyanin biosynthesis in virus-infected leaves is altered. The present study used HPLC to determine the types and levels of anthocyanins, and applied reverse transcription quantitative polymerase chain reaction (RT-qPCR) to analyze the expression of genes encoding enzymes for anthocyanin synthesis. Plantlets of Grapevine leafroll-associated virus 3 (GLRaV-3)-infected Vitis vinifera ‘Cabernet Sauvignon’ were grown in vitro under PEG-induced drought stress. HPLC found no anthocyanin-related peaks in the healthy plantlets with or without PEG-induced stress, while 11 peaks were detected in the infected plantlets with or without PEG-induced drought stress, but the peaks were significantly higher in infected drought-stressed plantlets. Increased accumulation of total anthocyanin compounds was related to the development of GLD symptoms in the infected plantlets under PEG stress. The highest level of up-regulated gene expression was found in GLRaV-3-infected leaves with PEG-induced drought stress. Analyses of variance and correlation of anthocyanin accumulation with related gene expression levels found that GLRaV-3-infection was the key factor in increased anthocyanin accumulation. This accumulation involved the up-regulation of two key genes, MYBA1 and UFGT, and their expression levels were further enhanced by drought stress.
Alternative treatments for chronic spontaneous urticaria beyond the guideline algorithm
Authors: Vena Gino A. , Maurer Marcus , Cassano Nicoletta , Zuberbier Torsten
Published: May 2017

Purpose of review

The international EAACI/GA2LEN/EDF/WAO guideline suggests a stepwise approach for the therapeutic management of chronic spontaneous urticaria (CSU), outlined in an algorithm. The aim of this article is to summarize and review the evidence available on alternative treatment options for CSU outside of this algorithm.

Recent findings

Although CSU is a common disease, there are a limited number of high-quality studies, and only antihistamines and omalizumab are licensed for its treatment. Most studies regarding alternative therapies for CSU show methodological limitations and a high risk of bias. For many therapies, only case reports and uncontrolled studies exist. Recent publications on alternative treatments for chronic urticaria/CSU include reports on the use of adalimumab, rituximab, vitamin D, probiotics, histaglobulin, injection of autologous whole blood or serum, and phototherapy.

Numerous treatments beyond the guideline algorithm have been evaluated in patients with refractory CSU. The global level of evidence to support their efficacy in CSU is low or very low. Further research is needed to assess the efficacy and safety of alternative therapies of CSU to manage adequately those patients who do not respond to the treatments included in the algorithm.
Antiphospholipid syndrome: an update for clinicians and scientists
Authors: Vreede Andrew P. , Bockenstedt Paula L. , Knight Jason S.
Published: May 2017

Purpose of review

Antiphospholipid syndrome (APS) is a leading acquired cause of thrombosis and pregnancy loss. Upon diagnosis (which is unlikely to be made until at least one morbid event has occurred), anticoagulant medications are typically prescribed in an attempt to prevent future events. This approach is not uniformly effective and does not prevent associated autoimmune and inflammatory complications. The goal of this review is to update clinicians and scientists on mechanistic and clinically relevant studies from the past 18 months, which have especially focused on inflammatory aspects of APS pathophysiology.

Recent findings

How antiphospholipid antibodies leverage receptors and signaling pathways to activate cells is being increasingly defined. Although established mediators of disease pathogenesis (like endothelial cells and the complement system) continue to receive intensive study, emerging concepts (such as the role of neutrophils) are also receiving increasing attention. In-vivo animal studies and small clinical trials are demonstrating how repurposed medications (hydroxychloroquine, statins, and rivaroxaban) may have clinical benefit in APS, with these concepts importantly supported by mechanistic data.

As anticoagulant medications are not uniformly effective and do not comprehensively target the underlying pathophysiology of APS, there is a continued need to reveal the inflammatory aspects of APS, which may be modulated by novel and repurposed therapies.
The Need for Multidimensional Stratification of Chronic Low Back Pain (LBP)
Authors: Rampersaud Yoga Raja , Bidos Andrew , Fanti Caroline , Perruccio Anthony V.
Published: May 2017

Study Design.

A cross-sectional study of Canadian patients suffering from low back pain (LBP) seeking primary care.

Objective.

The aim of this study was to determine which existing primary care LBP stratification schema is associated with distinct subpopulations as characterized by easily identifiable primary epidemiological factors.

Summary of Background Data.

LBP is among the most frequent reasons for visits to primary care physicians and a leading cause of years lived with disability. In an effort to improve treatment response/outcomes in LBP primary care, different classification systems have been proposed in an effort to provide more tailored treatment with the intent of improving outcomes. Group-specific risk factors and underlying etiology might suggest a need for, or inform, changes to treatment approaches to optimize LBP outcomes.

Methods.

Stratification by dominant mechanical pain patterns; chronicity risk; disability severity. Multinomial logistic regression was used to identify the system showing greatest variability in associations with age, sex, obesity, and comorbidity. Once identified, the remaining schemas were incorporated into the model.

Results.

N = 970; mean age: 50 years (range: 18–93); 56% female. Stratification by pain pattern revealed greater variability. Adjusted analysis: Increasing age was associated with greater odds of intermittent, extension-based back- or leg-dominant pain [odds ratio (OR): 1.02 and 1.06; P < 0.01]; being male with leg-dominant pain (ORs > 2; P < 0.01). Overweight/obesity was associated with extension-based leg-dominant pain (OR = 2.6; P < 0.02) and increasing comorbidity with extension-based back-dominant pain (OR = 1.3; P < 0.01). Severe disability was associated only with constant leg pain (OR = 3.9; P < 0.01), and high chronicity risk with extension-based leg-dominant pain (OR = 0.4; P = 0.03).

Conclusion.

Dominant mechanical symptom stratification resulted in further discrimination of an epidemiologically distinct and a large subgroup of LBP patients not identified by disability or chronicity risk stratification alone. Findings suggest a need for primary care initiated multidimensional stratification in chronic LBP.

Level of Evidence: 3
Differential Regulation of the Autophagy and Proteasome Pathways in Skeletal Muscles in Sepsis
Authors: Stana Flavia , Vujovic Marija , Mayaki Dominique , Leduc-Gaudet Jean-Philippe , Leblanc Philippe , Huck Laurent , Hussain Sabah N. A.
Published: May 2017

Objectives:

Skeletal muscle fiber atrophy develops in response to severe sepsis, but it is unclear as to how the proteolytic pathways that are involved in its development are differentially regulated. We investigated the link between sepsis-induced fiber atrophy and activation of the proteasome and autophagy pathways and whether the degree of activation is more severe and sustained in limb muscles than it is in the diaphragm.

Design:

Randomized controlled experiment.

Setting:

Animal research laboratory.

Subjects:

Adult male C57/BL6 mice.

Interventions:

Two groups of animals were studied. The sepsis group was subjected to a cecal ligation and perforation technique, whereas the control (sham) group was subjected to abdominal surgery without cecal ligation and perforation. Measurements for both groups were performed 24, 48, and 96 hours after the surgical procedure.

Measurements and Main Results:

Atrophy was quantified in the diaphragm and tibialis anterior by measuring fiber diameter. Autophagy was evaluated using electron microscopic detection of autophagosomes and by measuring LC3B protein lipidation and autophagy-related protein expressions. Proteasomal degradation was quantified by measuring chymotrypsin-like activity of the 26S proteasome and messenger RNA expressions of muscle-specific E3 ligases. Sepsis triggered transient fiber atrophy in the diaphragm that lasted for 24 hours and prolonged atrophy in the tibialis anterior that persisted for 96 hours. The autophagy and proteasome pathways were activated in both muscles at varying intensities over the time course of sepsis. Activation was more pronounced in the tibialis anterior than in the diaphragm. Sepsis inhibited the V-Akt thymoma viral oncogene homolog 1 and complex 1 of the mammalian target of rapamycin pathways and stimulated the AMP-activated protein kinase pathway in both muscles.

Conclusions:

Sepsis triggers more severe and sustained muscle fiber atrophy in limb muscles when compared with respiratory muscle. This response is associated with enhanced proteasomal and autophagic proteolytic pathway activities and is triggered by inhibition of the AKT and complex 1 of the mammalian target of rapamycin pathways and activation of the AMPK pathway.
Impact of Moderate Hyperchloremia on Clinical Outcomes in Intracerebral Hemorrhage Patients Treated With Continuous Infusion Hypertonic Saline: A Pilot Study
Authors: Riha Heidi M. , Erdman Michael J. , Vandigo Joseph E. , Kimmons Lauren A. , Goyal Nitin , Davidson K. Erin , Pandhi Abhi , Jones G. Morgan
Published: May 2017

Objectives:

Hyperchloremia has been associated with increased morbidity and mortality in critically ill patients. While previous research has demonstrated an association between hypertonic saline and hyperchloremia, limited data exist in neurocritical care patients. The objective of this study is to determine the impact of moderate hyperchloremia (chloride ≥ 115 mmol/L) on clinical outcomes in intracerebral hemorrhage patients treated with continuous IV infusion 3% hypertonic saline.

Design:

Multicenter, retrospective, propensity-matched cohort study.

Setting:

Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and comprehensive stroke center designation.

Patients:

Intracerebral hemorrhage patients discharged between September 2011 and September 2015 were evaluated and matched 1:1 based on propensity scoring.

Interventions:

Continuous IV infusion 3% hypertonic saline.

Measurements and Main Results:

A total of 219 patients were included in the unmatched cohort (143 moderate hyperchloremia and 76 nonhyperchloremia) and 100 patients in the propensity-matched cohort. In-hospital mortality was significantly higher in those who developed moderate hyperchloremia in a propensity-matched cohort (34% vs 14%; p = 0.02). Moderate hyperchloremia independently predicted in-hospital mortality in multivariable logistic regression analysis (odds ratio, 4.4 [95% CI, 1.4–13.5]; p = 0.01).

Conclusions:

We observed higher rates of in-hospital mortality in patients who developed moderate hyperchloremia during treatment with continuous IV infusion 3% hypertonic saline, with moderate hyperchloremia independently predicting in-hospital mortality. These results suggest that chloride values should be monitored closely during hypertonic saline treatment as moderate elevations may impact outcomes in intracerebral hemorrhage patients.
Making sense of effective partnerships among senior leaders in the National Health Service
Authors: Mitra Mahima , Hoff Timothy , Brankin Paul , Dopson Sue
Published: May 2017

Background:

Changing health care systems depend on strong organizational leadership that realizes the collaborative potential of both physician and nonphysician leaders.

Purpose:

The aim of this study was to seek insight into the everyday health care leader experience by examining 24 physician and nonphysician leaders working in the U.K. National Health Service. We explored (a) how they make sense of and act with respect to specific collaborative tensions in their interactions and (b) which aspects of their everyday leadership contexts heighten the probability for producing and resolving such tensions.

Methodology:

We conducted 24 in-depth interviews with physician and nonphysician leaders in job titles including Chief Operating Officer, Managing Director, Medical Director, and Clinical Director. Ideas from the social psychological perspectives of sensemaking, organizational role theory, and organizational citizenship behavior helped frame the study.

Results:

We identified four areas of ongoing tension between senior leaders. Each of these was linked to a set of underlying drivers, with the strongest support for drivers with interpersonal roots. Effective strategies for resolving tensions involved significant effort by leaders at improving the interpersonal dynamics associated with everyday interaction and forging relational connections through enhanced trust within the leadership team.

Conclusion:

This study outlines the organizational and individual characteristics that lend to effective collaboration among senior health care leadership and the types of collaborative tensions likely to be experienced by senior health care leaders.

Practice Implications:

Organizations should provide greater role clarity for senior leadership roles, promote “soft” interpersonal competencies within them, and better assess potential leaders for success in senior roles. Organizational support in the form of facilitation, time, and spaces to learn together can provide a better context for collaborative decision-making.
MORPHOFUNCTIONAL EVALUATION IN DOME-SHAPED MACULA
Authors: Pilotto Elisabetta , Guidolin Francesca , Parravano Mariacristina , Viola Francesco , De Geronimo Daniele , Convento Enrica , dell'Arti Laura , Tabacchi Elena , Parrozzani Raffaele , Cavarzeran Fabiano , Midena Edoardo
Published: May 2017

Purpose:

To investigate retinal sensitivity (Se) in dome-shaped macula (DSM) using microperimetry and to correlate functional findings to specific spectral domain optical coherence tomography features.

Methods:

Patients affected by DSM in at least 1 eye were consecutively enrolled in a prospective, cross-sectional study. All studied eyes performed best-corrected visual acuity measurement, microperimetry to assess Se and optical coherence tomography to investigate DSM pattern and to measure bulge height and retinal and choroidal thicknesses.

Results:

Fifty-three eyes of 29 patients were studied. Dome-shaped macula was vertically oriented (V-DSM) in 23 (43.4%), symmetric (S-DSM) in 17 (32.1%), and horizontally oriented (H-DSM) in 13 eyes (24.5%). Foveal subretinal fluid was present in 29/53 (54.7%) cases; it correlated to the bulge height (P < 0.0001) and determined a reduction of Se (P < 0.0001) not of best-corrected visual acuity (P = 0.7105). Mean Se was 13.9 ± 3.2 dB. Microperimetry parameters did not differ among the different DSM patterns. However, Se was significantly impaired if foveal subretinal fluid was present in V-DSM and in S-DSM, but not in H-DSM (V-DSM: P < 0.0001; S-DSM: P = 0.0252; H-DSM: P = 0.5723). In H-DSM, inferior choroidal thickness was thicker in cases with foveal subretinal fluid compared with those without it (P = 0.0363).

Conclusion:

In DSM, Se evaluation better reflects the central functional impairment than best-corrected visual acuity, particularly when some optical coherence tomography features, such as foveal subretinal fluid and higher bulge height, are present.
POLYPOIDAL CHOROIDAL VASCULOPATHY UPON OPTICAL COHERENCE TOMOGRAPHIC ANGIOGRAPHY
Authors: Chan Szy Yann , Wang Qian , Wang Ya Xing , Shi Xue Hui , Jonas Jost B. , Wei Wen Bin
Published: May 2017

Purpose:

To study polypoidal lesions and branching choroidal vascular networks in eyes with polypoidal choroidal vasculopathy by optical coherence tomography (OCT)–based angiography (OCTA).

Methods:

In the observational cross-sectional study, patients with polypoidal choroidal vasculopathy, as diagnosed by indocyanine green angiography, underwent OCTA.

Results:

Thirty-two eyes of 31 patients with an age of 61.1 ± 7.6 years were included. Branching choroidal vascular networks were detected by indocyanine green angiography and OCTA in 25 of 32 (78 ± 73%) and in 30 of 32 (94 ± 4%) eyes, respectively, with a marginally significant difference (P = 0.06) in the detection rate between both techniques. A total of 72 polyps (area, 0.06 ± 0.06 mm2; range, 0.01–0.27 mm2) were detected by indocyanine green angiography, and they were consistently present on the OCTA images. By moving the reference level in the OCT angiograms to the corresponding layer, the polypoidal lesions showed cluster-like structures in 53 of 72 polypoidal lesions (74%). In 60 of the 72 polypoidal lesions (83%), cluster-like structures were detected in the en face structural OCT images at the reference plane of the OCTA images. On the cross-sectional OCT images, some internal channels of flow were seen in 50 of the 72 polypoidal lesions (69%). Larger size of the polypoidal lesions was associated with a higher prevalence of cluster-like structures on the OCTA images, some internal channels of flow on the en face structural images, and clustered vascular structures on the cross-sectional OCT images.

Conclusion:

In conclusion, OCTA is a useful technique for the noninvasive detection of branching choroidal vascular networks including visualization of details such as cluster-like structures and flow. In some eyes, OCTA was superior to indocyanine green angiography to detect polypoidal choroidal vasculopathy and to show branching choroidal vascular networks.