bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms governing inflammasome activation, assembly and pyroptosis induction
Authors: Kesavardhana Sannula , Kanneganti Thirumala-Devi 
Published: May 2017

Abstract
Inflammasomes are multimeric protein complexes that regulate inflammatory responses and pyroptotic cell death to exert host defense against microbes. Intracellular pattern-recognition receptors such as nucleotide-binding domain and leucine-rich repeat receptors (NLRs) and absent in melanoma 2 like receptors (ALRs) assemble the inflammasome complexes in response to pathogens and danger or altered-self signals in the cell. Inflammasome sensors, in association with an adaptor protein—apoptosis-associated speck-like protein containing a caspase-activation and -recruitment domain (ASC)—activate inflammatory caspase-1 to enable the release of inflammatory cytokines and induce cell death, conferring host defense against pathogens. Beyond infectious diseases, the importance of inflammasomes is implicated in a variety of clinical conditions such as auto-inflammatory diseases, neuro-degeneration and metabolic disorders and the development of cancers. Understanding inflammasome activation and its molecular regulation can unveil therapeutic targets for controlling inflammasome-mediated disorders. In this review, we describe recent advances in inflammasome biology and discuss its activation, structural insights into inflammasome assembly and mechanisms for the execution of pyroptosis.
Outcomes of Elective Cerebral Aneurysm Treatment Performed by Attending Neurosurgeons after Night Work
Authors: Bekelis Kimon , Missios Symeon , MacKenzie Todd A 
Published: May 2017

Abstract

BACKGROUND
The association between long work hours and outcomes among attending surgeons remains an issue of debate.

OBJECTIVE
To investigate whether operating emergently the night before an elective case was associated with inferior outcomes among attending neurosurgeons.

METHODS
We executed a cohort study with unruptured cerebral aneurysm patients, who underwent endovascular coiling or surgical clipping from 2009 to 2013 and were registered in the Statewide Planning and Research Cooperative System database. We investigated the association of treatment by surgeons performing emergency procedures the night before with outcomes of elective cerebral aneurysm treatment using an instrumental variable analysis.

RESULTS
Overall, 4700 patients underwent treatment for unruptured cerebral aneurysms. There was no difference in inpatient mortality (adjusted difference, –0.7%; 95% confidence interval [CI], –1.4% to 0.02%), discharge to a facility (adjusted difference, –0.1%; 95% CI, –1.2% to 1.2%), or length of stay (adjusted difference, –0.58; 95% CI, –1.66 to 0.50) between patients undergoing elective cerebral aneurysm treatment by surgeons who performed emergency procedures the night before, and those who did not.

CONCLUSION
Using a comprehensive patient cohort in New York State for elective treatment of unruptured cerebral aneurysms, we did not identify an association of treatment by surgeons performing emergency procedures the night before, with mortality, discharge to a facility, or length of stay. Our study had 80% power to detect differences in mortality (our primary outcome), as small as 4.1%. The results of the present study do not support the argument for regulation of attending work hours.
Over-expression of the RieskeFeS protein increases electron transport rates and yield inArabidopsis
Authors: Simkin Andrew J. , McAusland Lorna , Lawson Tracy , Raines Christine A. 
Published: May 2017

AbstractIn this study we have generated transgenic Arabidopsis plants over-expressing the Rieske FeS protein (PetC), a component of the cytochromeb6f(cytb6f) complex. Increasing the levels of this protein, resulted in the concomitant increase in the levels of cytf(PetA) and cytb6(PetB), core proteins of the cytb6fcomplex. Interestingly, an increase in the levels of proteins in both the PSI and PSII complexes was also seen in the Rieske FeS ox plants. Although the mechanisms leading to these changes remain to be identified, the transgenic plants presented here provide novel tools to explore this. Importantly, the overexpression of the Rieske FeS protein resulted in a substantial and significant impact on the quantum efficiency of PSI and PSII, electron transport, biomass and seed yield in Arabidopsis plants. These results demonstrate the potential for manipulating electron transport processes to increase crop productivity.One-sentence summaryOver-expression of the Rieske FeS protein results in significant increases in the quantum efficiencies or PSI and PSII, increases in Amaxand has the potential to increase crop productivity
Activation of Piezo1 but not NaV1.2 Channels by Ultrasound at 43 MHz
Authors: Prieto Martin Loynaz , Firouzi Kamyar , Khuri-Yakub Butrus T. , Maduke Merritt 
Published: May 2017

ABSTRACTUltrasound (US) can modulate the electrical activity of the excitable tissues but the mechanisms underlying this effect are not understood at the molecular level or in terms of the physical modality through which US exerts its effects. Here we report an experimental system that allows for stable patch-clamp recording in the presence of US at 43 MHz, a frequency known to stimulate neural activity. We describe the effects of US on two ion channels proposed to be involved in the response of excitable cells to US: the mechanosensitive Piezo1 channel and the voltage-gated sodium channel NaV1.2. Our patch-clamp recordings, together with finite-element simulations of acoustic field parameters indicate that Piezo1 channels are activated by continuous wave US at 43 MHz and 50 or 90 W/cm2through cell membrane stress caused by acoustic streaming. NaV1.2 channels were not affected through this mechanism at these intensities, but their kinetics could be accelerated by US-induced heating.
CytoCensus: mapping cell identity and division in tissues and organs using machine learning
Authors: Hailstone Martin , Waithe Dominic , Samuels Tamsin J , Yang Lu , Costello Ita , Arava Yoav , Robertson Elizabeth J , Parton Richard M , Davis Ilan 
Published: May 2017

AbstractA major challenge in cell and developmental biology is the automated identification and quantitation of cells in complex multilayered tissues. We developed CytoCensus: an easily deployed implementation of supervised machine learning that extends convenient 2D “point- and-click” user training to 3D detection of cells in challenging datasets with ill-defined cell boundaries. In tests on these datasets, CytoCensus outperforms other freely available image analysis software in accuracy and speed of cell detection. We used CytoCensus to count stem cells and their progeny, and to quantify individual cell divisions from time-lapse movies of explantedDrosophilalarval brains, comparing wild-type and mutant phenotypes. We further illustrate the general utility and future potential of CytoCensus by analysing the 3D organisation of multiple cell classes in Zebrafish retinal organoids and cell distributions in mouse embryos. CytoCensus opens the possibility of straightforward and robust automated analysis of developmental phenotypes in complex tissues.SummaryHailstoneet al. develop CytoCensus, a “point-and-click” supervised machine-learning image analysis software to quantitatively identify defined cell classes and divisions from large multidimensional data sets of complex tissues. They demonstrate its utility in analysing challenging developmental phenotypes in living explantedDrosophilalarval brains, mammalian embryos and zebrafish organoids. They further show, in comparative tests, a significant improvement in performance over existing easy-to-use image analysis software.HighlightsCytoCensus: machine learning quantitation of cell types in complex 3D tissuesSingle cell analysis of division rates from movies of livingDrosophilabrains in 3DDiverse applications in the analysis of developing vertebrate tissues and organoidsOutperforms other image analysis software on challenging, low SNR datasets tested
Conformational dynamics in TRPV1 channels reported by an encoded coumarin amino acid
Authors: Steinberg Ximena , Kasimova Marina A. , Cabezas-Bratesco Deny , Galpin Jason , Ladrón-de-Guevara Ernesto , Villa Federica , Carnevale Vincenzo , Islas Leon D. , Ahern Christopher A. , Brauchi Sebastian E. 
Published: May 2017

ABSTRACTTransient Receptor Potential Vanilloid (TRPV1) channels support the detection and integration of nociceptive input. Currently available functional and structural data suggest that that TRPV1 channels have two potential gates within their cation selective permeation pathway: a barrier formed by a ‘bundle crossing’ at the intracellular entrance and a second constriction created by the ion selectivity filter. To describe conformational changes associated with channel gating within the pore, the fluorescent non-canonical amino acid (f- ncAA) coumarin-tyrosine was genetically encoded at Y671, a residue proximal to the selectivity filter. TRPV1 channels expressing coumarin at either site displayed normal voltage- and agonist-dependent gating. Next, total internal reflection microscopy (TIRF) was performed to enable ultra-rapid, millisecond imaging of the conformational dynamics in single TRPV1 channels in live cells. Here, the data obtained from channels expressed in human derived cells show that optical fluctuations, photon counts, and variance of noise analysis from Y671 coumarin encoded in TRPV1 tetramers correlates closely with channel activation by capsaicin, thus providing an direct optical marker of channel activation at the selectivity filter. In companion molecular dynamics simulations, Y671 displays alternating solvent exposure between the closed and open states, giving support to the optical data. These calculations further suggest a direct involvement of Y671 in controlling the relative position of the pore helix and its role in supporting ionic conductance at the TRPV1 selectivity filter.
An oomycete effector protein induces shade avoidance inArabidopsisand attenuates salicylate signaling by binding to host proteins of the RADICAL-INDUCED CELL DEATH1 family
Authors: Wirthmueller Lennart , Asai Shuta , Rallapalli Ghanasyam , Sklenar Jan , Fabro Georgina , Kim Dae Sung , Lintermann Ruth , Jaspers Pinja , Wrzaczek Michael , Kangasjärvi Jaakko , MacLean Daniel , Menke Frank L. H. , Banfield Mark J. , Jones Jonathan D. G. 
Published: May 2017

AbstractThe oomycete pathogenHyaloperonospora arabidopsidis(Hpa) causes downy mildew disease onArabidopsis. During infection,Hpalike other biotrophic pathogens, suppresses activation of plant innate immunity by translocating effector proteins into host cells. Some of these effectors localize to the host cell nucleus where they may manipulate transcriptional reprogramming of plant defense genes. Here we report that the nuclear-localizedHpaeffector HaRxL106, when expressed inArabidopsis, induces shade avoidance and attenuates the transcriptional response to the defense signaling molecule salicylic acid. HaRxL106 interacts with RADICAL-INDUCED CELL DEATH1 (RCD1) and loss of RCD1 function rendersArabidopsisresilient against HaRxL106-mediated suppression of immunity. To further characterize the molecular functions of RCD1 we solved a crystal structure of RCD1’s Poly-(ADP-ribose)-Polymerase (PARP) domain and, based on non-conservation of amino acids constituting the active site of canonical PARPs, conclude that RCD1 has no PARP activity. We report that RCD1-type proteins are phosphorylated and identified histone-modifying Mut9-like kinases (MLKs) as RCD1-interacting proteins. Amlk1,3,4triple mutant exhibits stronger SA-induced defense marker gene expression compared to wild-type plants. Our data suggest that HaRxL106 suppressesArabidopsisinnate immunity by manipulating the function(s) of RCD1 in the host cell nucleus and point towards a role of RCD1 as a transcriptional co-regulator that integrates signals from light and pathogen sensors.
The algorithmic neuroanatomy of action-outcome learning
Authors: Morris Richard W. , Dezfouli Amir , Griffiths Kristi R , Le Pelley Mike E , Balleine Bernard W 
Published: May 2017

AbstractAlthough it is well known that animals can encode the consequences of their actions and can use this information to control action selection and evaluation, it is not known what learning rules control action-outcome (AO) learning. Here we trained participants to encode specific AO associations whilst undergoing functional imaging (fMRI) and used computational modelling to evaluate competing models. This analysis revealed that a Kalman filter, which learned the unique causal effect of each action, best characterized AO learning and found the medial prefrontal cortex differentiated the unique effect of actions from background effects. We subsequently extended these findings to show that mPFC participated in a circuit with parietal cortex and caudate nucleus to segregate distinct contributions to AO learning. The results extend our understanding of goal-directed learning and demonstrate that sensitivity to the causal relationship between actions and outcomes guides goal-directed learning rather than contiguous state-action relations.
Rational Design of RNA Structures that Predictably Tune Eukaryotic Gene Expression
Authors: Weenink Tim , McKiernan Robert M. , Ellis Tom 
Published: May 2017

AbstractPredictable tuning of gene expression is essential for engineering genetic circuits and for optimising enzyme levels in metabolic engineering projects. In bacteria, gene expression can be tuned at the stage of transcription, by exchanging the promoter, or at stage of translation by altering the ribosome binding site sequence. In eukaryotes, however, only promoter exchange is regularly used, as the tools to modulate translation are lacking. Working inS. cerevisiaeyeast, we here describe how hairpin RNA structures inserted into the 5’ untranslated region (5’UTR) of mRNAs can be used to tune expression levels by altering the efficiency of translation initiation. We demonstrate a direct link between the calculated free energy of folding in the 5’UTR and protein abundance, and show that this enables rational design of hairpin libraries that give predicted expression outputs. Our approach is modular, working with different promoters and protein coding sequences, and it outperforms promoter mutation as a way to predictably generate a library where a protein is induced to express at a range of different levels. With this tool, computational RNA sequence design can be used to predictably fine-tune protein production, providing a new way to modulate gene expression in eukaryotes.
The dynamic core microbiome: Structure, dynamics and stability
Authors: Björk Johannes R. , O’Hara Robert B. , Ribes Marta , Coma Rafel , Montoya José M. 
Published: May 2017

AbstractThe long-term stability of microbiomes is crucial as the persistent occurrence of beneficial microbes and their associated functions ensure host health and well-being. Microbiomes are highly diverse and dynamic, making them challenging to understand. Because many natural systems work as temporal networks, we present an approach that allows identifying meaningful ecological patterns within complex microbiomes: the dynamic core microbiome. On the basis of six marine sponge species sampled monthly over three years, we study the structure, dynamics and stability of their microbiomes. What emerge for each microbiome is a negative relationship between temporal variability and mean abundance. The notion of the dynamic core microbiome allowed us to determine a relevant functional attribute of the microbiome: temporal stability is not determined by the diversity of a host’s microbial assemblages, but rather by the density of those microbes that conform its core microbiome. The core microbial interaction network consisted of complementary members interacting weakly with dominance of comensal and amensal interactions that suggests self-regulation as a key determinant of the temporal stability of the microbiome. These interactions have likely coevolved to maintain host functionality and fitness over ecological, and even evolutionary time scales.
Expression of Pokeweed Antiviral Protein Isoform S1 (PAP-S1) and of Ricin-A-Chain/PAP-S1 novel fusion protein (RTA/PAP-S1) inEscherichia coliand their comparative inhibition of protein synthesisin vitro
Authors: Hassan Yasser , Ogg Sherry 
Published: May 2017

AbstractFusion protein therapeutics engineering is advancing to meet the need for novel medicine. Herein, we further characterize the development of novel RTA & PAP-S1 antiviral fusion proteins. In brief, RTA/PAP-S1 and PAP-S1/RTA fusion proteins were produced in both cell free andE. coli in vivoexpression systems, purified by His-tag affinity chromatography, and protein synthesis inhibitory activity assayed by comparison to the production of a control protein, CalmL3. Results showed that the RTA/PAP-S1 fusion protein is amenable to standardized production and purification and has both increased potency and less toxicity compared to either RTA or PAP-S1 alone. Thus, this research highlights the developmental potential of novel fusion proteins with reduced cytotoxic risk and increased potency.
Aminoglycoside antibiotics perturb physiologically important microRNA contributing to drug toxicity
Authors: Jayaraj Gopal Gunanathan , Ramasamy Soundhar , Bose Debojit , Suryawanshi Hemant , Lalwani Mukesh , Sivasubbu Sridhar , Maiti Souvik 
Published: May 2017

ABSTRACTmiRNAs are key non-protein coding regulators of gene expression in various pathophysiological conditions. Targeting miRNA with small molecules offer an unconventional approach, where clinically active compounds with RNA binding activity can be tested for their ability to modulate miRNA levels and thus for drug repositioning. Aminoglycoside antibiotics are highly effective microbicidal RNA binding molecules that bind to prokaryotic rRNA secondary structures. Here, we report that specific subsets of miRNA can be modulated by aminoglycosides. However, ototoxicity (cochlear and vestibular) and nephrotoxicity of multiple origins resulting from prolonged use are a well-known disadvantage of aminoglycosides. Mature non-coding RNAs and their precursors can present off-target sites, by forming secondary structures that resemble ribosomal RNA, thus providing an additional molecular basis for the toxicity of aminoglycosides. Using in vitro, in cellulae and physiological responses, we provide evidence for the direct functional perturbation of the miR- 96 cluster leading to selective cell death in neuromasts- the zebrafish equivalent of cochlear hair cells, by Streptomycin, a prototype aminoglycoside antibiotic, thus contributing to the observed ototoxicity. Our observations, collectively underscore the importance of re- evaluating RNA binding drugs for their off-targeting effects in the context of miRNA and other functional non-coding RNA.
In depth analysis of kinase cross screening data to identify chemical starting points for inhibition of the nek family of kinases
Authors: Wells Carrow I. , Kapadia Nirav R. , Couñago Rafael M. , Drewry David H. 
Published: May 2017

AbstractPotent, selective, and cell active small molecule kinase inhibitors are useful tools to help unravel the complexities of kinase signaling. As the biological functions of individual kinases become better understood, they can become targets of drug discovery efforts. The small molecules used to shed light on function can also then serve as chemical starting points in these drug discovery efforts. The Nek family of kinases has received very little attention, as judged by number of citations in PubMed, yet they appear to play many key roles and have been implicated in disease. Here we present our work to identify high quality chemical starting points that have emerged due to the increased incidence of broad kinome screening. We anticipate that this analysis will allow the community to progress towards the generation of chemical probes and eventually drugs that target members of the Nek family.
Dendritic sodium spikes endow neurons with inverse firing rate response to correlated synaptic activity
Authors: Górski Tomasz , Veltz Romain , Galtier Mathieu , Fragnaud Hélissande , Goldman Jennifer S. , Teleńczuk Bartosz , Destexhe Alain 
Published: May 2017

AbstractMany neurons possess dendrites enriched with sodium channels and are capable of generating action potentials. However, the role of dendritic sodium spikes remain unclear. Here, we study computational models of neurons to investigate the functional effects of dendritic spikes. In agreement with previous studies, we found that point neurons or neurons with passive dendrites increase their somatic firing rate in response to the correlation of synaptic bombardment for a wide range of input conditions, i.e. input firing rates, synaptic conductances or refractory periods. However, neurons with active dendrites show the opposite behavior: for a wide range of conditions the firing rate decreases as a function of correlation. We found this property in three types of models of dendritic excitability: a Hodgkin-Huxley model of dendritic spikes, a model with integrate-and-fire dendrites, and a discrete-state dendritic model. We conclude that neurons equipped with with fast dendritic spikes confer much broader computational properties to neurons, sometimes opposite to that of point neurons.
Managerial perceptions of energy in logistics
Authors: Busse Christian , Regelmann Alexander , Chithambaram Hariganesh , Wagner Stephan M. 
Published: May 2017

PurposeBecause of the major contribution of logistics to the greenhouse gas effect, logistics research has begun to address the topic of energy, but it has not yet targeted the role of energy within logistical decision-making processes. To facilitate such endeavors, the purpose of this paper is to explore the perceptions of energy which managers in logistics organizations portray.Design/methodology/approachThis investigation is based on interviews with 17 managers. The findings are embedded in the theory of planned behavior (TPB) and stakeholder theory (SHT).FindingsThe study depicts initial insights on which energy-related perceptions exist, how they can be categorized into attitudes, subjective norms, and perceived behavioral controls (PBCs), and how different stakeholders seem to affect them.Research limitations/implicationsThis research suggests a tentative comprehensive conceptual framework that describes the role of energy in logistical decision-making processes. The findings on attitudes and subjective norms appear to be unspecific to the logistics domain, whereas some of the PBCs are presumably unique to the logistics context. Future logistics research should hence focus its efforts on the PBCs. Generalizability and completeness of the managerial perceptions must be validated by future research.Practical implicationsThe findings help logistics organizations in scrutinizing managerial perspectives on energy and in developing awareness-raising measures.Originality/valueThe behavioral perspective applied in this study can complement extant, more technically oriented views. The conceptual framework that integrates the TPB and SHT may also be useful for organizational research beyond the logistics domain.