bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis
Authors: Thonhoff Jason R. , Simpson Ericka P. , Appel Stanley H. 
Published: July 2018

Purpose of review
Neuroinflammation is increasingly recognized as an important mediator of disease progression in patients with amyotrophic lateral sclerosis (ALS), and is characterized by reactive central nervous system (CNS) microglia and astroglia as well as infiltrating peripheral monocytes and lymphocytes. Anti-inflammatory and neuroprotective factors sustain the early phase of the disease whereas inflammation becomes proinflammatory and neurotoxic as disease progression accelerates. Initially, motor neurons sustain injuries through multiple mechanisms resulting from harmful mutations causing disruptions of critical intracellular pathways. Injured motor neurons release distress signal(s), which induce inflammatory processes produced by surrounding glial cells in the CNS as well as peripheral innate and adaptive immune cells. This review will focus on mechanisms of neuroinflammation and their essential contributions in ALS pathogenesis.

Recent findings
Regulatory T lymphocytes (Tregs) are a subpopulation of immunosuppressive T lymphocytes that become reduced and dysfunctional as the disease progresses in ALS patients. Their degree of dysfunction correlates with the extent and rapidity of the disease. Treg numbers are boosted in transgenic mutant SOD1 (mSOD1) mice through the passive transfer of Tregs or through treatment with an interleukin-2/ interleukin-2 monoclonal antibody complex and rapamycin. Treating the transgenic mice with either of these modalities delays disease progression and prolongs survival. In addition, Treg function is restored when dysfunctional Tregs are isolated from ALS patients and expanded ex vivo in the presence of interleukin-2 and rapamycin. Based on these findings, a first-in-human phase 1 trial has been completed in which expanded autologous Tregs were infused back into ALS patients as a potential treatment. The infusions were safe and shown to ‘hit target’ by enhancing both Treg numbers and suppressive functions.

Summary
A delicate balance between anti-inflammatory and proinflammatory factors modulates the rates of disease progression and survival times in ALS. Tipping the balance toward the anti-inflammatory mediators shows promise in slowing the progression of this devastating disease.
Is it actionable? An Evaluation of the Rapid PCR-Based Blood Culture Identification Panel on the Management of Gram-Positive and Gram-Negative Blood Stream Infections
Authors: Tseng Andrew S. , Kasule Sabirah N. , Rice Felicia , Mi Lanyu , Chan Lynn , Seville Maria T. , Grys Thomas E. 
Published: July 2018

ABSTRACTBackgroundThere is growing interest in the use of rapid blood culture identification (BCID) panels in antimicrobial stewardship programs (ASP). While many studies have looked at its clinical and economic utility, its comparative utility in gram-positive and gram-negative blood stream infections (BSI) have not been as well characterized.MethodsThe study was a quasi-experimental retrospective study at the Mayo Clinic in Phoenix, Arizona. All adult patients with positive blood cultures before BCID implementation (June 2015 to December 2015) and after BCID implementation (June 2016 to December 2016) were included. The outcomes of interest included: time to first appropriate antibiotic escalation, time to first appropriate antibiotic de-escalation, time to organism identification, LOS, infectious disease consultation, discharge disposition, and in-hospital mortality.ResultsIn total, 203 patients were included in this study. There was a significant difference in the time to organism identification between pre- and post-BCID cohorts (27.1h vs. 3.3h, p<0.0001). BCID did not significantly reduce the time to first appropriate antimicrobial escalation or de-escalation for either GP-BSIs or GN-BSIs. Providers were more likely to escalate antimicrobial therapy in GP-BSIs after gram stain and more likely to de-escalate therapy in GN-BSIs after susceptibilities. While there were no significant differences in changes in antimicrobial therapy after organism identification by BCID, over a quarter of providers (28.1%) made changes after organism identification.ConclusionsWhile BCID significantly reduced the time to identification for both GP-BSIs and GN-BSIs, BCID did not reduce the time to first appropriate antimicrobial escalation and de-escalation.
A nonlinear simulation framework supports adjusting for age when analyzing BrainAGE
Authors: Le Trang T. , Kuplicki Rayus , McKinney Brett A. , Yeh Hung-wen , Thompson Wesley K. ,   Tulsa 1000 Investigators, Paulus Martin P. 
Published: July 2018

AbstractSeveral imaging modalities, including T1-weighted structural imaging, diffusion tensor imaging, and functional MRI can show chronological age related changes. Employing machine learning algorithms, an individual’s imaging data can predict their age with reasonable accuracy. While details vary according to modality, the general strategy is to: 1) extract image-related features, 2) build a model on a training set that uses those features to predict an individual’s age, 3) validate the model on a test dataset, producing a predicted age for each individual, 4) define the “Brain Age Gap Estimate” (BrainAGE) as the difference between an individual’s predicted age and his/her chronological age, and 5) estimate the relationship between BrainAGE and other variables of interest, and 6) make inferences about those variables and accelerated or delayed brain aging. For example, a group of individuals with overall positive BrainAGE may show signs of accelerated aging in other variables as well. There is inevitably an overestimation of the age of younger individuals and an underestimation of the age of older individuals due to ‘regression to the mean’. The correlation between chronological age and BrainAGE may significantly impact the relationship between BrainAGE and other variables of interest when they are also related to age. In this study, we examine the detectability of variable effects under different assumptions. We use empirical results from two separate datasets [training=475 healthy volunteers, aged 18 – 60 years (259 female); testing=489 participants including people with mood/anxiety, substance use, eating disorders and healthy controls, aged 18 – 56 years (312 female)] to inform simulation parameter selection. Outcomes in simulated and empirical data strongly support the proposal that models incorporating BrainAGE should include chronological age as a covariate. We propose either including age as a covariate in step 5 of the above framework, or employing a multistep procedure where age is regressed on BrainAGE prior to step 5, producing BrainAGE Residualized (BrainAGER) scores.
PIF transcription factors link a neighbor threat cue to accelerated reproduction in Arabidopsis
Authors: Galvāo V.C. , Fiorucci A.S , Trevisan M. , Franco-Zorrilla J.M. , Goyal A. , Schmid-Siegert E. , Solano R. , Fankhauser C. 
Published: July 2018

AbstractChanges in light quality indicative of competition for this essential resource influence plant growth and developmental transitions. Little is known about neighbor proximity-induced acceleration of reproduction. phytochrome B (phyB) senses light cues from plant competitors ultimately leading to the expression of the floral inducers FLOWERING LOCUS (FT) and TWIN SISTER of FT (TSF). Here we show that three PHYTOCHROME INTERACTING FACTOR (PIF) transcriptional regulators act directly downstream of phyB to promote expression of FT and TSF. Neighbor proximity enhances PIF accumulation towards the end of the day coinciding with enhanced floral inducer expression. We present evidence for direct PIF-mediated TSF expression. The relevance of our findings is illustrated by the prior identification of FT, TSF and PIF4 as loci underlying flowering time regulation in nature.One Sentence SummaryPIF transcription factors mediate reproductive transition in response to neighbor proximity light cues in Arabidopsis.
A low resolution epistasis mapping approach to identify chromosome arm interactions in allohexaploid wheat
Authors: Santantonio Nicholas , Jannink Jean-Luc , Sorrells Mark E. 
Published: July 2018

1AbstractEpistasis is an important contributor to genetic variance, even in inbred populations where it is present as additive by additive interactions. Testing for epistasis presents a multiple testing problem as the search space for modest numbers of markers is large. Additionally, single markers do not necessarily track functional units of interacting chromatin as well as haplotype based methods do. To harness the power of multiple markers while drastically minimizing the number of tests conducted, we present a low resolution test for epistatic interactions across whole chromosome arms. Two additive genetic covariance matrices are constructed from markers on two different chromosome arms. The Hadamard product of these additive covariance matrices is then used to produce the additive by additive epistasis covariance matrix between the two chromosome arms. The covariance matrices are subsequently used to estimate an epistatic interaction variance parameter in a mixed model framework, while correcting for background additive and epistatic effects. We find significant epistatic interactions for 2% of interactions tested for four agronomic traits in a population of winter wheat. Interactions across homeologous chromosome arms were identified, but were less abundant than other interaction chromosome arm pairs. Of these, homeologous chromosome arm pair 4BL and 4DL showed a strong relationship between the product of their additive effects and the interaction effect that may be indicative of functional redundancy. Several chromosome arms were involved in many interactions across the genome, suggesting that they may contain important large effect regulatory factors. The differential patterns of epistasis across different traits suggests that detection of epistatic interactions is robust when correcting for background additive and epistatic effects in the population. The low resolution epistasis mapping method presented here identifies important epistatic interactions with a limited number of statistical tests at the cost of relatively lower precision.
Dynamic multifactor hubs interact transiently with sites of active transcription inDrosophilaembryos
Authors: Mir Mustafa , Stadler Michael R. , Ortiz Stephan A. , Harrison Melissa M. , Darzacq Xavier , Eisen Michael B. 
Published: July 2018

AbstractThe regulation of transcription requires the coordination of numerous activities on DNA, yet it remains poorly understood how transcription factors facilitate these multiple functions. Here we use lattice light-sheet microscopy to integrate single-molecule and high-speed 4D imaging in developingDrosophilaembryos to study the nuclear organization and interactions of the key patterning factors Zelda and Bicoid. In contrast to previous studies suggesting stable, cooperative binding, we show that both factors interact with DNA with surprisingly high off-rates. We find that both factors form dynamic subnuclear hubs, and that Bicoid binding is enriched within Zelda hubs. Remarkably, these hubs are both short lived and interact only transiently with sites of active Bicoid dependent transcription. Based on our observations we hypothesize that, beyond simply forming bridges between DNA and the transcription machinery, transcription factors can organize other proteins into hubs that transiently drive multiple activities at their gene targets.
Auditory and Language Contributions to Neural Encoding of Speech Features in Noisy Environments
Authors: Zou Jiajie , Feng Jun , Xu Tianyong , Jin Peiqing , Luo Cheng , Chen Feiyan , Zhang Jianfeng , Ding Nai 
Published: July 2018

AbstractRecognizing speech in noisy environments is a challenging task that involves both auditory and language mechanisms. Previous studies have demonstrated noise-robust neural tracking of the speech envelope, i.e., fluctuations in sound intensity, in human auditory cortex, which provides a plausible neural basis for noise-robust speech recognition. The current study aims at teasing apart auditory and language contributions to noise-robust envelope tracking by comparing 2 groups of listeners, i.e., native listeners of the testing language and foreign listeners who do not understand the testing language. In the experiment, speech is mixed with spectrally matched stationary noise at 4 intensity levels and the neural responses are recorded using electroencephalography (EEG). When the noise intensity increases, an increase in neural response gain is observed for both groups of listeners, demonstrating auditory gain control mechanisms. Language comprehension creates no overall boost in the response gain or the envelope-tracking precision but instead modulates the spatial and temporal profiles of envelope-tracking activity. Based on the spatio-temporal dynamics of envelope-tracking activity, the 2 groups of listeners and the 4 levels of noise intensity can be jointly decoded by a linear classifier. All together, the results show that without feedback from language processing, auditory mechanisms such as gain control can lead to a noise-robust speech representation. High-level language processing, however, further modulates the spatial-temporal profiles of the neural representation of the speech envelope.
Stavudine Reduces NLRP3 Inflammasome Activation and Upregulates Aβ-Autophagy
Authors: Rosa Francesca La , Saresella Marina , Marventano Ivana , Piancone Federica , Ripamonti Enrico , Zoia Chiara Paola , Conti Elisa , Ferrarese Carlo , Clerici Mario 
Published: July 2018

AbstractAlzheimer’s disease (AD) is associated with amyloid-beta (Aβ) deposition and neuroinflammation, possibly driven by activation of the NLRP3 inflammasome. Nucleoside reverse transcriptase inhibitors (NRTI) hamper the assembly of the NLRP3 inflammasome; we analyzed whether stavudine (D4T), a prototypical NRTI, modulates Aβ-mediated inflammasome activation; because neuroinflammation impairs Aβ clearance by phagocytes, phagocytosis and autophagy were examined as well. THP-1-derived macrophages were stimulated in vitro with Aβ42 alone or after LPS priming with/without D4T. NLRP3 and TREM2 expression was analyzed by RT-PCR, phagocytosis and ASC-Speck by AmnisFlowSight, NLRP3-produced cytokines by ELISA, authophagy by P-ELISA evaluation of P-ERK and P-AKT. Results showed that IL1β, IL18 and caspase-1 were increased whereas Aβ-phagocytosis and TREM2 were reduced in LPS+Aβ42-stimulated cells. D4T reduced NLRP3 assembly as well as IL18 and caspase-1 production, but not IL1β, phagocytosis, and TREM2. P-AKT expression was augmented and P-ERK was reduced by D4T, suggesting a stimulatory effect on autophagy. D4T reduces NLRP3 inflammasome-associated inflammation, possibly restoring autophagy, in an in vitro model of AD; it will be interesting to verify its possibly beneficial effects in the clinical scenario.
Opposing effects of impulsivity and mindset on sources of science selfefficacy and STEM interest in adolescents
Authors: Marriott L.K. , Coppola L. , S.H. Mitchell , Bouwma-Gearhart J. , Chen Z. , Shifrer D. , Shannon J.S. 
Published: July 2018

AbstractImpulsivity has been linked to academic performance in the context of Attention Deficit Hyperactivity Disorder, though its influence on a wider spectrum of students remains largely unexplored, particularly in the context of STEM learning (i.e. science, technology, engineering, and math). STEM learning was hypothesized to be more challenging for impulsive students, since it requires the practice and repetition of tasks as well as concerted attention to task performance. Impulsivity was assessed in a cross-sectional sample of 2,476 students in grades 6-12. Results show impulsivity affects a larger population of students, not limited to students with learning disabilities. Impulsivity was associated with lower sources of science self-efficacy (SSSE) scores, interest in all STEM domains (particularly math), and self-reported STEM skills. The large negative effect observed for impulsivity was opposed by “growth” mindset, which describes a student’s belief in the importance of effort when learning is difficult. Mindset had a large positive effect, which was associated with greater SSSE, STEM interest, and STEM skills. When modeled together, results suggest that mindset interventions may benefit impulsive students who struggle with STEM. Together, these data suggest important interconnected roles for impulsivity and mindset that can influence secondary students’ STEM trajectories.
Desensitization of NMDA receptors depends of their association with plasma membrane sodium-calcium exchangers in lipid nanoclasters
Authors: Sibarov Dmitry A. , Poguzhelskaya Ekaterina E. , Antonov Sergei M. 
Published: July 2018

AbstractThe plasma membrane Na+/Ca2+-exchanger (NCX) has recently been shown to regulate Ca2+-dependent N-methyl-d-aspartate receptor (NMDAR) desensitization, suggesting tight interaction of NCXs and NMDARs in lipid nanoclaster or “rafts”. To evaluate possible role of this interaction we studied effects of Li+ on NMDA-elicited whole-cell currents and Ca2+ responses of rat cortical neurons in vitro before and after cholesterol extraction by methyl-β-cyclodextrin (MβCD). Substitution Li+ for Na+ in the external solution caused a concentration-dependent decrease of steady-state NMDAR currents from 440 ± 71 pA to 111 ± 29 pA in 140 mM Na+ and 140 mM Li+, respectively. Li+ inhibition of NMDAR currents disappeared in the absence of Ca2+ in the external solution (Ca2+-free), suggesting that Li+ enhanced Ca2+-dependent NMDAR desensitization. Whereas the cholesterol extraction with MβCD induced NMDAR current decrease to 136 ± 32 pA in 140 mM Na+ and 46 ± 15 pA in 140 mM Li+, the IC50 values for the Li+ inhibition were similar (about 44 mM Li+) before and after this procedure. In Ca2+-free Na+ solution steady-state NMDAR currents after the cholesterol extraction were 47 ± 6 % of control currents. Apparently this amplitude decrease was not Ca2+-dependent. In 1 mM Ca2+ Na+ solution the Ca2+-dependent NMDAR desensitization was greater when cholesterol was extracted. Obviously, this procedure promoted its development. In agreement, Li+ and KB-R7943, an inhibitor of NCX, both considerably reduced NMDAR-mediated Ca2+ responses. The cholesterol extraction itself caused a decrease of NMDAR-mediated Ca2+ responses and, in addition, abolished the effects of Li+ and KB-R7943. Taken together our data suggest that NCXs downregulate the Ca2+-dependent NMDAR desensitization. Most likely, this is determined by co-localization and tight functional interaction of NCX and NMDAR molecules in membrane lipid rafts. Their destruction is accompanied by an enhancement of NMDAR desensitization and a loss of NCX-selective agent effects on NMDARs.
On the impact of the pangenome and annotation discrepancies while building protein sequence databases for bacteria proteogenomics
Authors: Machado K.C.T. , Fortuin S. , Tomazella G.G. , Fonseca A.F. , Warren R. , Wiker H.G. , de Souza S.J. , de Souza G.A. 
Published: July 2018

AbstractIn proteomics, peptide information within mass spectrometry data from a specific organism sample is routinely challenged against a protein sequence database that best represent such organism. However, if the species/strain in the sample is unknown or poorly genetically characterized, it becomes challenging to determine a database which can represent such sample. Building customized protein sequence databases merging multiple strains for a given species has become a strategy to overcome such restrictions. However, as more genetic information is publicly available and interesting genetic features such as the existence of pan- and core genes within a species are revealed, we questioned how efficient such merging strategies are to report relevant information. To test this assumption, we constructed databases containing conserved and unique sequences for ten different species. Features that are relevant for probabilistic-based protein identification by proteomics were then monitored. As expected, increase in database complexity correlates with pangenomic complexity. However, Mycobacterium tuberculosis and Bortedella pertusis generated very complex databases even having low pangenomic complexity or no pangenome at all. This suggests that discrepancies in gene annotation is higher than average between strains of those species. We further tested database performance by using mass spectrometry data from eight clinical strains from Mycobacterium tuberculosis, and from two published datasets from Staphylococcus aureus. We show that by using an approach where database size is controlled by removing repeated identical tryptic sequences across strains/species, computational time can be reduced drastically as database complexity increases.
Tiling light sheet selective plane illumination microscopy using discontinuous light sheets
Authors: Gao Liang 
Published: July 2018

AbstractTiling light sheet selective plane illumination microscopy (TLS-SPIM) improves 3D imaging ability of SPIM by using a real-time optimized tiling light sheet. However, the imaging speed decreases, and size of the raw image data increases proportionally to the number of tiling positions in TLS-SPIM. The decreased imaging speed and the increased raw data size could cause significant problems when TLS-SPIM is used to image large specimens at high spatial resolution. Here, we present a novel method to solve the problem. Discontinuous light sheets created by scanning coaxial beam arrays synchronized with camera exposures are used for 3D imaging to decrease the number of tiling positions required at each image plane without sacrificing the spatial resolution. We investigate the performance of the method via numerical simulation and discuss the technical details of the method.
Lamin A/C controls nuclear matrin-3 levels and localization, but not alternative splicing of cassette exons
Authors: Rajgor Dipen , Gooding Clare , Hayward Robert , Coelho Miguel B , Smith Christopher WJ , Shanahan Catherine M 
Published: July 2018

AbstractDisruptions in connections between the nuclear lamina and nuclear matrix occur in myopathic disorders. However, the biological significance of nuclear lamina - nuclear matrix coupling still remains largely undetermined. Previously it has been demonstrated that the nuclear matrix protein, matrin-3, binds to lamin A/C and this interaction is disrupted in laminopathies resulting in enhanced separation between the lamina and matrix. Matrin-3 has recently been identified as a core regulator of alternative splicing, whereas the involvement of lamin A/C in splicing still remains controversial. In this study, we demonstrate that lamin A/C is not only required for maintaining the nuclear organization of matrin-3, but also of other splicing activators and small nuclear ribonucleoproteins (snRNP) components. Interestingly, mis-localization of these splicing components did not appear to significantly disrupt alternative splicing events of cassette exons regulated by matrin-3. Thus, the lamin A/C-matrin3 interaction is unlikely to be involved in controlling alternative splicing but could be important in coordinating other nuclear activities. Interestingly, matrin-3 knock-down results in misshapen nuclei suggesting its interaction with lamin A/C maybe important in maintaining nuclear structural integrity.