bluuebunny/crossref_metadata_2025 huggingface dataset:
Substance Use Disorder
Authors: Mahoney Kathleen , Reich Wendy , Urbanek Susan
Published: August 2019

The growing opioid crisis in the United States affects childbearing women and their infants at an alarming rate. Substance use disorders in pregnancy have transitioned from a topic barely addressed to one that has become mainstream in the issue of pregnancy management. Opioid use can include appropriate use of a prescribed medication, the misuse of street drugs, and maintenance on an opioid agonist treatment such as methadone. Identifying this population of childbearing women is critical to be able to organize the appropriate resources and to provide a comprehensive multidisciplinary evidence-based plan of care. All clinicians need to be educated in identifying and caring for the growing population of women with substance use disorders. Each component of the continuum from prenatal care, labor and birth, and postpartum has challenges and issues that can have a positive or negative impact on the outcome of the pregnancy and the mother–infant relationship. Risk assessment, medication-assisted treatment, pain management, and fostering maternal–infant bonding are important considerations in the care of the woman with substance use disorder. Unbiased empathetic nurses are well positioned to strongly advocate and intervene on behalf of women with substance use disorder, which in turn will help to create positive outcomes for the mother and her baby.
Pinna Bruising in Children
Authors: Brown Julie C. , Metz James B.
Published: August 2019

Pinna bruising can be associated with abuse, but can also be due to accidental injury. We present 3 cases of pinna bruises and discuss features associated with accidental and nonaccidental injury. Attention to the history, the pattern of bruising, and any other findings identified on a careful, thorough examination will help differentiate the two.
Insights on cannabidiol's antiallodynic and anxiolytic mechanisms of action in a model of neuropathic pain
Authors: Schott Marion
Published: August 2019

Recent studies have shown that cannabidiol (CBD) could have a great therapeutic potential for treating disorders such as chronic pain and anxiety. In the target article, the authors propose that CBD modulates serotonergic transmission and reverses allodynia and anxiety-like behaviour in a rat model of neuropathic pain. Furthermore, this study shows an antinociceptive effect mediated by TRPV1 and partially by 5-HT1A receptors, as well as an anxiolytic effect mediated by 5-HT1A receptors.

Commentary on: De Gregorio D, McLaughlin RJ, Posa L, Ochoa-Sanchez R, Enns J, Lopez-Canul M, Aboud M, Maione S, Comai S, and Gobbi G. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. PAIN 2019;160:36–150.
Does the IASP definition of pain need updating?
Authors: Aydede Murat
Published: August 2019

The current IASP definition of pain has come under renewed criticisms recently. There is a new momentum for its revision as reflected by the fact that IASP has now a Presidential Task Force dedicated to look into whether there is enough warrant to update the definition. I critically review all the major criticisms of the current definition in detail, and raise new difficulties rarely discussed before. I show that none of the major criticisms has enough warrant to force us to substantially revise the current definition. Combined with the discussion of the new difficulties, there is nonetheless a need to restate the definition using slightly different terminology that will make the original intent of the current definition clearer and more precise. A restatement of the definition is proposed and its potential is discussed in light of some empirical questions that remain.
Measuring Baseline Health with Individual Health-Adjusted Life Expectancy (iHALE)
Authors: Johansson Kjell Arne , Økland Jan-Magnus , Krüger Skaftun Eirin , Bukhman Gene , Norheim Ole Frithjof , Coates Matthew M. , Haaland Øystein Ariansen
Published: August 2019

Objectives

At any point of time, a person’s baseline health is the number of healthy life years they are expected to experience during the course of their lifetime. In this article we propose an equity-relevant health metric, illness-specific individual Health Adjusted Life Expectancy (iHALE), that facilitates comparison of baseline health for individuals at the onset of different medical conditions, and allows for the assessment of which patient groups are worse off. A method for calculating iHALE is presented, and we use this method to rank four conditions in six countries according to several criteria of “worse off” as a proof of concept.

Methods

iHALE measures baseline health at an individual level for specific conditions, and consists of two components: past health (before disease onset) and future expected health (after disease onset). Four conditions (acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), schizophrenia, and epilepsy) are analysed in six countries (Ethiopia, Haiti, China, Mexico, United States and Japan). Data for all countries and for all diseases in 2017 were obtained from the Global Burden of Disease Study database. In order to assess who are the worse off, we focus on four measures: the proportion of affected individuals who are expected to attain less than 20 healthy life years (T20), the 25th and 75th percentiles of healthy life years for affected individuals (Q1 and Q3, respectively), and the average iHALE across all affected individuals.

Results

Even in settings where average iHALE is similar for two conditions, other measures may vary. One example is AML (average iHALE=58.7, T20=2.1, Q3-Q1=15.3) and ALL (57.7, T20=4.7, Q3-Q1=21.8) in the US. Many illnesses, such as epilepsy, are associated with higher baseline health in high-income settings (average iHALE in Japan=64.3) than in low-income settings (average iHALE in Ethiopia=36.8).

Conclusion

iHALE allows for the estimation of the distribution of baseline health of all individuals in a population. Hence, baseline health can be incorporated as an equity consideration in setting priorities for health interventions.
Multidrug therapy with terbinafine and itraconazole is not superior to itraconazole alone in current epidemic of altered dermatophytosis in India: A randomized pragmatic trial
Authors: Singh Sanjay , Anchan Vinayak N , Chandra Usha , Raheja Radhika
Published: August 2019

Background

Treatment responsiveness of dermatophytosis has decreased considerably in recent past in India. We compared effectiveness of oral terbinafine daily (Terb) (active control) versus itraconazole daily (Itra) versus terbinafine plus itraconazole daily (TI) versus terbinafine daily plus itraconazole pulse (TIp) in tinea corporis, tinea cruris and tinea faciei in a pragmatic randomized open trial.

Methods

Ninety-two microscopically confirmed patients were allocated to Terb (6 mg/kg/day), Itra (5 mg/kg/day), TI (terbinafine 6 mg/kg/day, itraconazole 5 mg/kg/day), or TIp (terbinafine 6 mg/kg/day, itraconazole 10 mg/kg/day for 1 week in 4 weeks) group by concealed block randomization and treated for 8 weeks or cure.

Results

Cure rates were similar at 4 weeks (P=0.768). At 8 weeks, 5 (21.7%), 18 (78.3%), 16 (69.6%), and 16 (69.6%) patients were cured in Terb, Itra, TI, and TIp groups, respectively. All experimental regimens (Itra, TI, TIp) were more effective than Terb (P≤0.0027). All experimental regimens had similar effectiveness (P≥0.738). Relapse rates 4 and 8 weeks after cure were similar (P=0.869 and 0.314, respectively). Number-needed-to-treat (NNT) was 2 for Itra, 3 for TI, and 3 for TIp.

Conclusions

Oral itraconazole given daily (NNT=2) is the most effective treatment and combining it with terbinafine does not increase effectiveness.

One Sentence Summary

Combination of oral terbinafine and itraconazole is not more effective than itraconazole alone in current epidemic of altered dermatophytosis in India.
A Comparison of Contemporary versus Older Studies of Aspirin for Primary Prevention
Authors: Moriarty Frank , Ebell Mark H.
Published: August 2019

Objective

This study compares the benefits and harms of aspirin for primary prevention before and after widespread use of statins and colorectal cancer screening.

Methods

We compared studies of aspirin for primary prevention that recruited patients from 2005 onward with previous individual patient meta-analyses that recruited patients from 1978 to 2002. Data for contemporary studies were synthesized using random-effects models. We report vascular (major adverse cardiovascular events [MACE], myocardial infarction [MI], stroke), bleeding, cancer, and mortality outcomes.

Results

The IPD analyses of older studies included 95,456 patients for CV prevention and 25,270 for cancer mortality, while the four newer studies had 61,604 patients. Relative risks for vascular outcomes for older vs newer studies follow: MACE: 0.89 (95% CI 0.83-0.95) vs 0.93 (0.86-0.99); fatal hemorrhagic stroke: 1.73 (1.11-2.72) vs 1.06 (0.66-1.70); any ischemic stroke: 0.86 (0.74-1.00) vs 0.86 (0.75-0.98); any MI: 0.84 (0.77-0.92) vs 0.88 (0.77-1.00); and non-fatal MI: 0.79 (0.71-0.88) vs 0.94 (0.83-1.08). Cancer death was not significantly decreased in newer studies (RR 1.11, 0.92-1.34). Major hemorrhage was significantly increased for both older and newer studies (RR 1.48, 95% CI 1.25-1.76 vs 1.37, 95% CI 1.24-1.53). There was no effect in either group on all-cause mortality, cardiovascular mortality, fatal stroke, or fatal MI.

Conclusions

In the modern era characterized by widespread statin use and cancer screening, aspirin does not reduce the risk of non-fatal MI or cancer death. There are no mortality benefits and a significant risk of major hemorrhage. Aspirin should no longer be recommended for primary prevention.

Summary of current evidence and what this study adds

What is already known about this subject?

The cumulative evidence for aspirin suggests a role in the primary prevention of cardiovascular disease, and in reducing cancer incidence and mortality.

However most of the trials of aspirin for primary prevention were set in Europe and the United States and recruited patients prior to the year 2000.

The benefits and harms of aspirin should be considered separately in studies performed in the eras before and after widespread use of statins and colorectal cancer screening.

What does this study add?

This study provides the most detailed summary to date of cardiac, stroke, bleeding, mortality and cancer outcomes to date in the literature.

In trials of aspirin for primary prevention from 2005 onwards, aspirin reduced major adverse cardiovascular events but significantly increased the risk of bleeding, with no benefit for mortality or,

Unlike older studies, there was no reduction in cancer mortality and non-fatal myocardial infarction.

How does this impact on clinical practice?

Our study suggests aspirin should not be recommended for primary prevention in the modern era.
CLIC4 is a cytokinetic cleavage furrow protein that regulates cortical cytoskeleton stability during cell division
Authors: Peterman Eric , Valius Mindaugas , Prekeris Rytis
Published: August 2019

During mitotic cell division, the actomyosin cytoskeleton undergoes several dynamic changes that play key roles in progression through mitosis. While the regulators of cytokinetic ring formation and contraction are well-established, proteins that regulate cortical stability during anaphase and telophase have been understudied. Here, we describe a role for CLIC4 in regulating actin and actin-regulators at the cortex and cytokinetic cleavage furrow during cytokinesis. We first describe CLIC4 as a new component of the cytokinetic cleavage furrow that is required for successful completion of mitotic cell division. We also demonstrate that CLIC4 regulates the remodeling of sub-plasma membrane actomyosin network within the furrow by recruiting MST4 kinase and regulating ezrin phosphorylation. This work identifies and characterizes new molecular players involved in the transition from the contracting cytokinetic ring to the intercellular bridge during cytokinesis.
mTORC1 and mTORC2 regulate distinct aspects of glutamatergic synaptic transmission
Authors: McCabe Matthew P. , Cullen Erin R. , Barrows Caitlynn M. , Shore Amy N. , Tooke Katharine I. , Weston Matthew C.
Published: August 2019

Although mTOR signaling is known as a broad regulator of cell growth and proliferation, in neurons it regulates synaptic transmission, which is thought to be a major mechanism through which altered mTOR signaling leads to neurological disease. Although previous studies have delineated postsynaptic roles for mTOR, whether it regulates presynaptic function is largely unknown. Moreover, the mTOR kinase operates in two complexes, mTORC1 and mTORC2, suggesting that mTOR’s role in synaptic transmission may be complex-specific. To better understand each complex’s role in synaptic transmission, we genetically inactivated mTORC1 or mTORC2 in cultured mouse glutamatergic hippocampal neurons. Inactivation of either complex reduced neuron growth and evoked EPSCs, however, mTORC1 exerted its effects on eEPSCs at the postsynapse and mTORC2 at the presynapse. Furthermore, inactivation of each complex altered specific modes of synaptic vesicle release, suggesting that mTORC1 and mTORC2 differentially modulate postsynaptic responsiveness and presynaptic release to optimize glutamatergic synaptic transmission.
Sensitivity of the paired motor unit analysis for estimation of motoneuron excitability to commonly used constraints and filters
Authors: Hassan Altamash , Thompson Christopher K. , Negro Francesco , Cummings Mark , Powers Randy , Heckman CJ , Dewald Jules , McPherson Laura Miller
Published: August 2019

The nervous system has a tremendous ability to modify motoneuron excitability according to task demands through neuromodulatory synaptic input to motoneurons. Neuromodulatory inputs adjust the response of the motoneuron to excitatory and inhibitory ionotropic input and can facilitate the induction of persistent inward currents (PICs). PICs amplify and prolong the motoneuron response to synaptic inputs, and PIC impairment may play a major role in motor deficits observed in pathological conditions. Noninvasive estimation of the magnitude of neuromodulatory input and persistent inward currents in human motoneurons is achieved through a paired motor unit analysis (ΔF) that quantifies hysteresis in the firing rates at motor unit recruitment and derecruitment. While the ΔF technique is commonly used for estimating motoneuron excitability, computational parameters used for the technique vary across studies. In the present study, we assessed the sensitivity of the ΔF technique to several criteria commonly used in selecting motor unit pairs for analysis, as well as to methods used for smoothing the instantaneous motor unit firing rates. Using HD-sEMG and motor unit decomposition we obtained 5,409 motor unit pairs from the triceps brachii of ten healthy individuals during submaximal triangle contractions. The mean (SD) ΔF was 4.9 (1.08) pps, consistent with previous work using intramuscular recordings. There was an exponential plateau relationship between ΔF and the recruitment time difference between the motor unit pairs, with the plateau occurring at approximately 1 s. There was an exponential decay relationship between ΔF and the derecruitment time difference between the motor unit pairs, with the decay stabilizing at approximately 1.5 s. We found that reducing or removing the minimum threshold for the correlation of the rate-rate slope for the two units did not affect ΔF values or variance. Additionally, we found that removing motor unit pairs in which the control unit was saturated had no significant effect on ΔF. Smoothing filter selection had no substantial effect on ΔF values and ΔF variance; however, the length and type of smoothing filter affected the minimum recruitment and derecruitment time differences. Our results facilitate interpretation of findings from studies that implement the ΔF approach but use different computational parameters.
Magnetic manipulation of axonal endosome transport in live neurons
Authors: Chowdary Praveen D. , McGuire Allister F. , Lee Yujeong , Che Daphne L. , Hanson Lindsey , Osakada Yasuko , Ooi Chinchun , Xie Chong , Wang Shan , Cui Bianxiao
Published: August 2019

Noninvasive control of axonal cargos in live neurons is a challenging prospect that can enable novel research on the mechanisms of axonal cargo transport, cargo-mediated signaling and axonal traffic jams in neurons. However, conventional techniques for force manipulation such as optical traps are limited to a few micron-sized cargos and are not applicable to the small axonal cargos in live neurons. Here, we present a new methodology that permits the external control of axonal endosome transport via tailored magnetic forces. By culturing neurons in a microfluidic device made up of microfabricated magnetic arrays, we can exert 3 – 48 pN forces on retrograde axonal endosomes carrying fluorescent magnetic nanoparticles, 100 – 260 nm in size. The magnetic force counters the forces exerted by molecular motors driving the endosomes and results in a wide range of perturbations on endosome transport in axons. These perturbations, captured by oblique illumination fluorescence imaging, reveal new insights on the collective function of dyneins and the nature of paused and stationary states during retrograde endosome transport in axons. Most notably, we demonstrate controllable capture and release of retrograde endosomes in axons by toggling the external magnetic field. This technical advance has great potential to elucidate the spatiotemporal origins of long-distance endosome signaling pathways as well as the ramifications of axonal traffic jams in neurons.
Geomagnetic field intensity as a cue for the regulation of insect migration
Authors: Wan Guijun , Liu Ruiying , Li Chunxu , He Jinglan , Pan Weidong , Sword Gregory A. , Hu Gao , Chen Fajun
Published: August 2019

Geomagnetic field (GMF) intensity can be used by some animals to determine their direction and position during migration. However, its role, if any, in mediating other migration-related phenotypes remains largely unknown. Here, we simulated variation in GMF intensity between two locations along the migration route of a nocturnal insect migrant, the brown planthopper Nilaparvata lugens, that varied by ∼5 μT (GMF50μT vs. GMF45μT) in field intensity. After one generation of exposure, we tested for changes in key morphological, behavioural and physiological traits related to migratory performance including wing dimorphism, flight capacity and positive phototaxis. Our results showed that all three morphological and behavioural phenotypes responded to a small difference in magnetic field intensity between the simulated northern vs. southern locations in ways expected along the migratory route. Consistent magnetic responses in the expression of the phototaxis-related Drosophila-like cryptochrome 1 (Cry1) gene and levels of two primary energy substrates used during flight, triglyceride and trehalose, were also found. Our findings indicate GMF intensity can be a cue that regulates the expression of phenotypes critical for insect migration and highlight the unique role of magnetoreception as a trait that can help migratory insects express potentially beneficial phenotypes in geographically variable environments.
MetaboShiny – interactive processing, analysis and annotation of direct infusion metabolomics data
Authors: Wolthuis Joanna C. , Magnusdottir Stefania , Pras-Raves Mia , Moshiri Maryam , Jans Judith J.M. , Burgering Boudewijn , van Mil Saskia , de Ridder Jeroen
Published: August 2019

Direct infusion untargeted metabolomics, as mass-over-charge values and intensity of ions, allows for rapid insight into a sample’s metabolic activity. However, analysis is often complicated by the large array of detected m/z values and the difficulty to prioritize important m/z and simultaneously annotate their putative identities. To address this challenge, we developed MetaboShiny, a novel R/RShiny-based metabolomics package featuring data analysis, database- and formula-prediction-based annotation and visualization. To demonstrate this, we reproduce and further explore a MetaboLights metabolomics bioinformatics study on lung cancer patient urine samples. MetaboShiny enables rapid and rigorous analysis and interpretation of direct infusion untargeted metabolomics data.
Acoustic biomolecules enhance hemodynamic functional ultrasound imaging of neural activity
Authors: Maresca David , Payen Thomas , Lee-Gosselin Audrey , Ling Bill , Malounda Dina , Demené Charlie , Tanter Mickaël , Shapiro Mikhail G.
Published: August 2019

Hemodynamic functional ultrasound imaging (fUS) of neural activity provides a unique combination of spatial coverage, spatiotemporal resolution and compatibility with freely moving animals. However, deep and transcranial monitoring of brain activity and the imaging of dynamics in slow-flowing blood vessels remains challenging. To enhance fUS capabilities, we introduce biomolecular hemodynamic enhancers based on gas vesicles (GVs), genetically encodable ultrasound contrast agents derived from buoyant photosynthetic microorganisms. We show that intravenously infused GVs enhance ultrafast Doppler ultrasound contrast and visually-evoked hemodynamic contrast in transcranial fUS of the mouse brain. This hemodynamic contrast enhancement is smoother than that provided by conventional microbubbles, allowing GVs to more reliably amplify neuroimaging signals.
The evaluation of RNA-Seq de novo assembly by PacBio long read sequencing
Authors: Yang Yifan , Gribskov Michael
Published: August 2019

RNA-Seq de novo assembly is an important method to generate transcriptomes for non-model organisms before any downstream analysis. Given many great de novo assembly methods developed by now, one critical issue is that there is no consensus on the evaluation of de novo assembly methods yet. Therefore, to set up a benchmark for evaluating the quality of de novo assemblies is very critical. Addressing this challenge will help us deepen the insights on the properties of different de novo assemblers and their evaluation methods, and provide hints on choosing the best assembly sets as transcriptomes of non-model organisms for the further functional analysis. In this article, we generate a “real time” transcriptome using PacBio long reads as a benchmark for evaluating five de novo assemblers and two model-based de novo assembly evaluation methods. By comparing the de novo assmblies generated by RNA-Seq short reads with the “real time” transcriptome from the same biological sample, we find that Trinity is best at the completeness by generating more assemblies than the alternative assemblers, but less continuous and having more misassemblies; Oases is best at the continuity and specificity, but less complete; The performance of SOAPdenovo-Trans, Trans-AByss and IDBA-Tran are in between of five assemblers. For evaluation methods, DETONATE leverages multiple aspects of the assembly set and ranks the assembly set with an average performance as the best, meanwhile the contig score can serve as a good metric to select assemblies with high completeness, specificity, continuity but not sensitive to misassemblies; TransRate contig score is useful for removing misassemblies, yet often the assemblies in the optimal set is too few to be used as a transcriptome.
Progression from feature-specific brain activity to hippocampal binding during episodic encoding
Authors: Cooper Rose A. , Ritchey Maureen
Published: August 2019

The hallmark of episodic memory is recollecting multiple perceptual details tied to a specific spatial-temporal context. To remember an event, it is therefore necessary to integrate such details into a coherent representation during initial encoding. Here we tested how the brain encodes and binds multiple, distinct kinds of features in parallel, and how this process evolves over time during the event itself. We analyzed data from 27 human subjects (16 females, 11 males) who learned a series of objects uniquely associated with a color, a panoramic scene location, and an emotional sound while functional magnetic resonance imaging data were collected. By modeling how brain activity relates to memory for upcoming or just-viewed information, we were able to test how the neural signatures of individual features as well as the integrated event changed over the course of encoding. We observed a striking dissociation between early and late encoding processes: left inferior frontal and visuo-perceptual signals at the onset of an event tracked the amount of detail subsequently recalled and were dissociable based on distinct remembered features. In contrast, memory-related brain activity shifted to the left hippocampus toward the end of an event, which was particularly sensitive to binding item color and sound associations with spatial information. These results provide evidence of early, simultaneous feature-specific neural responses during episodic encoding that predict later remembering and suggest that the hippocampus integrates these features into a coherent experience at an event transition.

SIGNIFICANCE STATEMENT

Understanding and remembering complex experiences is crucial for many socio-cognitive abilities, including being able to navigate our environment, predict the future, and share experiences with others. Probing the neural mechanisms by which features become bound into meaningful episodes is a vital part of understanding how we view and reconstruct the rich detail of our environment. By testing memory for multimodal events, our findings show a functional dissociation between early encoding processes that engage lateral frontal and sensory regions to successfully encode event features, and later encoding processes that recruit hippocampus to bind these features together. These results highlight the importance of considering the temporal dynamics of encoding processes supporting multimodal event representations.
Chemotaxis and topotaxis add vectorially for amoeboid cell migration
Authors: Wondergem Joeri A. J. , Mytiliniou Maria , Wit Falko C. H. de , Reuvers Thom G. A. , Holcman David , Heinrich Doris
Published: August 2019

Cells encounter a wide variety of physical and chemical cues when navigating their native environments. However, their response to multiple simultaneous cues is not yet clear. In particular, the influence of topography, in the presence of a chemotactic gradient, on their migratory behavior is understudied. Here, we investigate the effects of topographical guidance on highly motile amoeboid cell migration (topotaxis) generated by asymmetrically placed micropillars. The micropillar field allows for an additional, natural chemotactic gradient in two different directions, thereby revealing the relevance of topotaxis in the presence of cell migration directed by chemical gradients (chemotaxis). Interestingly, we found that the topotactic drift generated by the pillar field is conserved during chemotaxis. We show that the drifts generated by both these cues add up linearly. A coarse-grained analysis as a function of pillar spacing subsequently revealed that the strength and direction of the topotactic drift is determined by (i) the pore size, (ii) space between pores, and (iii) the effective diffusion constant of the cells. Finally, we argue that topotaxis must be conserved during chemotaxis, as it is an emergent property of both the asymmetric properties of the pillar field and the inherent stochasticity of (biased) amoeboid migration.
Neurons that Function within an Integrator to Promote A Persistent Behavioral State in Drosophila
Authors: Jung Yonil , Kennedy Ann , Chiu Hui , Mohammad Farhan , Claridge-Chang Adam , Anderson David J.
Published: August 2019

Innate behaviors involve both reflexive motor programs and internal states. In Drosophila, optogenetic activation of male-specific P1 interneurons triggers courtship song, as well as a persistent behavioral state that prolongs courtship and enhances aggressiveness. Here we identify pCd neurons as persistently activated by repeated P1 stimulation. pCd neurons are required for P1-evoked persistent courtship and aggression, as well as for normal social behavior. Activation of pCd neurons alone is inefficacious, but enhances and prolongs courtship or aggression promoted by female cues. Transient female exposure induced persistent increases in male aggressiveness, an effect suppressed by transiently silencing pCd neurons. Transient silencing of pCd also disrupted P1-induced persistent physiological activity, implying a requisite role in persistence. Finally, P1 activation of pCd neurons enhanced their responsiveness to cVA, an aggression-promoting pheromone. Thus, pCd neurons function within a circuit that integrates P1 input, to promote a persistent internal state that enhances multiple social behaviors.
Potentiating antibiotic treatment using fitness-neutral gene expression perturbations
Authors: Otoupal Peter B. , Erickson Keesha E. , Eller Kristen A. , Campos Jocelyn , Aunins Thomas R. , Chatterjee Anushree
Published: August 2019

The rapid proliferation of multidrug-resistant (MDR) bacteria poses a critical threat to human health, for which new antimicrobial strategies are desperately needed. Here we outline a strategy for combating bacterial infections by administering fitness neutral gene expression perturbations as co-therapies to potentiate antibiotic lethality. We systematically explored the fitness of 270 gene knockout-drug combinations in Escherichia coli, identifying 114 synergistic interactions. Genes revealed in this screen were subsequently perturbed at the transcriptome level via multiplexed CRISPR-dCas9 interference to induce antibiotic synergy. These perturbations successfully sensitized E. coli to antibiotic treatment without imposing a separate fitness cost. We next administered these fitness neutral gene perturbations as co-therapies to potentiate antibiotic killing of Salmonella enterica in intracellular infections of HeLa epithelial cells, demonstrating therapeutic applicability. Finally, we utilized these results to design peptide nucleic acid (PNA) co-therapies for targeted gene expression reduction in four MDR, clinically isolated bacteria. Two isolates of Klebsiella pneumoniae and E. coli were each exposed to PNAs targeting homologs of the genes csgD, fnr, recA and acrA in the presence of sub-minimal inhibitory concentrations of trimethoprim. We successfully increased each strain’s susceptibility to trimethoprim treatment and identified eight cases in which re-sensitization occurred without a direct fitness impact of the PNA on MDR strains. Our results highlight a promising approach for combating MDR bacteria which could extend the utility of our current antibiotic arsenal.
Dynamic regulation of immunity through post-translational control of defense transcript splicing
Authors: Dressano Keini , Weckwerth Philipp R , Poretsky Elly , Takahashi Yohei , Villarreal Carleen , Shen Zhouxin , Schroeder Julian I. , Briggs Steven P. , Huffaker Alisa
Published: August 2019

Survival of all living organisms requires the ability to detect attack and swiftly counter with protective immune responses. Despite considerable mechanistic advances, interconnectivity of signaling circuits often remains unclear. A newly-characterized protein, IMMUNOREGULATORY RNA-BINDING PROTEIN (IRR), negatively regulates immune responses in both maize and Arabidopsis, with disrupted function resulting in enhanced disease resistance. IRR physically interacts with, and promotes canonical splicing of, transcripts encoding defense signaling proteins, including the key negative regulator of pattern recognition receptor signaling complexes, CALCIUM-DEPENDENT PROTEIN KINASE 28 (CPK28). Upon immune activation by Plant Elicitor Peptides (Peps), IRR is dephosphorylated, disrupting interaction withCPK28transcripts and resulting in accumulation of an alternative splice variant encoding a truncated CPK28 protein with impaired kinase activity and diminished function as a negative regulator. We demonstrate a novel circuit linking Pep-induced post-translational modification of IRR with post-transcriptionally-mediated attenuation of CPK28 function to dynamically amplify Pep signaling and immune output.

One Sentence Summary

Plant innate immunity is promoted by post-translational modification of a novel RNA-binding protein that regulates alternative splicing of transcripts encoding defense signaling proteins to dynamically increase immune receptor signaling capacity through deactivation of a key signal-buffering circuit.
Design of a transcriptional biosensor for the portable, on-demand detection of cyanuric acid
Authors: Liu Xiangyang , Silverman Adam D. , Alam Khalid K. , Iverson Erik , Lucks Julius B. , Jewett Michael C. , Raman Srivatsan
Published: August 2019

Rapid molecular biosensing is an emerging application area for synthetic biology. Here, we engineer a portable biosensor for cyanuric acid (CYA), an analyte of interest for human and environmental health, using a LysR-type transcription regulator (LTTR) from Pseudomonas within the context of Escherichia coli gene expression machinery. To overcome cross-host portability challenges of LTTRs, we rationally engineered hybrid Pseudomonas-E. coli promoters by integrating DNA elements required for transcriptional activity and ligand-dependent regulation from both hosts, which enabled E. coli to function as whole-cell biosensor for CYA. To alleviate challenges of whole-cell biosensing, we adapted these promoter designs to function within a freeze-dried E. coli cell-free system to sense CYA. This portable, on-demand system robustly detects CYA within an hour from laboratory and real-world samples and works with both fluorescent and colorimetric reporters. This work elucidates general principles to facilitate the engineering of a wider array of LTTR-based environmental sensors.
Classifying T cell activity in autofluorescence intensity images with convolutional neural networks
Authors: Wang Zijie J. , Walsh Alex J. , Skala Melissa C. , Gitter Anthony
Published: August 2019

The importance of T cells in immunotherapy has motivated developing technologies to better characterize T cells and improve therapeutic efficacy. One specific objective is assessing antigen-induced T cell activation because only functionally active T cells are capable of killing the desired targets. Autofluorescence imaging can distinguish T cell activity states of individual cells in a non-destructive manner by detecting endogenous changes in metabolic co-enzymes such as NAD(P)H. However, recognizing robust patterns of T cell activity is computationally challenging in the absence of exogenous labels or information-rich autofluorescence lifetime measurements. We demonstrate that advanced machine learning can accurately classify T cell activity from NAD(P)H intensity images and that those image-based signatures transfer across human donors. Using a dataset of 8,260 cropped single-cell images from six donors, we meticulously evaluate multiple machine learning models. These range from traditional models that represent images using summary statistics or extract image features with CellProfiler to deep convolutional neural networks (CNNs) pre-trained on general non-biological images. Adapting pre-trained CNNs for the T cell activity classification task provides substantially better performance than traditional models or a simple CNN trained with the autofluorescence images alone. Visualizing the images with dimension reduction provides intuition into why the CNNs achieve higher accuracy than other approaches. However, we observe that fine-tuning all layers of the pre-trained CNN does not provide a classification performance boost commensurate with the additional computational cost. Our software detailing our image processing and model training pipeline is available as Jupyter notebooks at https://github.com/gitter-lab/t-cell-classification.
Specialization of theDrosophilanuclear export family protein Nxf3 for piRNA precursor export
Authors: Kneuss Emma , Munafò Marzia , Eastwood Evelyn L. , Deumer Undine-Sophie , Preall Jonathan B. , Hannon Gregory J. , Czech Benjamin
Published: August 2019

The PIWI-interacting RNA (piRNA) pathway is a conserved small RNA-based immune system that protects animal germ cell genomes from the harmful effects of transposon mobilization. InDrosophilaovaries, most piRNAs originate from dual-strand clusters, which generate piRNAs from both genomic strands. Dual-strand clusters use noncanonical transcription mechanisms. Although transcribed by RNA polymerase II, cluster transcripts lack splicing signatures and poly(A) tails. mRNA processing is important for general mRNA export mediated by nuclear export factor 1 (Nxf1). Although UAP56, a component of the transcription and export complex, has been implicated in piRNA precursor export, it remains unknown how dual-strand cluster transcripts are specifically targeted for piRNA biogenesis by export from the nucleus to cytoplasmic processing centers. Here we report that dual-strand cluster transcript export requires CG13741/Bootlegger and theDrosophilanuclear export factor family protein Nxf3. Bootlegger is specifically recruited to piRNA clusters and in turn brings Nxf3. We found that Nxf3 specifically binds to piRNA precursors and is essential for their export to piRNA biogenesis sites, a process that is critical for germline transposon silencing. Our data shed light on how dual-strand clusters compensate for a lack of canonical features of mature mRNAs to be specifically exported via Nxf3, ensuring proper piRNA production.
Balanced actions of protein synthesis and degradation in memory formation
Authors: Park Hyungju , Kaang Bong-Kiun
Published: August 2019

Storage of long-term memory requires not only protein synthesis but also protein degradation. In this article, we overview recent publications related to this issue, stressing that the balanced actions of protein synthesis and degradation are critical for long-term memory formation. We particularly focused on the brain-derived neurotrophic factor signaling that leads to protein synthesis; proteasome- and autophagy-dependent protein degradation that removes molecular constraints; the role of Fragile X mental retardation protein in translational suppression; and epigenetic modifications that control gene expression at the genomic level. Numerous studies suggest that an imbalance between protein synthesis and degradation leads to intellectual impairment and cognitive disorders.
microRNA mir-598-3p mediates susceptibility to stress enhancement of remote fear memory
Authors: Jones Meghan E. , Sillivan Stephanie E. , Jamieson Sarah , Rumbaugh Gavin , Miller Courtney A.
Published: August 2019

microRNAs (miRNAs) have emerged as potent regulators of learning, recent memory, and extinction. However, our understanding of miRNAs directly involved in regulating complex psychiatric conditions perpetuated by aberrant memory, such as in posttraumatic stress disorder (PTSD), remains limited. To begin to address the role of miRNAs in persistent memories, we performed small-RNA sequencing on basolateral amygdala (BLA) tissue and identified miRNAs altered by auditory fear conditioning (FC) one month after training. mir-598-3p, a highly conserved miRNA previously unstudied in the brain, was down-regulated in the BLA. Further decreasing BLA mir-598-3p levels did not increase strength of the remote fear memory. Given that stress is a critical component in PTSD, we next assessed the impact of stress and stress-enhanced fear learning (SEFL) on mir-598-3p levels, finding the miRNA is elevated in the BLA of male, but not female, mice susceptible to the effects of stress in SEFL. Accordingly, intra-BLA inhibition of mir-598-3p interfered with expression and extinction of the remote fear memory in male, but not female, mice. This effect could not be attributed to an anxiolytic effect of miRNA inhibition. Finally, bioinformatic analysis following quantitative proteomics on BLA tissue collected 30 d post-SEFL training identified putative mir-598-3p targets and related pathways mediating the differential susceptibility, with evidence for regulation of the actin cytoskeleton, the core mediator of structural plasticity. Taken together, the results suggest BLA mir-598-3p may be recruited by stress to mediate a critical switch from a salient remote fear memory to one that is enhanced and extinction-resistant.
Examining the contribution of histone modification to sex differences in learning and memory
Authors: Keiser Ashley A. , Wood Marcelo A.
Published: August 2019

The epigenome serves as a signal integration platform that encodes information from experience and environment that adds tremendous complexity to the regulation of transcription required for memory, beyond the directions encoded in the genome. To date, our understanding of how epigenetic mechanisms integrate information to regulate gene expression required for memory is primarily obtained from male derived data despite sex-specific life experiences and sex differences in consolidation and retrieval of memory, and in the molecular mechanisms that mediate these processes. In this review, we examine the contribution of chromatin modification to learning and memory in both sexes. We provide examples of how exposure to a number of internal and external factors influence the epigenome in sex-similar and sex-specific ways that may ultimately impact transcription required for memory processes. We also pose a number of key open questions and identify areas requiring further investigation as we seek to understand how histone modifying mechanisms shape memory in females.
The role of MeCP2 in learning and memory
Authors: Robinson Holly A. , Pozzo-Miller Lucas
Published: August 2019

Gene transcription is a crucial step in the sequence of molecular, synaptic, cellular, and systems mechanisms underlying learning and memory. Here, we review the experimental evidence demonstrating that alterations in the levels and functionality of the methylated DNA-binding transcriptional regulator MeCP2 are implicated in the learning and memory deficits present in mouse models of Rett syndrome and MECP2 duplication syndrome. The significant impact that MeCP2 has on gene transcription through a variety of mechanisms, combined with well-defined models of learning and memory, make MeCP2 an excellent candidate to exemplify the role of gene transcription in learning and memory. Together, these studies have strengthened the concept that precise control of activity-dependent gene transcription is a fundamental mechanism that ensures long-term adaptive behaviors necessary for the survival of individuals interacting with their congeners in an ever-changing environment.
Crystallographic insights into diamond-shaped 7M martensite in Ni–Mn–Ga ferromagnetic shape-memory alloys
Authors: Li Zong-Bin , Yang Bo , Zhang Yu-Dong , Esling Claude , Zhao Xiang , Zuo Liang
Published: August 2019

For Heusler-type Ni–Mn–Ga ferromagnetic shape-memory alloys, the configuration of the martensite variants is a decisive factor in achieving a large magnetic shape-memory effect through field-induced variant reorientation. Based upon the spatially resolved electron backscatter diffraction technique, the microstructural evolution associated with the martensitic transformation from austenite to seven-layered modulated (7M) martensite was investigated on a polycrystalline Ni53Mn22Ga25alloy. It was clearly shown that grain interior nucleation led to the formation of diamond-shaped 7M martensite within the parent austenite matrix. This diamond microstructure underwent further growth through an isotropic expansion with the coordinated outward movement of four side habit planes, followed by an anisotropic elongation with the forward extension of a type-I twin pair. A two-step growth model is proposed to describe the specific morphology and crystallography of 7M martensite. In addition, the habit planes were revealed to possess a stepped structure, with the {1 0 1}Aplane as the terrace and the {0 1 0}Aplane as the step. The characteristic combination of martensite variants and the underlying mechanism of self-accommodation in the martensitic transformation have been analysed in terms of the minimum total transformation strain, where the deformation gradient matrix was constructed according to the experimentally determined orientation relationship between the two phases. The present results may deepen the understanding of special martensite microstructures during the martensitic transformation in ferromagnetic shape-memory alloys.
Synthesis and structure of push–pull merocyanines based on barbituric and thiobarbituric acid
Authors: Bogdanov Georgii , Tillotson John P. , Bustos Jenna , Timofeeva Tatiana V.
Published: August 2019

Two compounds, 1,3-diethyl-5-{(2E,4E)-6-[(E)-1,3,3-trimethylindolin-2-ylidene]hexa-2,4-dien-1-ylidene}pyrimidine-2,4,6(1H,3H,5H)-trione or TMI, C25H29N3O3, and 1,3-diethyl-2-sulfanylidene-5-[2-(1,3,3-trimethylindolin-2-ylidene)ethylidene]dihydropyrimidine-4,6(1H,5H)-dione or DTB, C21H25N3O2S, have been crystallized and studied. These compounds contain the same indole derivative donor group and differ in their acceptor groups (in TMI it contains oxygen in the para position, and in DTB sulfur) and the length of the π-bridge. In both materials, molecules are packed in a herringbone manner with differences in the twist and fold angles. In both structures, the molecules are connected by weak C—H...O and/or C—H...S bonds.
Factors influencing farmers’ use of the warehouse receipt system in Indonesia
Authors: Gunawan Endro , Kuwornu John K.M. , Datta Avishek , Nguyen Loc T.
Published: August 2019

Purpose

The purpose of this paper is to examine the factors influencing Indonesian farmers’ use of the warehouse receipt system (WRS) and their choice of private and public warehouses.

Design/methodology/approach

Primary data were collected through questionnaires administered to 500 farmers in two districts, Subang and Cianjur, in West Java Province in Indonesia. Binary logit regression was employed to examine the factors influencing farmers’ use of the WRS. Binary and bivariate probit regressions were employed to determine the factors influencing farmers’ choice of private and public warehouses.

Findings

The empirical results of the binary logit regression revealed that age, land ownership, selling price, the use of the warehouse receipt as collateral security and the availability of transportation facility positively influenced farmers’ use of the WRS, whereas education, income, farm profit and participation in farmers’ group negatively influenced farmers’ use of the WRS. The results of the binary probit regressions revealed that profit, availability of insurance and processing facility positively influenced the farmers’ decision to use the private WRS, whereas education, production, selling price and distance from the farm to the warehouse negatively influenced farmers’ decision to use the private WRS. Age, education, selling price and distance from the farm to the warehouse positively influenced the farmers’ decision to use the public WRS, whereas production and availability of processing facility negatively influenced the decision of farmers to use the public WRS.

Practical implications

This study highlights the importance of education and government assistance regarding the provision of facilities and price indemnified insurance for successful implementation of the WRS.

Originality/value

This study provides an empirical contribution to the existing literature on the development of WRS in Indonesia. In terms of methods of analysis, previous studies used purely qualitative and descriptive methods, whereas this study employed econometric techniques (i.e. binary logit, binary probit and bivariate probit regressions) to examine the WRS in Indonesia. In addition, whereas previous studies explored the WRS in general, this study investigated the farmers’ use of the public and private warehouses in addition to exploring the WRS in general. Finally, the finding that the average annual profit of non-users was significantly higher than that of the users of the WRS is striking, and this could be attributed to the current challenges of the implementation of the WRS, including high transportation and warehouse rental costs.