bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripheral Biomarkers of Tobacco-Use Disorder: A Systematic Review
Authors: Newton Dwight F.
Published: August 2019

Introduction

Tobacco use disorder (TUD) is a major worldwide healthcare burden resulting in 7 million deaths annually. TUD has few approved cessation aids, all of which are associated a high rate of relapse within one year. Biomarkers of TUD severity, treatment response, and risk of relapse have high potential clinical utility to identify ideal responders and guide additional treatment resources.

Methods

A MEDLINE search was performed using the terms biomarkers, dihydroxyacetone phosphate, bilirubin, inositol, cotinine, adrenocorticotropic hormone, cortisol, pituitary-adrenal system, homovanillic acid, dopamine, pro-opiomelanocortin, lipids, lipid metabolism all cross-referenced with tobacco-use disorder.

Results

The search yielded 424 results, of which 57 met inclusion criteria. The most commonly studied biomarkers were those related to nicotine metabolism, the hypothalamic-pituitary-adrenal (HPA) axis, and cardiovascular (CVD) risk. Nicotine metabolism was most associated with severity of dependence and treatment response, where as HPA axis and CVD markers showed less robust associations with dependence and relapse risk.

Conclusions

Nicotine-metabolite ratio, cortisol, and atherogenicity markers appear to be the most promising lead biomarkers for further investigation, though the body of literature is still preliminary. Longitudinal, repeated-measures studies are required to determine the directionality of the observed associations and determine true predictive power of these biomarkers. Future studies should also endeavour to study populations with comorbid psychiatric disorders to determine differences in utility of certain biomarkers.
Genetically encoded cell-death indicators (GEDI) to detect an early irreversible commitment to neurodegeneration
Authors: Linsley Jeremy W. , Shah Kevan , Castello Nicholas , Chan Michelle , Haddad Dominic , Mancini Jay , Oza Viral , Wang Shijie , Javaherian Ashkan , Kokel David , Finkbeiner Steven
Published: August 2019

Cell death is a critical process that occurs normally in health and disease. However, its study is limited due to available technologies that only detect very late stages in the process or specific death mechanisms. Here, we report the development of a new fluorescent biosensor called genetically encoded death indicator (GEDI). GEDI specifically detects an intracellular Ca2+ level that cells achieve early in the cell death process and marks a stage at which cells are irreversibly committed to die. The time-resolved nature of GEDI delineates a binary demarcation of cell life and death in real time, reformulating the definition of cell death. We demonstrate that GEDI acutely and accurately reports death of rodent and human neurons in vitro, and show GEDI enables a novel automated imaging platform for single cell detection of neuronal death in vivo in zebrafish larvae. With a quantitative pseudo-ratiometric signal, GEDI facilitates high-throughput analysis of cell death in time lapse imaging analysis, providing the necessary resolution and scale to identify early factors leading to cell death in studies of neurodegeneration.
SHIFT: speedy histological-to-immunofluorescent translation of whole slide images enabled by deep learning
Authors: Burlingame Erik A. , McDonnell Mary , Schau Geoffrey F. , Thibault Guillaume , Lanciault Christian , Morgan Terry , Johnson Brett E. , Corless Christopher , Gray Joe W. , Chang Young Hwan
Published: August 2019

Spatially-resolved molecular profiling by immunostaining tissue sections is a key feature in cancer diagnosis, subtyping, and treatment, where it complements routine histopathological evaluation by clarifying tumor phenotypes. In this work, we present a deep learning-based method called speedy histological-to-immunofluorescent translation (SHIFT) which takes histologic images of hematoxylin and eosin-stained tissue as input, then in near-real time returns inferred virtual immunofluorescence (IF) images that accurately depict the underlying distribution of phenotypes without requiring immunostaining of the tissue being tested. We show that deep learning-extracted feature representations of histological images can guide representative sample selection, which improves SHIFT generalizability. SHIFT could serve as an efficient preliminary, auxiliary, or substitute for IF by delivering multiplexed virtual IF images for a fraction of the cost and in a fraction of the time required by nascent multiplexed imaging technologies.

KEY POINTS

Spatially-resolved molecular profiling is an essential complement to histopathological evaluation of cancer tissues.

Information obtained by immunofluorescence imaging is encoded by features in histological images.

SHIFT leverages previously unappreciated features in histological images to facilitate virtual immunofluorescence staining.

Feature representations of images guide sample selection, improving model generalizability.
PalaeoChip Arctic1.0: An optimised eDNA targeted enrichment approach to reconstructing past environments
Authors: Murchie Tyler J. , Kuch Melanie , Duggan Ana , Ledger Marissa L. , Roche Kévin , Klunk Jennifer , Karpinski Emil , Hackenberger Dirk , Sadoway Tara , MacPhee Ross , Froese Duane , Poinar Hendrik
Published: August 2019

Ancient environmental DNA has been established as a viable biomolecular proxy for tracking taxonomic presence through time in a local environment, even in the total absence of primary tissues. It is thought that sedimentary ancient DNA (sedaDNA) survives through mineral binding. And while these organo-mineral complexes likely facilitate long-term preservation, they also challenge our ability to release and isolate target molecules. Two limitations in sedaDNA extraction impede many palaeoenvironmental reconstructions: the post-extraction carryover of enzymatic inhibitors, and sedaDNA loss when attempting to reduce inhibitor co-elution. Here, we present an optimised eDNA targeted enrichment approach for reconstructing past environments. Our new extraction protocol with targeted enrichment averages a 14.6-fold increase in on-target plant and animal DNA compared to a commercial soil extraction kit, and a 22.6-fold increase compared to a PCR metabarcoding approach. To illustrate the effectiveness of the PalaeoChip Arctic1.0 protocol, we present results of plant and animal presence from permafrost samples and discuss new potential evidence for the late survival (ca. 9685 BP) of mammoth (Mammuthus sp.) and horse (Equus sp.) in the Klondike Region of Yukon, Canada. This approach translates to a more diverse and sensitive dataset with increased sequencing efficiency of ecologically informative sedaDNA.
Mercator: An R Package for Visualization of Distance Matrices
Authors: Abrams Zachary B. , Coombes Caitlin E. , Li Suli , Coombes Kevin R.
Published: August 2019

Unsupervised data analysis in many scientific disciplines is based on calculating distances between observations and finding ways to visualize those distances. These kinds of unsupervised analyses help researchers uncover patterns in large-scale data sets. However, researchers can select from a vast number of different distance metrics, each designed to highlight different aspects of different data types. There are also numerous visualization methods with their own strengths and weaknesses. To help researchers perform unsupervised analyses, we developed the Mercator R package. Mercator enables users to see important patterns in their data by generating multiple visualizations using different standard algorithms, making it particularly easy to compare and contrast the results arising from different metrics. By allowing users to select the distance metric that best fits their needs, Mercator helps researchers perform unsupervised analyses that use pattern identification through computation and visual inspection.

Availability and Implementation

Mercator is freely available at the Comprehensive R Archive Network (https://cran.r-project.org/web/packages/Mercator/index.html)

Contact

Kevin.Coombes@osumc.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
Flies exploit predictable perspectives and backgrounds to enhance iridescent signal salience and mating success
Authors: White Thomas E. , Vogel-Ghibely Nina , Butterworth Nathan J.
Published: August 2019

Communication requires both the encoding of information and its effective transmission, but little is known about display traits that primarily serve to enhance efficacy. Here we examined the visual courtships of Lispe cana, a cursorial fly that lives and mates in heterogeneous foreshores, and tested the prediction that males should seek to enhance signal salience and consequent fitness through the flexible choice of display locations. We show that courting males access the field of view of females by straddling them and holding their wings closed, before moving ahead to present their structurally coloured faces in ritualised dances. Males preferentially present these UV-white signals against darker backgrounds, and the magnitude of contrast predicts female attention, which in turn predict mating success. Our results demonstrate a striking interplay between the physical and attentional manipulation of receivers and reveal novel routes to the enhancement of signal efficacy in noisy environments.
EPIFANY – A method for efficient high-confidence protein inference
Authors: Pfeuffer Julianus , Sachsenberg Timo , Dijkstra Tjeerd M. H. , Serang Oliver , Reinert Knut , Kohlbacher Oliver
Published: August 2019

Accurate protein inference under the presence of shared peptides is still one of the key problems in bottom-up proteomics. Most protein inference tools employing simple heuristic inference strategies are efficient, but exhibit reduced accuracy. More advanced probabilistic methods often exhibit better inference quality but tend to be too slow for large data sets.

Here we present a novel protein inference method, EPIFANY, combining a loopy belief propagation algorithm with convolution trees for efficient processing of Bayesian networks. We demonstrate that EPIFANY combines the reliable protein inference of Bayesian methods with significantly shorter runtimes. On the 2016 iPRG protein inference benchmark data EPIFANY is the only tested method which finds all true-positive proteins at a 5% protein FDR without strict pre-filtering on PSM level, yielding an increase in identification performance (+10% in the number of true positives and +35% in partial AUC) compared to previous approaches. Even very large data sets with hundreds of thousands of spectra (which are intractable with other Bayesian and some non-Bayesian tools) can be processed with EPIFANY within minutes. The increased inference quality including shared peptides results in better protein inference results and thus increased robustness of the biological hypotheses generated.

EPIFANY is available as open-source software for all major platforms at https://OpenMS.de/epifany.
An ethnobotanical study of the genusElymus
Authors: Frawley Emma S. , Ciotir Claudia , Micke Brooke , Rubin Matthew J. , Miller Allison J.
Published: August 2019

Grains of domesticated grasses (Poaceae) have long been a global food source and constitute the bulk of calories in the human diet. Recent efforts to establish more sustainable agricultural systems have focused in part on the development of herbaceous, perennial crops. Perennial plants have extensive root systems that stabilize soil and absorb water and nutrients at greater rates than their annual counterparts; consequently, perennial grasses are important potential candidates for grain domestication. While most contemporary grass domesticates consumed by humans are annual plants, there are over 7,000 perennial grass species that remain largely unexplored for domestication purposes. Documenting ethnobotanical uses of wild perennial grasses could aid in the evaluation of candidate species forde novocrop development. The objectives of this study are 1) to provide an ethnobotanical survey of the grass genusElymus; and 2) to investigate floret size variation in species used by people.Elymusincludes approximately 150 perennial species distributed in temperate and subtropical regions, of which at least 21 taxa have recorded nutritional, medicinal, and/or material uses.Elymusspecies used for food by humans warrant pre-breeding and future analyses to assess potential utility in perennial agricultural systems.
Evolutionarily Conserved Transcription Factors Drive the Oxidative Stress Response in Drosophila
Authors: Ryan Sarah M. , Wildman Kaitie , Oceguera-Perez Briseida , Barbee Scott , Mortimer Nathan T. , Vrailas-Mortimer Alysia D.
Published: August 2019

As organisms are constantly exposed to the damaging effects of oxidative stress through both environmental exposure as well as internal metabolic processes, they have evolved a variety of mechanisms to cope with this stress. One such mechanism is the highly conserved p38 MAPK (p38K) pathway, which is known to be to post-translationally activated in response to oxidative stress resulting in the activation of downstream antioxidant targets. However, little is known about the role of p38K transcriptional regulation in response to oxidative stress. Therefore, we analyzed the p38K gene family across the genus Drosophila to identify conserved regulatory elements. We find that oxidative stress exposure results in increased p38K protein levels in multiple Drosophila species and is associated with increased oxidative stress resistance. We also find that the p38Kb genomic locus includes conserved binding sites for the AP-1 and lola-PT transcription factors. Accordingly, over-expression of these transcription factors in D. melanogaster is sufficient to induce transcription of p38Kb and enhances resistance to oxidative stress. We further find that the presence of a lola-PT binding site in the p38Kb locus of a given species is predictive of the species’ survival in response to oxidative stress. Through our comparative genomics approach, we have identified biologically relevant transcription factor binding sites that regulate the expression of p38Kb and are associated with resistance to oxidative stress. These findings reveal a novel mode of regulation for p38K genes and suggests that transcription may play as important a role in p38K mediated stress responses as post-translational modifications.

Significance Statement

Organisms encounter a variety of environmental stresses such as oxidative stress throughout their lifetime. Therefore, organisms have evolved a number of mechanisms to combat these stresses. In order to understand how these mechanisms evolved, we have compared the genomes of a diverse set of species across the genus Drosophila to examine the p38 MAPK stress response gene family. Our analysis was able to successfully predict transcription factors that not only regulate our target gene, p38Kb, but do so under different conditions to ensure an appropriate stress response. Therefore, we find that in addition to post-translational regulation, transcriptional regulation of signaling pathways may also play an important role in how organisms are able to adapt to stressful environments or respond to stress conditions as they arise. Furthermore, our comparative genomics approach may be utilized to identify transcriptional regulators of other highly conserved signaling pathways.
The chromosomal-level genome assembly and comprehensive transcriptomes of Chinese razor clam (Sinonovacula constricta) with deep-burrowing life style and broad-range salinity adaptation
Authors: Dong Yinghui , Zeng Qifan , Ren Jianfeng , Yao Hanhan , Ruan Wenbin , Lv Liyuan , He Lin , Xue Qinggang , Bao Zhenmin , Wang Shi , Lin Zhihua
Published: August 2019

Background

The Chinese razor clam, Sinonovacula constricta, is one of the commercially important marine bivalves with deep-burrowing lifestyle and remarkable adaptability of broad-range salinity. Despite its economic impact and representative of the less-understood deep-burrowing bivalve lifestyle, there are few genomic resources for exploring its unique biology and adaptive evolution. Herein, we reported a high-quality chromosomal-level reference genome of S. constricta, the first genome of the family Solenidae, along with a large amount of short-read/full-length transcriptomic data of whole-ontogeny developmental stages, all major adult tissues, and gill tissues under salinity challenge.

Findings

A total of 101.79 Gb and 129.73 Gb sequencing data were obtained with the PacBio and Illumina platforms, which represented approximately 186.63X genome coverage. In addition, a total of 160.90 Gb and 24.55 Gb clean data were also obtained with the Illumina and PacBio platforms for transcriptomic investigation. A de novo genome assembly of 1,340.13 Mb was generated, with a contig N50 of 689.18 kb. Hi-C scaffolding resulted in 19 chromosomes with a scaffold N50 of 57.99 Mb. The repeat sequences account for 50.71% of the assembled genome. A total of 26,273 protein-coding genes were predicted and 99.5% of them were annotated. Phylogenetic analysis revealed that S. constricta diverged from the lineage of Pteriomorphia at approximately 494 million years ago. Notably, cytoskeletal protein tubulin and motor protein dynein gene families are rapidly expanded in the S. constricta genome and are highly expressed in the mantle and gill, implicating potential genomic bases for the well-developed ciliary system in the S. constricta.

Conclusions

The high-quality genome assembly and comprehensive transcriptomes generated in this work not only provides highly valuable genomic resources for future studies of S. constricta, but also lays a solid foundation for further investigation into the adaptive mechanisms of benthic burrowing mollusks.
Characterizing upper extremity motor behavior in the first week after stroke
Authors: Barth Jessica , Geed Shashwati , Mitchell Abigail , Lum Peter S. , Edwards Dorothy F. , Dromerick Alexander W.
Published: August 2019

Background

Animal models of brain recovery identify the first days after lesioning as a time of great flux in sensorimotor function and physiology; these findings have implications for human stroke recovery. After rodent motor system lesioning, daily skill training in the less affected forelimb reduces skill acquisition in the more affected forelimb. We asked whether spontaneous human motor behaviors of the less affected upper extremity (UE) early after stroke resemble the animal training model, with the potential to suppress clinical recovery.

Methods

This prospective observational study used a convenience sample of patients <7 days after stroke (n=25) with a wide severity range; Controls were hospitalized for non-neurological conditions (n=12). Outcome measures were Accelerometry, Upper-Extremity Fugl-Meyer (UEFM), Action Research Arm Test (ARAT), Shoulder Abduction/ Finger Extension Test (SAFE), NIH Stroke Scale (NIHSS).

Results

Accelerometry indicated total paretic UE movement was reduced compared to controls, primarily due to a 44% reduction of bilateral UE use. Unilateral paretic movement was unchanged. Movement shifted to unilateral use of the nonparetic UE, which increased by 77%. Low correlations between movement time and motor performance prompted an exploratory factor analysis (EFA) revealing a 2-component solution; motor performance tests load on one component (motor performance) whereas accelerometry-derived variables load on a second non-orthogonal component (quantity of movement).

Conclusions

Early after stroke, spontaneous overall UE movement is reduced, and movement shifts to unilateral use of the nonparetic UE. Thus, spontaneously-arising UE motor behaviors early after stroke are potential substrates for two mechanisms associated with poorer motor outcomes in animal models: learned non-use and inhibition of motor recovery through training of the nonparetic side. Accurate UE motor assessment requires two independent constructs: motor performance and quantity of movement. These findings provide opportunities and measurement methods for studies to develop new behaviorally-based stroke recovery treatments that begin early after onset.
Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications
Authors: Soto-Mercado Viviana , Mendivil-Perez Miguel , Velez-Pardo Carlos , Lopera Francisco , Jimenez-Del-Rio Marlene
Published: August 2019

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies. Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intra- and extracellular Aβ42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys106-SH into DJ-1Cys106-SO3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the PSEN1 E280A mutation are a valid model of AD and provide important clues for the identification of targetable pathological molecules.
Level of completion along continuum of care for maternal and child health services and factors associated with it among women in Arba Minch Zuria Woreda, Gamo Zone, Southern Ethiopia: a community based cross-sectional study
Authors: Haile Dereje , Kondale Mekdes , Andarge Eshetu , Tunje Abayneh , Fikadu Teshale , Boti Nigussie
Published: August 2019

Background

Completion along continuum of care for maternal and newborn health(MNH) service like antenatal care, skilled birth attendance and postnatal care services is one of the currently recommended strategies to reduce both maternal and neonatal mortality to achieve the global target of ending preventable maternal and under five children’s mortality. Although studies on factors affecting each segment of MNH services were well documented in Ethiopia, there is a dearth of evidence on the level of continuum of care and factors associated with it. Thus, this study tries to fill this gap in the country in general and in the study area in particular.

Methods

A community-based cross sectional study was conducted among 438 postnatal women who gave births in the last one year in Arba Minch Health and Demographic Surveillance Site. The sample women were selected by using computer generated random numbers from the list of women who gone at least six-weeks after birth. A pre-tested structured interviewer-administered questionnaire was used for data collection. Data was entered and coded in Epi-data and analysed using SPSS software version 23. Binary logistic regression model was fitted to identify factors associated with the outcome variable.

Results

The overall completion along the continuum of care was 42(9.7%). The factors significantly associated with continuum of care completion were early antenatal booking (before 16 weeks) [AOR: 10.751, CI (5.095, 22.688], birth preparedness and complication readiness [AOR: 2.934, CI (1.414, 6.087), pre-pregnancy contraception utilization [AOR: 3.963, CI: 1.429,

10.990], employed women [AOR: 2.586, CI: ((1.245, 5.371))], and planned pregnancy [AOR: 3.494 CI :(1.068, 11.425)].

Conclusion

Completion along continuum of care was low in the study area. Thus, efforts in improving completion of the cares should focus on early booking during antenatal period, reducing unplanned pregnancy, and improvement on birth preparedness and complication readiness interventions.
Perturbation-based gene regulatory network inference to unravel oncogenic mechanisms
Authors: Morgan Daniel , Studham Matthew , Tjärnberg Andreas , Weishaupt Holger , Swartling Fredrik J. , Nordling Torbjörn E. M. , Sonnhammer Erik L.L.
Published: August 2019

The gene regulatory network (GRN) of human cells encodes mechanisms to ensure proper functioning. However, if this GRN is dysregulated, the cell may enter into a disease state such as cancer. Understanding the GRN as a system can therefore help identify novel mechanisms underlying disease, which can lead to new therapies. Reliable inference of GRNs is however still a major challenge in systems biology.

To deduce regulatory interactions relevant to cancer, we applied a recent computational inference framework to data from perturbation experiments in squamous carcinoma cell line A431. GRNs were inferred using several methods, and the false discovery rate was controlled by the NestBoot framework. We developed a novel approach to assess the predictiveness of inferred GRNs against validation data, despite the lack of a gold standard. The best GRN was significantly more predictive than the null model, both in crossvalidated benchmarks and for an independent dataset of the same genes under a different perturbation design. It agrees with many known links, in addition to predicting a large number of novel interactions from which a subset was experimentally validated. The inferred GRN captures regulatory interactions central to cancer-relevant processes and thus provides mechanistic insights that are useful for future cancer research.

Data available at GSE125958

Inferred GRNs and inference statistics available at https://dcolin.shinyapps.io/CancerGRN/ Software available at https://bitbucket.org/sonnhammergrni/genespider/src/BFECV/

Author Summary

Cancer is the second most common cause of death globally, and although cancer treatments have improved in recent years, we need to understand how regulatory mechanisms are altered in cancer to combat the disease efficiently. By applying gene perturbations and inference of gene regulatory networks to 40 genes known or suspected to have a role in cancer due to interactions with the oncogene MYC, we deduce their underlying regulatory interactions. Using a recent computational framework for inference together with a novel method for cross validation, we infer a reliable regulatory model of this system in a completely data driven manner, not reliant on literature or priors. The novel interactions add to the understanding of the progressive oncogenic regulatory process and may provide new targets for therapy.
Placebo-induced pain reduction is associated with inverse network coupling at rest
Authors: Wagner Isabella C. , Rütgen Markus , Hummer Allan , Windischberger Christian , Lamm Claus
Published: August 2019

Placebos can reduce pain by inducing beliefs in the effectiveness of an actually inert treatment. Such top-down effects on pain typically engage lateral and medial prefrontal regions, the insula, somatosensory cortex, as well as the thalamus and brainstem during pain anticipation or perception. Considering the level of large-scale brain networks, these regions spatially align with fronto-parietal/executive control, salience, and sensory-motor networks, but it is unclear if and how placebos alter interactions between them during rest. Here, we investigated how placebo analgesia affected intrinsic network coupling. Ninety-nine human participants were randomly assigned to a placebo or control group and underwent resting-state fMRI after pain processing. Results revealed inverse coupling between sensory-motor and salience-like networks in placebo but not control participants. Specifically, networks were centered on the bilateral somatosensory cortex, as well as on the brainstem, thalamus, striatal regions, dorsal and rostral anterior cingulate cortex, and the insula, respectively. Across participants, more negative between-network coupling was associated with lower individual pain intensity as assessed during a preceding pain task, but was unrelated to expectations of medication effectiveness in the placebo group. Altogether, these findings provide initial evidence that placebo analgesia affects the intrinsic communication between large-scale brain networks, even in the absence of pain. We suggest a model where placebo analgesia increases activation within a descending pain-modulatory network, segregating it from somatosensory regions that might code for painful experiences.

Highlights

Placebo analgesia affects resting-state connectivity between networks.

Salience-related and somatosensory regions are negatively coupled at rest.

This coupling is negative following placebo, but not in control participants.

More negative between-network coupling is related to lower pain intensity.
Volumetric Lissajous Confocal Microscopy
Authors: Deguchi Takahiro , Bianchini Paolo , Palazzolo Gemma , Oneto Michele , Diaspro Alberto , Duocastella Martí
Published: August 2019

Dynamic biological systems present challenges to existing three-dimensional (3D) optical microscopes because of their continuous temporal and spatial changes. Most techniques are based on rigid architectures, as in confocal microscopy, where a laser beam is sequentially scanned at a predefined spatial sampling rate and pixel dwell time. Here, we developed volumetric Lissajous confocal microscopy to achieve unsurpassed 3D scanning speed with a tunable sampling rate. The system combines an acoustic liquid lens for continuous axial focus translation with a resonant scanning mirror. Accordingly, the excitation beam follows a dynamic Lissajous trajectory enabling sub-millisecond acquisitions of image series containing 3D information at a sub-Nyquist sampling rate. By temporal accumulation and/or advanced interpolation algorithms, volumetric imaging rate is selectable using a post-processing step at the desired spatiotemporal resolution for events of interest. We demonstrate multicolor and calcium imaging over volumes of tens of cubic microns with acquisition speeds up to 5 kHz.
Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ Channel
Authors: Nematian-Ardestani Ehsan , Abd-Wahab M. Firdaus , Chatelain Franck C. , Sun Han , Schewe Marcus , Baukrowitz Thomas , Tucker Stephen J
Published: August 2019

Two-pore domain (K2P) K+ channels have many important physiological functions. However, the functional properties of the TWIK-1 (K2P1.1/KCNK1) K2P channel remain poorly characterized because heterologous expression of this ion channel yields only very low levels of functional activity. Several underlying reasons have been proposed, including TWIK-1 retention in intracellular organelles, inhibition by post-translational sumoylation, a hydrophobic barrier within the pore, and a low open probability of the selectivity filter (SF) gate. By evaluating these various potential mechanisms, we found that the latter dominates the low intrinsic functional activity of TWIK-1. Investigating the underlying mechanism, we observed that the low activity of the SF gate appears to arise from the inefficiency of K+ in stabilizing an active (i.e. conductive) SF conformation. In contrast, other permeant ion species, such as Rb+, NH4+, and Cs+, strongly promoted a pH-dependent activated conformation. Furthermore, many K2P channels are activated by membrane depolarization via a SF-mediated gating mechanism, but we found here that only very strong, non-physiological depolarization produces voltage-dependent activation of heterologously expressed TWIK-1. Remarkably, we also observed that TWIK-1 Rb+ currents are potently inhibited by intracellular K+ (IC50 = 2.8 mM). We conclude that TWIK-1 displays unique SF gating properties among the family of K2P channels. In particular, the apparent instability of the conductive conformation of the TWIK-1 SF in the presence of K+ appears to dominate the low levels of intrinsic functional activity observed when the channel is expressed at the cell surface.
Single Cell RNAseq Reveals A Critical Role of Chloride Channels in Airway Development
Authors: He Mu , Wu Bing , Le Daniel D. , Ye Wenlei , Sinclair Adriane W. , Padovano Valeria , Chen Yuzhang , Li Kexin , Sit Rene , Tan Michelle , Caplan Michael J. , Neff Norma , Jan Yuh Nung , Darmanis Spyros , Jan Lily Y.
Published: August 2019

The conducting airway forms a protective mucosal barrier and is the primary target of airway disorders. To better understand how airway developmental programs are established to support air breathing and barrier functions, we constructed a single-cell atlas of the human and mouse developing trachea. In this study, we uncover hitherto unrecognized heterogeneity of cell states with distinct differentiation programs and immune features of the developing airway. In addition, we find ubiquitous expression ofCFTRandANO1/TMEM16Achloride channels in the embryonic airway epithelium. We show that genetic inactivation of TMEM16A leads to airway defects commonly seen in cystic fibrosis patients with deficient CFTR, alters the differentiation trajectory of airway basal progenitors, and results in mucus cell hyperplasia and aberrant epithelial antimicrobial expression. Together, our study illuminates conserved developmental features of the mammalian airway and implicates chloride homeostasis as a key player in regulating mucosal barrier formation and function relevant to early onset airway diseases.
Collective interactions augment influenza A virus replication in a host-dependent manner
Authors: Phipps Kara L. , Ganti Ketaki , Jacobs Nathan T. , Lee Chung-Young , Carnaccini Silvia , White Maria C. , Manandhar Miglena , Pickett Brett E. , Tan Gene S. , Ferreri Lucas M. , Perez Daniel R. , Lowen Anice C.
Published: August 2019

Infection with a single influenza A virus (IAV) is only rarely sufficient to initiate productive infection. Here, we exploit both single-cell approaches and whole-animal systems to show that IAV reliance on multiple infection can form an important species barrier to infection. Namely, we find that H9N2 subtype viruses representative of those circulating widely at the poultry-human interface exhibit acute dependence on collective interactions in mammalian systems. This need for multiple infection is greatly reduced in the natural host. Quantification of incomplete viral genomes showed that their complementation accounts for the more moderate reliance on coinfection seen in avian cells, but not the added reliance seen in mammalian cells. This finding suggests an additional form of virus-virus interaction is needed to support infection in mammalian cells. Genetic mapping implicated the PA gene segment as a major driver of this phenotype and quantification of viral RNA synthesis indicated that both replication and transcription were affected. These findings indicate that multiple distinct mechanisms underlie IAV reliance on multiple infection and underscore the importance of virus-virus interactions in IAV infection, evolution and emergence.
Stability Analysis of a Bulk-Surface Reaction Model for Membrane-Protein Clustering
Authors: Stolerman Lucas M. , Getz Michael , Llewellyn Smith Stefan G. , Holst Michael , Rangamani Padmini
Published: August 2019

Protein aggregation on the plasma membrane (PM) is of critical importance to many cellular processes such as cell adhesion, endocytosis, fibrillar conformation, and vesicle transport. Lateral diffusion of protein aggregates or clusters on the surface of the PM plays an important role in governing their heterogeneous surface distribution. However, the stability behavior of the surface distribution of protein aggregates remains poorly understood. Therefore, understanding the spatial patterns that can emerge on the PM solely through protein-protein interaction, lateral diffusion, and feedback is an important step towards a complete description of the mechanisms behind protein clustering on the cell surface. In this work, we investigate the pattern formation of a reaction-diffusion model that describes the dynamics of a system of ligand-receptor complexes. The purely diffusive ligand in the cytosol can bind receptors in the PM, and the resultant ligand-receptor complexes not only diffuse laterally but can also form clusters resulting in different oligomers. Finally, the largest oligomers recruit ligands from the cytosol in a positive feedback. From a methodological viewpoint, we provide theoretical estimates for diffusion-driven instabilities of the protein aggregates based on the Turing mechanism. Our main result is a threshold phenomenon, in which a sufficiently high recruitment of ligands promotes the input of new monomeric components and consequently drives the formation of a single-patch spatially heterogeneous steady-state.
Drought sensitivity of leaflet growth, biomass accumulation, and resource partitioning predicts yield in common bean
Authors: Hageman Amber , Urban Milan O. , Van Volkenburgh Elizabeth
Published: August 2019

While drought limits yield largely by its impact on photosynthesis and therefore biomass accumulation, biomass is not the strongest predictor of yield under drought. Instead, resource partitioning efficiency, measured by how much total pod weight is contained in seeds at maturity (Pod Harvest Index), is the stronger correlate in Phaseolus vulgaris. Using 20 field-grown genotypes, we expanded on this finding by pairing yield and resource partitioning data with growth rates of leaflets and pods. We hypothesized that genotypes which decreased partitioning and yield most under drought would also have strongest decreases in growth rates. We found that while neither leaflet nor pod growth rates correlated with seed yield or partitioning, impacts to leaflet growth rates under drought correlate with impacts to yield and partitioning. As expected, biomass production correlated with yield, yet correlations between the decreases to these two traits under drought were even stronger. This suggests that while biomass contributes to yield, biomass sensitivity to drought is a stronger predictor. Lastly, under drought, genotypes may achieve similar canopy biomass yet different yields, which can be explained by higher or lower partitioning efficiencies. Our findings suggest that inherent sensitivity to drought may be used as a predictor of yield.

HIGHLIGHT

In common bean, higher biomass accumulation under drought alone does not guarantee higher yield, as maintenance of higher growth rates and partitioning processes act as an additional requirement.
Genome-wide analysis of transcriptional bursting-induced noise in mammalian cells
Authors: Ochiai Hiroshi , Hayashi Tetsutaro , Umeda Mana , Yoshimura Mika , Harada Akihito , Shimizu Yukiko , Nakano Kenta , Saitoh Noriko , Kimura Hiroshi , Liu Zhe , Yamamoto Takashi , Okamura Tadashi , Ohkawa Yasuyuki , Nikaido Itoshi
Published: August 2019

Transcriptional bursting is stochastic activation and inactivation of promoters, leading to discontinuous production of mRNA, and is considered to be a contributing factor to cell-to-cell heterogeneity in gene expression. However, it remains elusive how the kinetic properties of transcriptional bursting (e.g., burst size, burst frequency, and noise induced by transcriptional bursting) are regulated in mammalian cells. In this study, we performed a genome-wide analysis of transcriptional bursting in mouse embryonic stem cells (mESCs) using single-cell RNA-sequencing. We found that the kinetics of transcriptional bursting was determined by a combination of promoter and gene body binding proteins, including polycomb repressive complex 2 and transcription elongation-related factors. Furthermore, large-scale CRISPR-Cas9-based screening and functional analysis revealed that the Akt/MAPK signaling pathway regulated bursting kinetics by modulating transcription elongation efficiency. These results uncover key molecular mechanisms underlying transcriptional bursting and cell-to-cell gene expression noise in mammalian cells.
Emodin Attenuates Renal Interstitial Fibrosis via Regulation of TIMP1/MM9 Pathway in Rats
Authors: Li Dongmei , Zhang Qingchuan , Lou Yujiao , He Chunfeng , Gu Renze , Liu Wei
Published: August 2019

Emodin has a variety of pharmacological functions including anti-bacterial infection, anti-inflammatory, anti-oxidation, anti-tumor, regulation of gastrointestinal activities and anti-hepatic and lung fibrosis. However, the role of emodin in the regulation of renal interstitial fibrosis(RIF) remains poorly understood. In this study, we investigated the regulation of emodin in RIF and revealed the underlying molecular mechanisms. We established a unilateral ureter obstruction(UUO) model to simulate renal interstitial fibrosis in rats. We found that UUO rats were observed a large amount of inflammatory cell infiltration, more fibroblast proliferation, collagen fiber proliferation. Furthermore, we demonstrated that the up-regulation of TIMP1 and down-regulation of MMP9 were related to renal fibrosis. However, those phenomena in emodin-treated UUO rats were ameliorated. Collectively, our results provide new insights into the treatment of RIF and suggest that the TIMP1/MM9 signaling axis may be a potential therapeutic target for RIF.
Translating from cancer to the brain: regulation of protein synthesis by eIF4F
Authors: Kats Ilona R. , Klann Eric
Published: August 2019

Formation of eukaryotic initiation factor 4F (eIF4F) is widely considered to be the rate-limiting step in cap-dependent translation initiation. Components of eIF4F are often up-regulated in various cancers, and much work has been done to elucidate the role of each of the translation initiation factors in cancer cell growth and survival. In fact, many of the basic mechanisms describing how eIF4F is assembled and how it functions to regulate translation initiation were first investigated in cancer cell lines. These same eIF4F translational control pathways also are relevant for neuronal signaling that underlies long-lasting synaptic plasticity and memory, and in neurological diseases where eIF4F and its upstream regulators are dysregulated. Although eIF4F is important in cancer and for brain function, there is not always a clear path to use the results of studies performed in cancer models to inform one of the roles that the same translation factors have in neuronal signaling. Issues arise when extrapolating from cell lines to tissue, and differences are likely to exist in how eIF4F and its upstream regulatory pathways are expressed in the diverse neuronal subtypes found in the brain. This review focuses on summarizing the role of eIF4F and its accessory proteins in cancer, and how this information has been utilized to investigate neuronal signaling, synaptic function, and animal behavior. Certain aspects of eIF4F regulation are consistent across cancer and neuroscience, whereas some results are more complicated to interpret, likely due to differences in the complexity of the brain, its billions of neurons and synapses, and its diverse cell types.
Effect of the third undulator field harmonic on spontaneous and stimulated undulator radiation
Authors: Zhukovsky K. V.
Published: August 2019

The effect of undulator field harmonics on spontaneous and stimulated undulator radiation, both on and off the undulator axis, is studied. Bessel factors for the undulators with field harmonics have been analytically calculated and numerically verified. The influence of the third undulator field harmonic on single-pass free-electron laser radiation is explored. Harmonic generation at the LCLS and SPring-8 free-electron lasers is modeled and analyzed.
Synthesis and crystal structure of 1,3-bis(4-hydroxyphenyl)-1H-imidazol-3-ium chloride
Authors: Mertens R. Tyler , Parkin Sean R. , Awuah Samuel G.
Published: August 2019

Imidazolium salts are common building blocks for functional materials and in the synthesis of N-heterocyclic carbene (NHC) as σ-donor ligands for stable metal complexes. The title salt, 1,3-bis(4-hydroxyphenyl)-1H-imidazol-3-ium chloride (IOH·Cl), C15H13N2O2+·Cl−, is a new imidazolium salt with a hydroxy functionality. The synthesis of IOH·Cl was achieved in high yieldviaa two-step procedure involving a diazabutadiene precursor followed by ring closure using trimethylchlorosilane and paraformaldehyde. The structure of IOH·Cl consists of a central planar imidazolium ring (r.m.s. deviation = 0.0015 Å), with out-of-plane phenolic side arms. The dihedral angles between the 4-hydroxyphenyl substituents and the imidazole ring are 55.27 (7) and 48.85 (11)°. In the crystal, O—H...Cl hydrogen bonds connect the distal hydroxy groups and Cl−anions in adjacent asymmetric units, one related by inversion (−x + 1, −y + 1, −z + 1) and one by then-glide (x − {1\over 2}, −y + {1\over 2},z − {1\over 2}), with donor–acceptor distances of 2.977 (2) and 3.0130 (18) Å, respectively. The phenolic rings are each π–π stacked with their respective inversion-related [(−x + 1, −y + 1, −z + 1) and (−x, −y + 1, −z + 1)] counterparts, with interplanar distances of 3.560 (3) and 3.778 (3) Å. The only other noteworthy intermolecular interaction is an O...O (not hydrogen bonded) close contact of 2.999 (3) Å between crystallographically different hydroxy O atoms on translationally adjacent molecules (x + 1,y,x + 1).
The fumarate salts of the N-isopropyl-N-methyl derivatives of DMT and psilocin
Authors: Chadeayne Andrew R. , Pham Duyen N. K. , Golen James A. , Manke David R.
Published: August 2019

The solid-state structures of the salts of two substituted tryptamines, namely N-isopropyl-N-methyltryptaminium (MiPT) fumarate {systematic name: [2-(1H-indol-3-yl)ethyl](methyl)propan-2-ylazanium 3-carboxyprop-2-enoate}, C14H21N2
+·C4H3O4
−, and 4-hydroxy-N-isopropyl-N-methyltryptaminium (4-HO-MiPT) fumarate monohydrate {systematic name: [2-(4-hydroxy-1H-indol-3-yl)ethyl](methyl)propan-2-ylazanium 3-carboxyprop-2-enoate monohydrate}, C14H21N2O+·C4H3O4
−·H2O, are reported. Both salts possess a protonated tryptammonium cation and a 3-carboxyacrylate (hydrogen fumarate) anion in the asymmetric unit; the 4-HO-MiPT structure also contains a water molecule of crystallization. Both cations feature disorder of the side chain over two orientations, in a 0.630 (3):0.370 (3) ratio for MiPT and a 0.775 (5):0.225 (5) ratio for 4-HO-MiPT. In both extended structures, N—H...O and O—H...O hydrogen bonds generate infinite two-dimensional networks.
6-Nitro-1,3-benzoxazole-2(3H)-thione
Authors: Jebbari Said , Abdellatif El Kihel , Ahbala Mustapha , Saadi Mohamed , El Ammari Lahcen
Published: August 2019

In the title compound, C7H4N2O3S, the dihedral angle between the fused ring system (r.m.s. deviation = 0.008 Å) and the nitro group at the 6-position is 7.3 (2)°. In the crystal, bifurcated N—H...(O,O) hydrogen bonds link the molecules into [010] chains. The chains are cross-linked by π–π stacking interactions to form (001) sheets.