bluuebunny/crossref_metadata_2025 huggingface dataset:
QTL-Seq Identifies QTL for Relative Electrical Conductivity Associated with Heat Tolerance in Bottle Gourd (Lagenaria Siceraria)
Authors: Song Hui , Huang Yunping , Gu Binquan
Published: December 2019

Heat is a major abiotic stressor seriously affects watermelon produce; however, its effects may be mitigated through grafting onto heat tolerant bottle gourd rootstock. To understand the genetic basis and select reliable markers are necessary in the variety breeding process. In this paper, the relative electric conductivity (REC) was used as a visual indicator for heat stress to study the genetics and SNP marker of heat tolerance in bottle gourd via QTL-seq approach. The results showed that recessive inheritance and a major QTL locus controlled REC related to heat tolerance. Seven heat-tolerant loci (qHT1.1, qHT2.1, qHT2.2, qHT5.1, qHT6.1, qHT7.1, andqHT8.1) exhibited high Δ(SNP-index) values (ranging from 0.19-0.38), and of these, the greatest value (0.32, P < 0.01) and greatest number of detected SNPs (9052) were found in chromosome 2 atqHT2.1region (11.03 - 19.25 Mb);qHT2.1was taken as a promising major QTL for heat tolerance in bottle gourd. A total of 34 putative candidate genes related to heat stress were detected within theqHT2.1region. Three polymorphic SNPs (BG_GLEAN_10022642, BG_GLEAN_10022727, and BG_GLEAN_10022589) that are involved in pollen sterility, intracellular transport, and signal recognition were validated and exhibited significant marker-trait association that could be used in heat tolerant molecular breeding for bottle gourd. TheqHT2.1region is an important finding can be used for fine mapping and discovering new genes associated with heat tolerance in bottle gourd.
Tackling misinformation in agriculture
Authors: Stroud Jacqueline L.
Published: December 2019

Farmers are encouraged to embrace digital media to fill the voids caused by the privatisation of Agricultural Knowledge and Information Systems. Widespread sustainable agriculture misinformation undermines the role of science, participatory research, and evidence-based decision making. Simply providing information is insufficient, misinformation is tackled by creating a network that fosters accurate information exchange. Here I used Twitter and blended learning technologies to create a research partnership with farmers based on their beliefs that earthworms indicate good soils management. Through co-design, farmers transformed this symbol into a systematic field observation network, assessing earthworm populations to the ecological group level. Our community (#WorldWormWeek) revealed the falsehoods in misinformation such as: “Farmers around the world have been turning their fields into subterranean deserts”. This social learning network was resilient to further misinformation by the national press. Real data trends were fundamentally different to predictions made by science advancing models of global earthworm populations. Anecic earthworms (including middens) were absent in 1 in 5 fields, directly informing management practices to avoid soil biological pitfalls in no-tillage adoption. Simplistic earthworm counts to indicate soil health are rendered obsolete, a depth of information exchange can be achieved by building science-farmer partnerships using digital communications and co-designed frameworks. However, the scientific consensus, whilst generally positive about the research impact, revealed 42 % scientists rated this research as “not at all useful” or “slightly useful” to scientists. This reveals the hopeless situation where the co-production of knowledge and feedback loop linking farming-science is not broadly considered ‘science advancing’, and brought #Wormscience to an end. The next step would have been to optimizeLumbricus terrestrisbiocontrol actions targeting the soil-borne crop pathogenFusariumspp. and detoxification of its mycotoxins, to reduce fungicide dependency in staple crop production; aligned with societal sustainable agriculture aspirations.
QTL Mapping and integration as well as candidate gene prediction for branch number in soybean
Authors: Yang Yuhua , Lei Yang , Bai zhiyuan , Wei Yichao , Zhang Ruijun
Published: December 2019

Branch number is an important factor that affects crop plant architecture and yield in soybean. With the aim of elucidating the genetic basis of branch number, we identified 10 consensus quantitative trait loci (QTLs) through preliminary mapping, which were on chromosome A1, B2, C1, C2, D1a, D1b, F, L and N, explained 0.3-33.3% of the phenotypic variance. Of these, three QTLs were identical to previously identified ones, whereas the other seven were novel. In addition, one major QTL- qBN.C2 (R 2 =33.3%) was detected in all three environments and another new major QTL- qBN.N (R 2 =19.6%) was detected in two environments (Taiyuan 2017 and Taiyuan 2018), but only in Taiyuan. Thus, the QTL × environment interaction analysis confirmed that QTL- qBN.N was strongly affected by the environment. We compared the physical positions of the QTL intervals of the candidate genes potentially involved in branching development, and five orthologous genes were ultimately selected and related to the establishment of axillae meristem organization and lateral organs, qBN.A1 (SoyZH13_05G177000.m1), qBN.C2 (SoyZH13_06G176500.m1, SoyZH13_06G185600.m1), and qBN.D1b-1 (SoyZH13_02G035400.m1, SoyZH13_02G070000.m3). The results of our study reveal a complex and relatively complete genetic architecture and can serve as a basis for the positional gene cloning of branch number in soybean.
Distance preserving dimension reduction with local-topology based scaling for improved classification of Biomedical data-sets
Authors: Khosla Karaj , Jha Indra Prakash , Kumar Vibhor
Published: December 2019

Dimension reduction is often used for several procedures of analysis of high dimensional biomedical data-sets such as classification or outlier detection. To improve performance of such data-mining steps, preserving both distance information and local topology among data-points could be more useful than giving priority to visualisation in low dimension. Therefore, we introduce topology preserving distance scaling (TPDS) to augment dimension reduction method meant to reproduce distance information in higher dimension. Our approach involves distance inflation to preserve local topology to avoid collapse during distance preservation based optimisation. Applying TPDS on diverse biomedical data-sets revealed that besides providing better visualisation than typical distance preserving methods, TPDS leads to better classification of data points in reduced dimension. For data-sets with outliers, the approach of TPDS also proves to be useful, even for purely distance-preserving method for achieving better convergence.
Validation of a Mathematical Model of Cancer Incorporating Spontaneous and Induced Evolution to Drug Resistance
Authors: Gevertz Jana L. , Greene James M. , Sontag Eduardo D.
Published: December 2019

This paper continues the study of a model which was introduced in earlier work by the authors to study spontaneous and induced evolution to drug resistance under chemotherapy. The model is fit to existing experimental data, and is then validated on additional data that had not been used when fitting. In addition, an optimal control problem is studied numerically.
Stimulus dependent relationships between behavioral choice and sensory neural responses
Authors: Chicharro Daniel , Panzeri Stefano , Haefner Ralf M.
Published: December 2019

Understanding the relationship between trial-to-trial variability in neural responses of sensory areas and behavioral choices is fundamental to elucidate the mechanisms of perceptual decision-making. In two-choice tasks, activity-choice co-variations have traditionally been quantified with choice probabilities (CP). It has been so far commonly assumed that choice-related neural signals are separable from stimulus-driven responses, which has led to characterizing activity-choice covariations only with a single CP value estimated combining trials from all stimulus levels. In this work we provide theoretical and experimental evidence for the stimulus dependence of the relationship between neural responses and behavioral choices. We derived a general analytical CP expression for this dependency under the general assumption that a decision threshold converts an internal stimulus estimate into a binary choice. This expression predicts a stereotyped threshold-induced CP modulation by the stimulus information content. We reanalyzed data from Britten et al. (1996) and found evidence of this modulation in the responses of macaque MT cells during a random dot discrimination task. Moreover, we developed new methods of analysis that allowed us to further identify a richer structure of cell-specific CP stimulus dependencies. Finally, we capitalised on this progress to develop new generalized linear models (GLMs) with stimulus-choice interaction terms, which show a higher predictive power and lead to a more precise assessment of how much each neuron is stimulus- or choice-driven, hence allowing a more accurate comparison across areas or cell types. Our work suggests that characterizing the patterns of stimulus dependence of choice-related signals is essential to properly determine how neurons in different areas contribute to linking sensory representations to perceptual decisions.
Optimal evolutionary control for artificial selection on molecular phenotypes
Authors: Nourmohammad Armita , Eksin Ceyhun
Published: December 2019

Controlling an evolving population is an important task in modern molecular genetics, including directed evolution for improving the activity of molecules and enzymes, in breeding experiments in animals and in plants, and in devising public health strategies to suppress evolving pathogens. An optimal intervention to direct evolution should be designed by considering its impact over an entire stochastic evolutionary trajectory that follows. As a result, a seemingly suboptimal intervention at a given time can be globally optimal as it can open opportunities for desirable actions in the future. Here, we propose a feedback control formalism to devise globally optimal artificial selection protocol to direct the evolution of molecular phenotypes. We show that artificial selection should be designed to counter evolutionary tradeoffs among multi-variate phenotypes to avoid undesirable outcomes in one phenotype by imposing selection on another. Control by artificial selection is challenged by our ability to predict molecular evolution. We develop an information theoretical framework and show that molecular time-scales for evolution under natural selection can inform how to monitor a population in order to acquire sufficient predictive information for an effective intervention with artificial selection. Our formalism opens a new avenue for devising artificial selection methods for directed evolution of molecular functions.
Live and inanimate predator-associated cues suppress the population of sap-feeding prey and induce polyphenism
Authors: Khudr Mouhammad Shadi , Dobberke Tabea , Buzhdygan Oksana Y. , Wurst Susanne
Published: December 2019

Non-consumptive effect of predation is a well-researched subject of which certain non-consumptive and predator-mimetic facets are yet to be investigated in plant-parasite systems

One clone of the green peach aphidMyzus persicae(Sulzer), raised on a model cropBrassica oleracea(L.), was exposed to different regimes of risks associated with ladybirdCoccinella septempunctata(L.). This encompassed consumption, consumption alternated by non-consumptive effects, isolated predators, dead predator, predator dummy, as well as dummy, plants or soil cued with predator-borne suspension, and predator removal (exposure to plants previously visited and marked by a predator).

Over time, the respective risk regimes variably negatively impacted the prey population; the corpses, cued plants and dummies had considerable persistent negative effects on aphid reproductive success, contrary to the observation under predator removal. By the end of the experiment, polyphenism (winged morph production) also differed and was animated under the presence of a starved isolated predator; but faded when a predator corpse was present; and vanished under the dummy. Our findings, in this model aphid-crop system, contribute to the rapidly developing area of the ecology of fear, as we provide insights and novel means for aphid management that merit further examination across different eco-agricultural contexts.
UPϕ phages, a new group of filamentous phages found in several members ofEnterobacteriales
Authors: Shapiro Jason W. , Putonti Catherine
Published: December 2019

Filamentous phages establish chronic infections in their bacterial hosts, and new phages are secreted by infected bacteria for multiple generations, typically without causing host death. Often, these viruses integrate in their host’s genome by co-opting the host’s XerCD recombinase system. In several cases, these viruses also encode genes that increase bacterial virulence in plants and animals. Here, we describe a new filamentous phage, UPϕ901, which we originally found integrated in a clinical isolate of uropathogenicEscherichia coli. UPϕ901 and closely related phages can be found in published genomes of over 200 other bacteria, including strains ofCitrobacter koseri,Salmonella enterica,Yersinia enterocolitica, andKlebsiella pneumoniae. Its closest relatives are consistently found in urine or in the blood and feces of patients with urinary tract infections. More distant relatives can be found in isolates from other environments, including sewage, water, soil, and contaminated food. Each of these phages, which we collectively call “UPϕ viruses,” also harbors two novel genes of unknown function.
Serotonergic Axons as Fractional Brownian Motion Paths: Insights into the Self-organization of Regional Densities
Authors: Janušonis Skirmantas , Detering Nils , Metzler Ralf , Vojta Thomas
Published: December 2019

All vertebrate brains contain a dense matrix of thin fibers that release serotonin (5-hydroxytryptamine), a neurotransmitter that modulates a wide range of neural, glial, and vascular processes. Perturbations in the density of this matrix have been associated with a number of mental disorders, including autism and depression, but its self-organization and plasticity remain poorly understood. We introduce a model based on reflected Fractional Brownian Motion (FBM), a rigorously defined stochastic process, and show that it recapitulates some key features of regional serotonergic fiber densities. Specifically, we use supercomputing simulations to model fibers as FBM-paths in two-dimensional brain-like domains and demonstrate that the resultant steady state distributions approximate the fiber distributions in physical brain sections immunostained for the serotonin transporter (a marker for serotonergic axons in the adult brain). We suggest that this framework can support predictive descriptions and manipulations of the serotonergic matrix and that it can be further extended to incorporate the detailed physical properties of the fibers and their environment.
Touch-induced Mechanical Strain in Somatosensory Neurons is Independent of Extracellular Matrix Mutations inC. elegans
Authors: Nekimken Adam L. , Pruitt Beth L. , Goodman Miriam B.
Published: December 2019

Cutaneous mechanosensory neurons are activated by mechanical loads applied to the skin, and these stimuli are proposed to generate mechanical strain within sensory neurons. Using a microfluidic device to deliver controlled stimuli to intact animals and large, immobile, and fluorescent protein-tagged mitochondria as fiducial markers in the touch receptor neurons (TRNs), we visualized and measured touch-induced mechanical strain inC. elegansworms. At steady-state, touch stimuli sufficient to activate TRNs induce an average strain of 3.1% at the center of the actuator and this strain decays to near zero at the edges of the actuator. We also measured strain in animals carrying mutations affecting links between the extracellular matrix (ECM) and the TRNs but could not detect any differences in touch-induced mechanical strain between wild-type and mutant animals. Collectively, these results demonstrate that touching the skin induces local mechanical strain in intact animals and suggest that a fully intact ECM is not essential for transmitting mechanical strain from the skin to cutaneous mechanosensory neurons.
Evolution of olfactory receptors tuned to mustard oils in herbivorous Drosophilidae
Authors: Matsunaga Teruyuki , Reisenman Carolina E. , Goldman-Huertas Benjamin , Brand Philipp , Miao Kevin , Suzuki Hiromu C. , Verster Kirsten I. , Ramírez Santiago R. , Whiteman Noah K.
Published: December 2019

The diversity of herbivorous insects is attributed to their propensity to specialize on toxic plants. In an evolutionary twist, toxins betray the identity of their bearers when herbivores co-opt them as cues for host-plant finding, but the mechanisms underlying this process are poorly understood. We focused onScaptomyza flava, an herbivorous drosophilid specialized on isothiocyanate (ITC)-producing (Brassicaceae) plants, and identifiedOr67bparalogs that were triplicated as mustard-specific herbivory evolved. Using heterologous systems for the expression of olfactory receptors, we found thatS. flavaOr67bs, but not homologs from microbe-feeding relatives, responded selectively to ITCs, each paralog detecting different ITC subsets. Consistent with this,S. flavawas attracted to ITCs, as wasDrosophila melanogasterexpressingS. flavaOr67b3 in the homologousOr67bolfactory circuit. Thus, our results show that plant toxins were likely co-opted as olfactory attractants through gene duplication and functional specialization (neofunctionalization and subfunctionalization) in drosophilid flies.
Activity and cytosolic Na+regulates synaptic vesicle endocytosis
Authors: Zhu Yun , Li Dainan , Huang Hai
Published: December 2019

Retrieval of synaptic vesicles via endocytosis is essential for maintaining sustained synaptic transmission, especially for neurons that fire action potentials at high frequencies. However, how activity regulates synaptic vesicles recycling is largely unknown. Here we report that Na+substantially accumulated in the mouse calyx of Held terminals during repetitive high-frequency spiking. Elevated presynaptic Na+accelerated both slow and rapid forms of endocytosis and facilitated endocytosis overshoot but did not affect the readily releasable pool size, Ca2+influx, or exocytosis. To examine whether this facilitation of endocytosis is related to the Na+-dependent vesicular content change, we dialyzed increasing concentrations of glutamate into the presynaptic cytosol or blocked the vesicular glutamate uptake with bafilomycin and found the rate of endocytosis was not affected by regulating the glutamate content in the presynaptic terminal. Endocytosis is critically dependent on intracellular Ca2+, and the activity of Na+/Ca2+exchanger (NCX) may be altered when the Na+gradient is changed. However, neither NCX blocker nor change of extracellular Na+concentration affected the endocytosis rate. Moreover, two-photon Ca2+imaging showed that presynaptic Na+did not affect the action potential-evoked intracellular Ca2+transient and decay. Therefore, we revealed a novel mechanism of cytosolic Na+in accelerating vesicle endocytosis. During high-frequency synaptic transmission, when large amounts of synaptic vesicles are fused, Na+accumulated in terminals, facilitated vesicle recycling and sustained reliable synaptic transmission.
Geometry-based navigation in the dark: Layout symmetry facilitates spatial learning in the house cricket,Acheta domesticus, in the absence of visual cues
Authors: Baran Bartosz , Krzyżowski Michał , Rádai Zoltán , Francikowski Jacek , Hohol Mateusz
Published: December 2019

The capacity to navigate by layout geometry has been widely recognized as a robust navigational strategy. It was reported in various species, albeit most studies were performed with vision-based paradigms. In the presented study, we aimed to investigate layout symmetry-based navigation in the house cricket,Acheta domesticus, in the absence of visual cues. For this purpose, we used a non-visual paradigm modeled on the Tennessee Williams setup. We also verified the inaccessibility of visual cues for tested insects using antennal positioning reflex towards looming stimulus and by testing the performance of blinded crickets. In the main experiment, we tested the crickets’ capacity to learn to find a cool spot positioned centrally in heated arenas of different shapes (i.e., circular, square, triangular, and asymmetric quadrilateral). We found that the symmetry of the arena significantly facilitates crickets’ learning to find the cool spot, indicated by the increase of time spent on the cool spot and decrease of the latency of locating it in subsequent trials. To investigate possible mechanisms utilized by crickets during the experiment, we analyzed insects’ approach paths to the spot. The trajectories were grouped in four distinct clusters corresponding to both heuristic and directed strategies of approaching the target, with the dominance of a semi-directed strategy (thigmotactic phase preceding direct navigation to the target). Against these results, we discuss the possibility of insects’ navigation by using a non-visual space representation and possible limitations of navigation capacities in such conditions in relation to multimodally-guided navigation.
Deep, soft, and dark sounds induce autonomous sensory meridian response
Authors: Koumura Takuya , Nakatani Masashi , Liao Hsin-I , Kondo Hirohito M.
Published: December 2019

There has been a growing interest in the autonomous sensory meridian response (ASMR). The ASMR is characterized by a tingling sensation around the scalp and neck and often induces a feeling of relaxation and a reduction of a negative mood. However, it is still unknown what factors affect the ASMR. The present study focused on stimulus characteristics and individuals’ mood states and personality traits. Participants filled out self-reported questionnaires (the Profile of Mood States, Beck Depression Inventory, and Big Five Inventory) and reported ASMR estimates throughout a 17-min experiment while listening to binaural tapping and brushing sounds. Cross-correlation results showed that the ASMR estimates were strongly associated with the acoustic features of auditory stimuli, such as their amplitude, spectral centroid, and spectral bandwidth. This indicates that low-pitched sounds with dark timbre trigger the ASMR. The maximum ASMR was observed around 2 s after the acoustic features changed, suggesting that the sluggishness of multisensory integration may lead to the ASMR experience. In addition, individual differences in the ASMR experience were closely linked to participants’ mood states, such as anxiety, but not to their personality traits. Our results provide important clues to understand the mechanisms of auditory-somatosensory interactions.

Significant Statements

The autonomous sensory meridian response (ASMR) is characterized by a tingling, electrostatic-like sensation across the scalp and back of the neck. This phenomenon can be triggered by a variety of audiovisual stimuli, and many people seek out the ASMR via the internet to receive a feeling of relaxation and reduce a negative mood. We show that the ASMR is induced about 2 s after acoustic features, such as the amplitude, spectral centroid, and spectral bandwidth are changed. This suggests that low-pitched sounds with dark timbre lead to the ASMR experience. The stimulus-driven ASMR effect is found regardless of the personality traits or mood states of participants. Our findings provide a critical clue to understand the mechanisms of auditory–somatosensory interactions.
z-STED imaging and spectroscopy to investigate nanoscale membrane structure and dynamics
Authors: Barbotin Aurélien , Urbančič Iztok , Galiani Silvia , Eggeling Christian , Booth Martin , Sezgin Erdinc
Published: December 2019

Super-resolution STED microcopy provides optical resolution beyond the diffraction limit. The resolution can be increased laterally (xy/2D) or axially (z/3D). 2D STED has been extensively used to elucidate the nanoscale membrane structure and dynamics, via imaging or combined with spectroscopy techniques such as fluorescence correlation spectroscopy (FCS) and spectral imaging. On the contrary, z-STED has not been used in this context. Here, we show that a combination of z-STED with FCS or spectral imaging enables us to see previously unobservable aspects of cellular membranes. We show that thanks to an axial resolution of approximately 100 nm, z-STED can be used to distinguish axially close-by membranes, early endocytic vesicles or tubular membrane structures. Combination of z-STED with FCS and spectral imaging showed diffusion dynamics and lipid organization in these structures, respectively.
Bayesian inference of the gene expression states of single cells from scRNA-seq data
Authors: Breda Jérémie , Zavolan Mihaela , van Nimwegen Erik
Published: December 2019

In spite of a large investment in the development of methodologies for analysis of single-cell RNA-seq data, there is still little agreement on how to best normalize such data, i.e. how to quantify gene expression states of single cells from such data. Starting from a few basic requirements such as that inferred expression states should correct for both intrinsic biological fluctuations and measurement noise, and that changes in expression state should be measured in terms of fold-changes rather than changes in absolute levels, we here derive a unique Bayesian procedure for normalizing single-cell RNA-seq data from first principles. Our implementation of this normalization procedure, called Sanity (SAmpling Noise corrected Inference of Transcription activitY), estimates log expression values and associated errors bars directly from raw UMI counts without any tunable parameters.

Comparison of Sanity with other recent normalization methods on a selection of scRNA-seq datasets shows that Sanity outperforms other methods on basic downstream processing tasks such as clustering cells into subtypes and identification of differentially expressed genes. More importantly, we show that all other normalization methods present severely distorted pictures of the data. By failing to account for biological and technical Poisson noise, many methods systematically predict the lowest expressed genes to be most variable in expression, whereas in reality these genes provide least evidence of true biological variability. In addition, by confounding noise removal with lower-dimensional representation of the data, many methods introduce strong spurious correlations of expression levels with the total UMI count of each cell as well as spurious co-expression of genes.
Characterization of human iPSC-derived astrocytes with potential for disease modeling and drug discovery
Authors: Soubannier Vincent , Maussion Gilles , Chaineau Mathilde , Sigutova Veronika , Rouleau Guy , Durcan Thomas , Stifani Stefano
Published: December 2019

Astrocytes play a number of key functions in health and disease. Reactivation of astrocytes occurs in most, if not all, neurological diseases. Most current information on the mechanisms underlying astrogliosis derives from studies using rodent experimental systems, mainly because the ability to study human astrocytes under healthy and pathological conditions has been hampered by the difficulty in obtaining primary human astrocytes. Here we describe robust and reliable derivation of astrocytes from human induced pluripotent stem cells (iPSCs). Phenotypically characterized human iPSC-derived astrocytes exhibit typical traits of physiological astrocytes, including spontaneous and induced calcium transients. Moreover, human iPSC-derived astrocytes respond to stimulation with a pro-inflammatory combination of tumor necrosis factor alpha, interleukin 1-alpha, and complement component C1q by undergoing changes in gene expression patterns suggesting acquisition of a reactive astrocyte phenotype. Together, these findings provide evidence suggesting that human iPSC-derived astrocytes are a suitable experimental model system to study astrocyte function and reactivation in healthy and pathological conditions of the human nervous system.
Membrane insertion of chromogranin B for granule maturation in regulated secretion
Authors: Yadav Gaya P. , Wang Haiyuan , Ouwendijk Joke , Annamalai Mani , Cross Stephen , Wang Qiaochu , Hagan D. Walker , Mathews Clayton , Phelps Edward A. , Verkade Paul , Zhu Michael X. , Jiang Qiu-Xing
Published: December 2019

Regulated secretion serves responses to specific stimuli in eukaryotes. An anion conductance was found essential for maturation and acidification of secretory granules four decades ago, but its genetic identity was unknown. We now demonstrate that chromogranin B (CHGB), an obligate granule protein, constitutes the long-sought anion channel. High-pressure freezing immuno-electron microscopy and biochemical assays showed native CHGB in close proximity to secretory granule membranes, and its membrane-bound and soluble forms both reconstituted Cl-channels. Release of secretory granules delivered CHGB clusters to plasma membranes, which dominate whole-cell anion conductance. Intragranular pH measurements and cargo maturation assays found that CHGB channels supported proinsulin - insulin conversion and dopamine-loading in neuroendocrine cells. β-cells fromChgb-/-mice exhibited significant granule deacidification, accounting for hyperproinsulinemia, altered glucose-tolerance response and lower dopamine concentration in chromaffin granules in these animals. Membrane insertion of well-conserved CHGB is thus indispensable for granule maturation in exocrine, endocrine and neuronal cells.

Highlights

Native CHGB is amphipathic and distributes in the lumen and membranes of secretory granules with contrastingly different destinies and functions.

Native CHGB, once delivered to cell surface via granule exocytosis, dominates anion conductance in plasma membranes.

CHGB channels facilitate granule acidification and cargo maturation in cultured and primary neuroendocrine cells.

CHGB channels from bovine, rat and mouse cells all serve the long-missing, intra-organellar anion shunt pathway in the secretory granules for regulated secretion.
Lithium attenuates d‐amphetamine‐induced hyperlocomotor activity in mice via inhibition of interaction between cyclooxygenase‐2 and indoleamine‐2,3‐dioxygenase
Authors: Phan Dieu‐Hien , Shin Eun‐Joo , Jeong Ji Hoon , Tran Hai‐Quyen , Sharma Naveen , Nguyen Bao Trong , Jung Tae Woo , Nah Seung‐Yeol , Saito Kuniaki , Nabeshima Toshitaka , Kim Hyoung‐Chun
Published: December 2019

In the present study, we investigated whether mood stabilizer lithium (Li) protects against d‐amphetamine (AMP)‐induced mania‐like behaviours via modulating the novel proinflammatory potential. Repeated treatment with AMP resulted in significant increases in proinflammatory cyclooxygenase‐2 (COX‐2) and indolemaine‐2,3‐dioxygenase‐1 (IDO)‐1 expression in the prefrontal cortex (PFC) of mice. However, AMP treatment did not significantly change IDO‐2 and 5‐lipoxygenase (5‐LOX) expression, suggesting that proinflammatory parameters such as COX‐2 and IDO‐1 are specific for AMP‐induced behaviours. AMP‐induced initial expression of COX‐2 (15 minutes post‐AMP) was earlier than that of IDO‐1 (1 hour post‐AMP). Mood stabilizer Li and COX‐2 inhibitor meloxicam significantly attenuated COX‐2 expression 15 minutes post‐AMP, whereas IDO‐1 inhibitor 1‐methyl‐DL‐tryptophan (1‐MT) did not affect COX‐2 expression. However, AMP‐induced IDO‐1 expression was significantly attenuated by Li, meloxicam or 1‐MT, suggesting that COX‐2 is an upstream molecule for the induction of IDO‐1 caused by AMP. Consistently, co‐immunoprecipitation between COX‐2 and IDO‐1 was observed at 30 minutes, 1, 3, and 6 hours after the final AMP treatment. This interaction was also significantly inhibited by Li, meloxicam or 1‐MT. Furthermore, AMP‐induced hyperlocomotion was significantly attenuated by Li, meloxicam or 1‐MT. We report, for the first time, that mood stabilizer Li attenuates AMP‐induced mania‐like behaviour via attenuation of interaction between COX‐2 and IDO‐1, and that the interaction of COX‐2 and IDO‐1 may be critical for the therapeutic intervention mediated by mood stabilizer.
Risk of preterm birth after prior term cesarean
Authors: Visser L , Slaager C , Kazemier BM , Rietveld AL , Oudijk MA , de Groot CJM , Mol BW , de Boer MA
Published: December 2019

Objective

To determine the risk of overall preterm birth (PTB) and spontaneous PTB in a pregnancy after a caesarean section (CS) at term.

Design

Longitudinal linked national cohort study.

Setting

The Dutch Perinatal Registry (1999–2009).

Population

268 495 women with two subsequent singleton pregnancies were identified.

Methods

A cohort study based on linked registered data from two subsequent pregnancies in the Netherlands.

Main outcome measures

The incidence of overall PTB and spontaneous PTB with subgroup analysis on gestational age at first delivery and type of CS (planned or unplanned).

Results

Of 268 495 women with a singleton first pregnancy who delivered at term, 15.76% (n = 42 328) had a CS. The incidence of PTB in the second pregnancy was 2.79% (n = 1182) in women with a previous CS versus 2.46% (n = 5570) in women with a previous vaginal delivery (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.07–1.21). This increased risk is mainly driven by an increased risk of spontaneous PTB after previous CS at term (aOR 1.50, 95% CI 1.38–1.70). Analysis for type of CS compared with vaginal delivery showed an aOR on spontaneous PTB of 1.86 (95% CI 1.58–2.18) for planned CS and an aOR of 1.40 (95% CI 1.24–1.58) for unplanned CS.

Conclusions

CS at term is associated with a marginally increased risk of spontaneous PTB in a subsequent pregnancy.

Tweetable abstract

Caesarean section at term is associated with a marginally increased risk of spontaneous PTB in a subsequent pregnancy.
Insider Trading, Informativeness, and Price Efficiency Around the World
Authors: Kim Donghyun , Ng Lilian , Wang Qinghai , Wang Xiaoqiong
Published: December 2019

This paper provides the first direct evidence of the impact of enforcing insider regulations on the informativeness of insider trades and stock price efficiency across 44 countries with varying levels of insider trading regulations. Results suggest that insider purchases earn abnormal profits, especially in countries with active enforcement of insider trading regulations. We further show that while insiders trade less before earnings announcements in countries with active enforcement, their stock prices react more to earnings news than those in countries without active enforcement. Overall, our results support the view that effective insider trading regulation promotes price efficiency.
Bad News Withholding and Stock Price Crash Risk of Banks
Authors: Jung Taejin , Kim Natalie Kyung Won , Kim Young Jun , Na Hyun Jong
Published: December 2019

Using US banks’ quarterly data from 1995 to 2014, this study examines the mechanism by which delayed expected loss recognition (DELR) affects the stock price crash risk of banks. We first show that greater DELR is positively associated with a subsequent crash in stock price. We then find that this association is only present when bank managers have more discretion in concealing bad news, which is proxied by the high proportion of heterogeneous loans. These findings provide policy implications for bank regulators regarding the importance of specific loan types and time horizons when monitoring the accounting treatment of banks.
Beyond “Intent‐to‐treat” and “Per protocol”: Improving assessment of treatment effects in clinical trials through the specification of an estimand
Authors: Pétavy Frank , Guizzaro Lorenzo , Antunes dos Reis Inês , Teerenstra Steven , Roes Kit C.B.
Published: December 2019

There is a key problem in randomised clinical trials as outcomes can be distorted due to informative post‐randomisation events. This is inadequately addressed by the use of traditional intention‐to‐treat or per protocol analysis sets and often either ignored or wrongly labelled as missing data. As a consequence, the treatment effects of interest in a clinical trial are not well defined and their estimates might be misinterpreted.

The estimand framework should help all those planning, conducting and analysing clinical trials as well as those interpreting the results to better define, estimate and understand the treatment effects of interest.

This framework is described in the addendum to ICH E9 and addresses precisely this problem. It is relevant for regulatory drug trials and academic‐run trials, as well as for trials of nonpharmacological interventions.
The effects of anti‐VEGF and kinin B1 receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization
Authors: Hachana Soumaya , Fontaine Olivier , Sapieha Przemyslaw , Lesk Mark , Couture Réjean , Vaucher Elvire
Published: December 2019

Background and Purpose

Age‐related macular degeneration (AMD) is a complex neurodegenerative disease treated by anti‐VEGF intravitreal injections. As inflammation is potentially involved in retinal degeneration, the pro‐inflammatory kallikrein–kinin system is a possible alternative pharmacological target. Here, we investigated the effects of anti‐VEGF and anti‐B1 receptor treatments on the inflammatory mechanisms in a rat model of choroidal neovascularization (CNV).

Experimental Approach

Immediately after laser‐induced CNV, Long–Evans rats were treated by eye‐drop application of a B1 receptor antagonist (R‐954) or by intravitreal injection of B1 receptor siRNA or anti‐VEGF antibodies. Effects of treatments on gene expression of inflammatory mediators, CNV lesion regression and integrity of the blood‐retinal barrier was measured 10 days later in the retina. B1 receptor and VEGF‐R2 cellular localization was assessed.

Key Results

The three treatments significantly inhibited the CNV‐induced retinal changes. Anti‐VEGF and R‐954 decreased CNV‐induced up‐regulation of B1 and B2 receptors, TNF‐α, and ICAM‐1. Anti‐VEGF additionally reversed up‐regulation of VEGF‐A, VEGF‐R2, HIF‐1α, CCL2 and VCAM‐1, whereas R‐954 inhibited gene expression of IL‐1β and COX‐2. Enhanced retinal vascular permeability was abolished by anti‐VEGF and reduced by R‐954 and B1 receptor siRNA treatments. Leukocyte adhesion was impaired by anti‐VEGF and B1 receptor inhibition. B1 receptors were found on astrocytes and endothelial cells.

Conclusion and Implications

B1 receptor and VEGF pathways were both involved in retinal inflammation and damage in laser‐induced CNV. The non‐invasive, self‐administration of B1 receptor antagonists on the surface of the cornea by eye drops might be an important asset for the treatment of AMD.
Donecopride, a Swiss army knife with potential against Alzheimer's disease
Authors: Rochais Christophe , Lecoutey Cédric , Hamidouche Katia , Giannoni Patrizia , Gaven Florence , Cem Eleazere , Mignani Serge , Baranger Kevin , Freret Thomas , Bockaert Joël , Rivera Santiago , Boulouard Michel , Dallemagne Patrick , Claeysen Sylvie
Published: December 2019

Background and Purpose

We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5‐HT4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD).

Experimental Approach

We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid‐β peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro‐cognitive and anti‐amnesic effects were evaluated with novel object recognition, Y‐maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid‐β peptides on neuronal survival and neurite formation determined in vitro.

Key Results

In vivo, chronic (3 months) administration of donecopride displayed potent anti‐amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long‐term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation. In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid‐β peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses.

Conclusions and Implications

Donecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential disease‐modifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.
Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP‐1 and HER2 expression and converted MCF7 breast cancer subtype
Authors: Al‐Zeheimi Noura , Adham Sirin A.
Published: December 2019

Background and Purpose

Patients with locally advanced breast cancer usually receive third‐generation neoadjuvant chemotherapy (NAC). Although NAC treatment improved the overall survival, patients' response varies, some acquire resistance and others exhibit a conversion in their breast cancer molecular subtype. We aimed to identify the molecular changes involved in NAC resistance attempting to find new therapeutic targets in different breast cancer subtypes.

Experimental Approach

We modelled NAC treatments used in clinical practice and generated resistant cell lines in vitro. The resistant cells were generated by consecutive treatment with four cycles of doxorubicin (adriamycin)/cyclophosphamide (4xAC) followed by an additional four cycles of paclitaxel (4xAC + 4xPAC).

Key Results

Our data revealed distinct mechanisms of resistance depending on breast cancer subtype and drugs used. MDA‐MB‐231 cells resistant to 4xAC + 4xPAC activated neuropilin‐1/TNC/integrin β3/FAK/NF‐κBp65 axis and displayed a decrease in breast cancer resistance protein (BCRP/ABCB2). However, MCF7 cells resistant to 4xAC treatments induced HER2 expression, which converted MCF7 subtype from luminal A to luminal B HER2 type, up‐regulated neuropilin‐1, oestrogen receptor‐α, and EGFR, and activated PI3K/Akt/NF‐κBp65 axis. However, MCF7 cells resistant to 4xAC + 4xPAC exhibited down‐regulation of the survival axis and up‐regulated BCRP/ABCG2. Co‐immunoprecipitation demonstrated a novel interaction between HER2 and neuropilin‐1 driving the resistance features.

Conclusions and Implications

The concurrent increase in neuropilin‐1 and HER2 upon resistance and the inverse relationship between neuropilin‐1 and BCRP/ABCG2 suggest that, in addition to HER2, neuropilin‐1 status should be assessed in patients undergoing NAC, and as a potential drug target for refractory breast cancer.
Eucalyptol alleviates inflammation and pain responses in a mouse model of gout arthritis
Authors: Yin Chengyu , Liu Boyu , Wang Ping , Li Xiaojie , Li Yuanyuan , Zheng Xiaoli , Tai Yan , Wang Chuan , Liu Boyi
Published: December 2019

Background and Purpose

Gout arthritis, which is provoked by monosodium urate (MSU) crystal accumulation in the joint and periarticular tissues, induces severe pain and affects quality of life of the patients. Eucalyptol (1,8‐cineol), the principal component in the essential oils of eucalyptus leaves, is known to possess anti‐inflammatory and analgesic properties. We aimed to examine the therapeutic effects of eucalyptol on gout arthritis and related mechanisms.

Experimental Approach

A mouse model of gout arthritis was established via MSU injection into the ankle joint. Ankle oedema, mechanical allodynia, neutrophil infiltration, oxidative stress, NLRP3 inflammasome, and TRPV1 expression were examined.

Key Results

Eucalyptol attenuated MSU‐induced mechanical allodynia and ankle oedema in dose‐dependently, with effectiveness similar to indomethacin. Eucalyptol reduced inflammatory cell infiltrations in ankle tissues. Eucalyptol inhibited NLRP3 inflammasome activation and pro‐inflammatory cytokine production induced by MSU in ankle tissues in vivo. Eucalyptol reduced oxidative stress induced by MSU in RAW264.7 cells in vitro as well as in ankle tissues in vivo, indicated by an increase in activities of antioxidant enzymes and reduction of ROS. Eucalyptol attenuated MSU‐induced up‐regulation of TRPV1 expression in ankle tissues and dorsal root ganglion neurons innervating the ankle. The in vivo effects of eucalyptol on ankle oedema, mechanical allodynia, NLRP3 inflammasome, IL‐1β, and TRPV1 expression were mimicked by treating MSU‐injected mice with antioxidants.

Conclusion and Implications

Eucalyptol alleviates MSU‐induced pain and inflammation via mechanisms possibly involving anti‐oxidative effect. Eucalyptol and other antioxidants may represent promising therapeutic options for gout arthritis.
MicroRNA‐493‐5p‐mediated repression of the MYCN oncogene inhibits hepatic cancer cell growth and invasion
Authors: Yasukawa Ken , Liew Lee Chuen , Hagiwara Keitaro , Hironaka‐Mitsuhashi Ai , Qin Xian‐Yang , Furutani Yutaka , Tanaka Yasuhito , Nakagama Hitoshi , Kojima Soichi , Kato Takashi , Ochiya Takahiro , Gailhouste Luc
Published: December 2019

Primary hepatic tumors mainly include hepatocellular carcinoma (HCC), which is one of the most frequent causes of cancer‐related deaths worldwide. Thus far, HCC prognosis has remained extremely poor given the lack of effective treatments. Numerous studies have described the roles played by microRNAs (miRNAs) in cancer progression and the potential of these small noncoding RNAs for diagnostic or therapeutic applications. The current consensus supports the idea that direct repression of a wide range of oncogenes by a single key miRNA could critically affect the malignant properties of cancer cells in a synergistic manner. In this study, we aimed to investigate the oncogenes controlled by miR‐493‐5p, a major tumor suppressor miRNA that inactivates miR‐483‐3p oncomir in hepatic cancer cells. Using global gene expression analysis, we highlighted a set of candidate genes potentially regulated by miR‐493‐5p. In particular, the canonical MYCN protooncogene (MYCN) appeared to be an attractive target of miR‐493‐5p given its significant inhibition through 3′‐UTR targeting in miR‐493‐5p‐rescued HCC cells. We showed that MYCN was overexpressed in liver cancer cell lines and clinical samples from HCC patients. Notably, MYCN expression levels were inversely correlated with miR‐493‐5p in tumor tissues. We confirmed that MYCN knockdown mimicked the anticancer effect of miR‐493‐5p by inhibiting HCC cell growth and invasion, whereas MYCN rescue hindered miR‐493‐5p activity. In summary, miR‐493‐5p is a pivotal miRNA that modulates various oncogenes after its reexpression in liver cancer cells, suggesting that tumor suppressor miRNAs with a large spectrum of action could provide valuable tools for miRNA replacement therapies.