bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative visualization of gene expression inPseudomonas aeruginosaaggregates reveals peak expression of alginate in the hypoxic zone
Authors: Jorth Peter , Spero Melanie A. , Newman Dianne K.
Published: May 2019

It is well appreciated that oxygen- and nutrient-limiting gradients characterize microenvironments within chronic infections that foster bacterial tolerance to treatment and the immune response. However, determining how bacteria respond to these microenvironments has been limited by a lack of tools to study bacterial functions at the relevant spatial scalesin situ. Here we report the application of the hybridization chain reaction (HCR) v3.0 toPseudomonas aeruginosaaggregates as a step towards this end. As proof-of-principle, we visualize the expression of genes needed for the production of alginate (algD) and the dissimilatory nitrate reductase (narG). Using an inducible bacterial gene expression construct to calibrate the HCR signal, we were able to quantifyalgDandnarGgene expression across microenvironmental gradients both within single aggregates and within aggregate populations using the Agar Block Biofilm Assay (ABBA). For the ABBA population, alginate gene expression was restricted to hypoxic regions within the environment (~40-200 μM O2), as measured by an oxygen microelectrode. Within individual biofilm aggregates, cells proximal to the surface expressed alginate genes to a greater extent than interior cells. Lastly, mucoid biofilms consumed more oxygen than nonmucoid biofilms. These results establish that HCR has a sensitive dynamic range and can be used to resolve subtle differences in gene expression at spatial scales relevant to microbial assemblages. Because HCR v3.0 can be performed on diverse cell types, this methodological advance has the potential to enable quantitative studies of microbial gene expression in diverse contexts, including pathogen behavior in human chronic infections.

Importance

The visualization of microbial activities in natural environments is an important goal for numerous studies in microbial ecology, be the environment a sediment, soil, or infected human tissue. Here we report the application of the hybridization chain reaction (HCR) v3.0 to measure microbial gene expressionin situat single-cell resolution in aggregate biofilms. UsingPseudomonas aeruginosawith a tunable gene expression system, we show that this methodology is quantitative. Leveraging HCR v3.0 to measure gene expression within aP. aeruginosaaggregate, we find that bacteria just below the aggregate surface are the primary cells expressing genes that protect the population against antibiotics and the immune system. This observation suggests that therapies targeting bacteria growing with small amounts of oxygen may be most effective against these hard-to-treat infections. More generally, HCR v3.0 has potential for broad application into microbial activitiesin situat small spatial scales.
CTCF controls imprinted gene activity at the mouseDlk1-Dio3andIgf2-H19domains by modulating allele-specific sub-TAD structure
Authors: Llères David , Moindrot Benoît , Pathak Rakesh , Piras Vincent , Matelot Mélody , Pignard Benoît , Marchand Alice , Poncelet Mallory , Perrin Aurélien , Tellier Virgile , Feil Robert , Noordermeer Daan
Published: May 2019

Mammalian genomic imprinting is essential for development and provides a unique paradigm to explore intra-cellular differences in chromatin configuration. Here, we compared chromatin structure of the two conserved imprinted domains controlled by paternal DNA methylation imprints—theIgf2-H19and theDlk1-Dio3domains—and assessed the involvement of the insulator protein CTCF. At both domains, CTCF binds the maternal allele of a differentially-methylated region (DMR), in addition to multiple instances of bi-allelic CTCF binding in their surrounding TAD (Topologically Associating Domain). On the paternal chromosome, bi-allelic CTCF binding alone is sufficient to structure a first level of sub-TAD organization. Maternal-specific CTCF binding at the DMRs adds a further layer of sub-TAD organization, which essentially hijacks the existing paternal sub-TAD organisation. Genome-editing experiments at theDlk1-Dio3locus confirm that the maternal sub-TADs are essential during development to maintain the imprintedDlk1gene in an inactive state on the maternal chromosome.
Quantifying nerve decussation abnormalities in the optic chiasm
Authors: Puzniak Robert J. , Ahmadi Khazar , Kaufmann Jörn , Gouws Andre , Morland Antony B. , Pestilli Franco , Hoffmann Michael B.
Published: May 2019

Objective

The human optic chiasm comprises partially crossing optic nerve fibres. Here we used diffusion MRI (dMRI) for the in-vivo identification of the abnormally high proportion of crossing fibres found in the optic chiasm of people with albinism.

Methods

In 9 individuals with albinism and 8 controls high-resolution 3T dMRI data was acquired and analyzed with a set of methods for signal modeling [Diffusion Tensor (DT) and Constrained Spherical Deconvolution (CSD)], tractography, and streamline filtering (LiFE, COMMIT, and SIFT2). The number of crossing and non-crossing streamlines and their weights after filtering entered ROC-analyses to compare the discriminative power of the methods based on the area under the curve (AUC). The dMRI results were cross-validated with fMRI estimates of misrouting in a subset of 6 albinotic individuals.

Results

We detected significant group differences in chiasmal crossing for both unfiltered DT (p=0.014) and CSD tractograms (p=0.0009) also reflected by AUC measures (for DT and CSD: 0.61 and 0.75, respectively), underlining the discriminative power of the approach. Estimates of crossing strengths obtained with dMRI and fMRI were significantly correlated for CSD (R2=0.83, p=0.012). The results show that streamline filtering methods in combination with probabilistic tracking, both optimized for the data at hand, can improve the detection of crossing in the human optic chiasm.

Conclusions

Especially CSD-based tractography provides an efficient approach to detect structural abnormalities in the optic chiasm. The most realistic results were obtained with filtering methods with parameters optimized for the data at hand.

Significance

Our findings demonstrate a novel anatomy-driven approach for the individualized diagnostics of optic chiasm abnormalities.

Highlights

Diffusion MRI is capable of detecting structural abnormalities of the optic chiasm.

Quantification of crossing strength in optic chiasm is of promise for albinism diagnostics.

Optic chiasm is a powerful test model for neuroimaging methods resolving crossing fibers.
MRGPRX4 is a novel bile acid receptor in cholestatic itch
Authors: Yu Huasheng , Zhao Tianjun , Liu Simin , Wu Qinxue , Johnson Omar , Wu Zhaofa , Zhuang Zihao , Shi Yaocheng , He Renxi , Yang Yong , Sun Jianjun , Wang Xiaoqun , Xu Haifeng , Zeng Zheng , Lei Xiaoguang , Luo Wenqin , Li Yulong
Published: May 2019

Patients with liver diseases often suffer from chronic itch or pruritus, yet the itch-causing pruritogen(s) and their cognate receptor(s) remain largely elusive. Using transcriptomics and GPCR activation assays, we found that an orphan, primate specific MRGPRX4 is expressed in human dorsal root ganglia (hDRG) and selectively activated by bile acids. In situ hybridization and immunohistochemistry revealed that MRGPRX4 is expressed in ∼7% of hDRG neurons and co-localizes with HRH1, a known itch-inducing GPCR. Bile acids elicited a robust Ca2+ response in a subset of cultured hDRG neurons, and intradermal injection of bile acids and an MRGPRX4 specific agonist induced significant itch in healthy human subjects. Surprisingly, application of agonist for TGR5, a known sequence conserved bile acid receptor previously implicated in cholestatic itch, failed to elicit Ca2+ response in cultured hDRG neurons, nor did it induce pruritus in human subjects. In situ hybridization and immunostaining results revealed that hTGR5 is selectively expressed in satellite glial cells, unlike mTGR5 (in mouse DRG neurons), likely accounting for the inter-species difference functionally. Finally, we found that patients with cholestatic itch have significantly higher plasma bile acid levels compared to non-itchy patients and the bile acid levels significantly decreased after itch relief. This elevated bile acid level in itchy patients is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch, providing a promising new drug target for anti-itch therapies.
DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress in triplenegative breast cancer
Authors: Moreno Rita , Banerjee Sourav , Jackson Angus W. , Quinn Jean , Baillie Gregg , Dixon Jack E. , Dinkova-Kostova Albena T. , Edwards Joanne , de la Vega Laureano
Published: May 2019

To survive aneuploidy-induced proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive target. As developing HSF1 inhibitors is challenging, the identification and targeting of upstream regulators of HSF1 presents a tractable alternative strategy. Here we demonstrate that in triple negative breast cancer (TNBC) cells, the dual-specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. Thus, DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. In agreement with this, DYRK2 depletion reduces tumour growth in a TNBC xenograft model. These findings identify DYRK2 as both, a key modulator of the HSF1 transcriptional program, and a potential therapeutic target.
Tumor Evolution Decoder (TED): Unveiling Tumor Evolution Based on Mutation Profiles of Subclones or Single Cells
Authors: Zhu Yitan , Sengupta Subhajit , Wei Lin , Yang Shengjie , Ji Yuan
Published: May 2019

Cancer cells constantly evolve accumulating somatic mutations. To describe the tumor evolution process, we develop the Tumor Evolution Decoder (TED), a novel algorithm for constructing phylogenetic tree based on somatic mutation profiles of tumor subclones or single cells. TED takes a unique strategy that reduces the total number of duplicated mutations and dropout mutations in the tumor evolution process, which has not been explored by previous phylogenetic tree methods. TED allows multiple types of somatic mutations as input, such as point mutations, copy number alterations, gene fusion, and their combinations. Theoretical properties of TED are derived while its numerical performance is examined using simulated data. We applied TED to analyze single-cell sequencing data from an essential thrombocythemia tumor and a clear cell renal cell carcinoma, to investigate the ancestral relationships between tumor cells, and found genes related to disease initialization and development mutated in the early steps of evolution. We also applied TED to the subclones of a breast invasive carcinoma and provided important insights on the evolution and metastasis of the tumor.
Stress-driven transposable element de-repression dynamics in a fungal pathogen
Authors: Fouché Simone , Badet Thomas , Oggenfuss Ursula , Plissonneau Clémence , Francisco Carolina Sardinha , Croll Daniel
Published: May 2019

Transposable elements (TEs) are drivers of genome evolution and affect the expression landscape of the host genome. Stress is a major factor inducing TE activity, however the regulatory mechanisms underlying de-repression are poorly understood. Key unresolved questions are whether different types of stress differentially induce TE activity and whether different TEs respond differently to the same stress. Plant pathogens are excellent models to dissect the impact of stress on TEs, because lifestyle transitions on and off the host impose exposure to a variety of stress conditions. We analyzed the TE expression landscape of four well-characterized strains of the major wheat pathogenZymoseptoria tritici. We experimentally exposed strains to nutrient starvation and host infection stress. Contrary to expectations, we show that the two distinct conditions induce the expression of different sets of TEs. In particular, the most highly expressed TEs, including MITE and LTR-Gypsyelements, show highly distinct de-repression across stress conditions. Both the genomic context of TEs and the genetic background stress (i.e.different strains harboring the same TEs) were major predictors of de-repression dynamics under stress. Genomic defenses inducing point mutations in repetitive regions were largely ineffective to prevent TE de-repression. Consistent with TE de-repression being governed by epigenetic effects, we found that gene expression profiles under stress varied significantly depending on the proximity to the closest TEs. The unexpected complexity in TE responsiveness to stress across genetic backgrounds and genomic locations shows that species harbor substantial genetic variation to control TEs.
MicroRNA Dynamics and Functions DuringArabidopsisEmbryogenesis
Authors: Plotnikova Alexandra , Kellner Max J. , Mosiolek Magdalena , Schon Michael A. , Nodine Michael D.
Published: May 2019

MicroRNAs (miRNAs) are short non-coding RNAs that mediate the repression of target transcripts in plants and animals. Although miRNAs are required throughout plant development, relatively little is known regarding their embryonic functions. To systematically characterize embryonic miRNAs inArabidopsis thaliana,we developed or applied high-throughput sequencing based methods to profile hundreds of miRNAs and associated targets throughout embryogenesis. We discovered dozens of miRNAs that dynamically cleave and repress target transcripts including 30 that encode transcription factors. Transcriptome analyses indicated that these miRNA:target interactions have a profound impact on embryonic gene expression programs, and we further demonstrated that the miRNA-mediated repression of six transcription factors were individually required for embryo morphogenesis. These data indicate that the miRNA-directed repression of multiple transcription factors is critically important for the establishment of the plant body plan, and provide a foundation to further investigate how miRNAs contribute to these initial cellular differentiation events.
Predictive modeling of co-evolving growing populations
Authors: Altrock Philipp M. , Ferrall-Fairbanks Meghan C. , Kimmel Gregory J.
Published: May 2019

How can we best explore and fit density and frequency dependence in the evolutionary and ecological dynamics of growing tumors? Here, we present an introduction to recent developments in our lab, and give two examples of complex interaction-driven tumor growth combined with statistical outcomes of treatment.
An essential periplasmic protein coordinates lipid trafficking and is required for asymmetric polar growth in mycobacteria
Authors: Gupta Kuldeepkumar R. , Gwin Celena M. , Rahlwes Kathryn C. , Biegas Kyle J. , Wang Chunyan , Park Jin Ho , Liu Jun , Swarts Benjamin M. , Morita Yasu S. , Rego E. Hesper
Published: May 2019

Mycobacteria, including the human pathogen Mycobacterium tuberculosis, grow by inserting new cell wall material at their poles. This process and that of division are asymmetric, producing a phenotypically heterogeneous population of cells that respond non-uniformly to stress (Aldridge et al., 2012; Rego et al., 2017; Richardson et al., 2016). Surprisingly, deletion of a single gene – lamA – leads to more symmetry, and to a population of cells that is more uniformly killed by antibiotics (Rego et al., 2017). How does LamA create asymmetry? Here, using a combination of quantitative time-lapse imaging, bacterial genetics, and lipid profiling, we find that LamA recruits essential proteins involved in cell wall synthesis to one side of the cell – the old pole. One of these proteins, MSMEG_0317, here renamed PgfA, was of unknown function. We show that PgfA is a periplasmic protein that interacts with MmpL3, an essential transporter that flips mycolic acids in the form of trehalose monomycolate (TMM), across the plasma membrane. PgfA interacts with a TMM analog suggesting a direct role in TMM transport. Yet our data point to a broader function as well, as cells with altered PgfA levels have differences in the abundance of other lipids and are differentially reliant on those lipids for survival. Overexpression of PgfA, but not MmpL3, restores growth at the old poles in cells missing lamA. Together, our results suggest that PgfA is a key regulator of polar growth and cell envelope composition in mycobacteria, and that the LamA-mediated recruitment of this protein to one side of the cell is a required step in the establishment of cellular asymmetry.
Swim exercise in C. elegans extends neuromuscular and intestinal healthspan, enhances learning ability, and protects against neurodegeneration
Authors: Laranjeiro Ricardo , Harinath Girish , Hewitt Jennifer E. , Hartman Jessica H. , Royal Mary Anne , Meyer Joel N. , Vanapalli Siva A. , Driscoll Monica
Published: May 2019

Exercise can protect against cardiovascular disease, neurodegenerative disease, diabetes, cancer, and age-associated declines in muscle, immune, and cognitive function. In fact, regular physical exercise is the most powerful intervention known to enhance robustness of health and aging. Still, the molecular and cellular mechanisms that mediate system-wide exercise benefits remain poorly understood, especially as applies to “off target” tissues that do not participate directly in training activity. Elaborating molecular mechanisms of whole-animal exercise benefits is therefore of considerable importance to human health. The development of exercise protocols for short-lived genetic models holds great potential for deciphering fundamental mechanisms of exercise trans-tissue signaling during the entire aging process. Here, we report on the optimization of a long-term swim exercise protocol for C. elegans and we demonstrate its benefits to diverse aging tissues, even if exercise occurs only during a restricted phase during early adulthood. We found that multiple daily swim sessions are essential for exercise adaptation in C. elegans, leading to body wall muscle improvements in structural gene expression, locomotory performance, and mitochondrial morphology. Swim exercise training enhances whole-animal health parameters such as mitochondrial respiration and mid-life survival and increases the functional healthspan of pharynx and intestine. Importantly, we show that swim exercise also enhances nervous system health: exercise increases learning ability of adult animals and protects against neurodegeneration in C. elegans models of tauopathy, Alzheimer’s disease, and Huntington’s disease. An important point is that swim training only during C. elegans early adulthood induces long-lasting systemic benefits that in several cases are still detectable well into mid-life. Overall, our data reveal the broad impact of swim exercise in promoting extended healthspan of multiple C. elegans tissues, underscore the potency of early exercise experience to influence long-term health (even after cessation of exercise), and establish the foundation for exploiting the powerful advantages of this genetic model to dissect the exercise-dependent molecular circuitry that confers long-lasting system-wide health benefits to aging or diseased adults.
Nonreciprocal and Conditional Cooperativity Directs the Pioneer Activity of Pluripotency Transcription Factors
Authors: Li Sai , Bo Zheng Eric , Zhao Li , Liu Shixin
Published: May 2019

Cooperative binding of transcription factors (TFs) to chromatin orchestrates gene expression programming and cell fate specification. However the biophysical principles of TF cooperativity remain incompletely understood. Here we use single-molecule fluorescence microscopy to study the partnership between Sox2 and Oct4, two core members of the pluripotency gene regulatory network. We find that Sox2’s pioneer activity (the ability to target DNA inside nucleosomes) is strongly affected by the translational and rotational positioning of its binding motif, while Oct4 can access nucleosomal sites with equal capacities. Furthermore, the Sox2-Oct4 pair displays nonreciprocal cooperativity, with Oct4 modulating Sox2’s binding to the nucleosome but not vice versa. Such cooperativity is conditional upon the composite motif residing at specific nucleosomal locations. These results reveal that pioneer factors possess distinct properties of nucleosome targeting and suggest that the same set of TFs may differentially regulate transcriptional activity in a gene-specific manner on the basis of their motif positioning in the nucleosomal context.
Auditory cortical generators of the Frequency Following Response are modulated by intermodal attention
Authors: Hartmann Thomas , Weisz Nathan
Published: May 2019

The vast efferent connectivity of the auditory system suggests that subcortical (thalamic and brainstem) auditory regions should also be sensitive to top-down processes such as selective attention. In electrophysiology, the Frequency Following Response (FFR) to simple speech stimuli has been used extensively to study these subcortical areas. Despite being seemingly straight-forward in addressing the issue of attentional modulations of subcortical regions by means of the FFR, the existing results are highly inconsistent. Moreover, the notion that the FFR exclusively represents subcortical generators has been recently challenged. By applying these techniques to data recorded from 102 magnetoencephalography (MEG) magnetometers in 34 participants during a cross-modal attention task, we aimed to gain a more differentiated perspective on how the generators of the FFR are modulated by either attending to the visual or auditory input. In a first step our results confirm the strong contribution of also cortical regions to the FFR. Interestingly, of all regions exhibiting a measurable FFR response, only the right primary auditory cortex was significantly affected by intermodal attention. By showing a clear cortical contribution to the attentional FFR effect, our work significantly extends previous reports that focus on surface level recordings only. It underlines the importance of making a greater effort to disentangle the different contributing sources of the FFR and serves as a clear precaution of simplistically interpreting the FFR as brainstem response.
Dual NMDAR signaling in astrocytes: flux-independent pH sensor & flux-dependent mitochondrial regulator through membrane-mitochondria communication
Authors: Montes Oca Balderas Pavel , Hernández-Cruz Arturo
Published: May 2019

Glutamate N-methyl-D-aspartate (NMDA) receptor (NMDAR) is critical for neurotransmission as a Ca2+ channel. Nonetheless, several reports have also demonstrated flux-independent signaling. Astrocytes express NMDAR distinct from its neuronal counterpart, but cultured astrocytes have no electrophysiological response and controversial findings have questioned NMDAR function. We recently demonstrated that in cultured astrocytes NMDA at pH6 (NMDA/pH&) elicits flux-independent Ca2+ release from the Endoplasmic Reticulum (ER) and depletes mitochondrial membrane potential (mΔψ). Here we show that flux-independent Ca2+ release is mainly due to pH6, whereas mΔψ depletion requires both pH6 and flux-dependent NMDAR signaling. Immunofluorescence exhibited that plasma membrane (PM) NMDAR is apposed to ER and mitochondria or surrounds these organelles. Moreover, NMDA/pH6 treatment generated ER stress, increased endocytosis, mitochondria-ER and -nuclear contacts and strikingly, PM invaginations near mitochondria along with electrodense structures referred here as PM-mitochondrial bridges (PM-m-br). These data and earlier observations strongly suggest PM-mitochondria communication. As a proof of concept of this notion, NMDA/pH6 provoked mitochondria labeling by the PM dye FM-4-64FX. Finally, we analyzed by WB NMDAR subunit GluN1 to explore putative causes of NMDAR dual function, we found fragments with M.W. consistent with previously identified cleavage sites. Accordingly, GluN1 intracellular and extracellular domains presented little colocalization. Our findings demonstrate that NMDAR plays a dual function: a flux-independent pH sensor and a flux-dependent regulator of mΔψ. More importantly, mΔψ depletion seems to be mediated by PM-mitochondria communication. Finally, we found different GluN1 fragments that could be involved in NMDAR dual signaling, although causality awaits demonstration.
Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer
Authors: Dorvash Mohammadreza , Farahmandnia Mohammad , Mosaddeghi Pouria , Farahmandnejad Mitra , Saber Hosein , Khorraminejad-Shirazi Mohammadhossein , Azadi Amir , Tavassoly Iman
Published: May 2019

Signal integration in the mTOR pathway plays a vital role in cell fate decision making in cancer cells. As a signal integrator, mTOR shows a complex dynamical behavior which determines the cell fate at different cellular processes levels including cell cycle progression, cell survival, cell death, metabolic reprogramming, and aging. The dynamics of the complex responses to rapamycin in cancer cells have been attributed to its differential time-dependent inhibitory effects on mTORC1 and mTORC2, the two main complexes of mTOR. Two explanations were previously provided for this phenomenon: 1-Rapamycin does not inhibit mTORC2 directly, whereas it prevents mTORC2 formation by sequestering free mTOR protein. 2-Components like Phosphatidic Acid further stabilize mTORC2 compared with mTORC1. To understand the mechanism by which rapamycin differentially inhibits the mTOR complexes, we present a mathematical model of rapamycin mode of action based on the first explanation, i.e., Le Chatelier’s principle. Translating the interactions among components of mTORC1 and mTORC2 into a mathematical model revealed the dynamics of rapamycin action in different doses and time-intervals of rapamycin treatment. The model shows that rapamycin has stronger effects on mTORC1 compared with mTORC2, simply due to its direct interaction with free mTOR and mTORC1, but not mTORC2, without the need to consider other components that might further stabilize mTORC2. Based on our results, even when mTORC2 is less stable compared with mTORC1, it can be less inhibited by rapamycin.
Estimating serotype-specific efficacy of pneumococcal conjugate vaccines using hierarchical models
Authors: Warren Joshua L , Weinberger Daniel M.
Published: May 2019

Pneumococcal conjugate vaccines (PCVs) target 10 or 13 specific serotypes. To evaluate vaccine efficacy for these products, the vaccine-targeted serotypes are typically aggregated into a single group to estimate an overall effect. However, it is often desirable to evaluate variations in effects for different serotypes. These serotype-specific estimates are often based on small numbers, resulting in a high degree of uncertainty and instability in the individual estimates. A better approach is to use a Bayesian hierarchical statistical model, which estimates an overall effectiveness of the vaccine across all vaccine-targeted serotypes but also allows the effect to vary by serotype. We re-analyzed published data from a large randomized controlled trial on the efficacy of PCV13 against non-bacteremic community-acquired pneumonia caused by vaccine-targeted serotype. This model provides a potential framework for obtaining more credible and stable estimates of serotype-specific vaccine efficacy and effectiveness.
The effect of global signal regression on DCM estimates of noise and effective connectivity from resting state fMRI
Authors: Almgren Hannes , Van de Steen Frederik , Razi Adeel , Friston Karl , Marinazzo Daniele
Published: May 2019

The influence of the global BOLD signal on resting state functional connectivity in fMRI data remains a topic of debate, with little consensus. In this study, we assessed the effects of global signal regression (GSR) on effective connectivity within and between resting-state networks – as estimated with dynamic causal modelling (DCM) for resting state fMRI (rsfMRI). DCM incorporates a forward (generative) model that quantifies the contribution of different types of noise (including global measurement noise), effective connectivity, and (neuro)vascular processes to functional connectivity measurements. DCM analyses were applied to two different designs; namely, longitudinal and cross-sectional designs. In the modelling of longitudinal designs, we included four extensive longitudinal resting state fMRI datasets with a total number of 20 subjects. In the analysis of cross-sectional designs, we used rsfMRI data from 361 subjects from the Human Connectome Project. We hypothesized that (1) GSR would have no discernible impact on effective connectivity estimated with DCM, and (2) GSR would be reflected in the parameters representing global measurement noise. Additionally, we performed comparative analyses of the informative value of data with and without GSR. Our results showed negligible to small effects of GSR on connectivity within small (separately estimated) RSNs. For between-network connectivity, we found two important effects: the effect of GSR on between-network connectivity (averaged over all connections) was negligible to small, while the effect of GSR on individual connections was non-negligible. Contrary to our expectations, we found either no effect (in the longitudinal designs) or a non-specific (cross-sectional design) effect of GSR on parameters representing (global) measurement noise. Data without GSR were found to be more informative than data with GSR; however, in small resting state networks the precision of posterior estimates was greater using data after GSR. In conclusion, GSR is a minor concern in DCM studies; however, individual between-network connections (as opposed to average between-network connectivity) and noise parameters should be interpreted quantitatively with some caution. The Kullback-Leibler divergence of the posterior from the prior, together with the precision of posterior estimates, might offer a useful measure to assess the appropriateness of GSR, when nuancing data features in resting state fMRI.
Ocular vestibular evoked myogenic potential (VEMP) reveals subcortical HTLV-1-associated neurological disease
Authors: Silva Tatiana Rocha , Santos Marco Aurélio Rocha , de Resende Luciana Macedo , Labanca Ludimila , Dias Rafael Teixeira Scoralick , Gonçalves Denise Utsch
Published: May 2019

Introduction

Vestibular Myogenic Evoked Potential (VEMP) evaluates vestibulo-ocular and vestibulospinal reflexes associated with posture.

Purpose

To compare cervical and ocular VEMP in individuals with HTLV-1 associated myelopathy (HAM) and with HTLV-1-asymptomatic infection.

Materials and Methods

This cross-sectional study included 52 HTLV-1-infected individuals (26 HAM and 26 asymptomatic carriers) and 26 negative controls. The groups were similar regarding age and gender. Participants underwent ocular and cervical VEMP that were performed simultaneously. The stimulus used to generate VEMP was a sound, low-frequency toneburst, intensity of 120 decibels normalized hearing level (dB nHL), bandpass filter from 10 to 1,500 Hz, with 100 stimuli at 500 Hertz (Hz) and 50 milliseconds (ms) recording time. An alteration in the electrophysiological waves P13 and N23 for cervical VEMP and N10 and P15 waves for ocular VEMP was compared between groups.

Results

Cervical VEMP was different among the groups for P13 (p=0.001) and N23 (p=0.003). Ocular VEMP was similar for N10 (p=0.375) and different for P15 (p=0.000). In the HTLV-1-asymptomatic group, 1(3.8%) individual presented changes in both ocular and cervical VEMP, while in HAM group, 16(61.5%) presented changes in both tests.

Conclusion

Neurological impairment in HAM was not restricted to the spinal cord. The mesencephalic and thalamic connections, tested by ocular VEMP, were also altered. Damage of the oculomotor system, responsible for eye stabilization during head and body movements, may explain why dizziness is such a frequent complaint in HAM.

Authors’ summary

Human T-cell lymphotropic virus type 1 (HTLV-1) infection is endemic in Brazil and can cause HTLV-1-associated myelopathy (HAM). This neurological disease progresses slowly and, within ten years after its onset, can confine the patient to a wheelchair. Changes in HAM inflammatory characteristics can subsequently occur in the cortex, subcortical white matter, cerebellum, and brainstem. In the present study, we used the electrophysiological test Vestibular Myogenic Evoked Potential (VEMP) to evaluate the thalamic, brainstem, and spinal neural connections. This test evaluates the peripheral and the central vestibular pathway and has been used to test the postural reflexes involved in the control of one’s balance. The VEMP from the oculomotor muscles demonstrated that a subcortical impairment occurs in HAM and can also occur in the asymptomatic phase of HTLV-1 infection.
CDK1 phosphorylates ULK1-ATG13 complex to regulate mitotic autophagy and Taxol chemosensitivity
Authors: Li Zhiyuan , Tian Xiaofei , Ji Xinmiao , Wang Dongmei , Zhang Xin
Published: May 2019

ULK1-ATG13 is the most upstream autophagy initiation complex that is phosphorylated by mTORC1 and AMPK to induce autophagy in asynchronous conditions. However, the phospho-regulation and function of ULK1-ATG13 in mitosis and cell cycle remains unknown. Here we show that ULK1-ATG13 complex is differentially regulated throughout the cell cycle. Notably, in mitosis, both ULK1 and ATG13 are highly phosphorylated by CDK1/cyclin B, the key cell cycle machinery. Combining mass spectrometry and site-directed mutagenesis, we found that CDK1-induced ULK1-ATG13 phosphorylation positively regulates mitotic autophagy and Taxol chemosensitivity, and some phosphorylation sites occur in cancer patients. Moreover, double knockout of ULK1 and ATG13 could block cell cycle progression and significantly decrease cancer cell proliferation in cell line and mouse models. Our results not only bridge the mutual regulation between the core machineries of autophagy and mitosis, illustrate the mitotic autophagy regulation mechanism, but also provide ULK1-ATG13 as potential targets for cancer therapy.
Resolving noise-control conflict by gene duplication
Authors: Chapal Michal , Mintzer Sefi , Brodsky Sagie , Carmi Miri , Barkai Naama
Published: May 2019

Gene duplication promotes adaptive evolution in two principle ways: allowing one duplicate to evolve a new function and resolving adaptive conflicts by splitting ancestral functions between the duplicates. In an apparent departure from both scenarios, low-expressing transcription factor (TF) duplicates commonly regulate similar sets of genes and act in overlapping conditions. To examine for possible benefits of such apparently redundant duplicates, we examined the budding yeast duplicated stress regulators Msn2 and Msn4. We show that Msn2,4 indeed function as one unit, inducing the same set of target genes in overlapping conditions, yet this two-factor composition allows its expression to be both environmental-responsive and with low-noise, thereby resolving an adaptive conflict that inherently limits expression of single genes. Our study exemplified a new model for evolution by gene duplication whereby duplicates provide adaptive benefit through cooperation, rather than functional divergence: attaining two-factor dynamics with beneficial properties that cannot be achieved by a single gene.
Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer
Authors: Van Arsdale Anne , Patterson Nicole E. , Maggi Elaine C. , Agoni Lorenzo , Van Doorslaer Koenraad , Harmon Bryan , Nevadunsky Nicole , Kuo Dennis Y.S. , Einstein Mark H , Lenz Jack , Montagna Cristina
Published: May 2019

Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV-negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR- E6-E7-E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B-cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flankingBCL11BDNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70-BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novelBCL11Bvariants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV-associated tumorigenesis.

Statement of Significance

Multiple HPV types have been defined as high risk for cancer causation. However, genomic analyses applied here detected a non-high risk HPV in a carcinoma that was HPV negative, and elucidated virally-associated tumorigenic genetic events. This stresses the importance of thorough genomic analyses for elucidating genetic processes in HPV-associated tumorigenesis.

Author Summary

Cervical cancer is the second leading cause of cancer death in women worldwide. Most cervical cancers are caused by one of 15 high risk types of human papilloma viruses (HPVs), although hundreds of types of HPVs exist. We used a series of contemporary genomics analyses to examine a cervical cancer that was clinically determined to be HPV-negative. These detected DNA of HPV70, an HPV type not considered to be high risk, in the tumor. Approximately half of the HPV70 DNA genome was present including the viral E6 and E7 oncogenes. Moreover, the viral DNA was inserted into theBCL11Bgene in the human genome.BCL11Bis known to be mutated in certain human cancers. The HPV70 DNA interacted with the humanBCL11Bgene to produce altered forms of RNA encoding unusual, truncated forms of theBCL11Bprotein. These results strongly implicate HPV70 as being oncogenic, suggest that this tumor was caused by a combination of viral oncogenes plus the virally-activated humanBCL11Bgene, demonstrate novel truncatedBCL11Bvariants with oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate HPV tumorigenesis insights
Crystal structure and Hirshfeld surface analysis of a conformationally unsymmetrical bischalcone: (1E,4E)-1,5-bis(4-bromophenyl)penta-1,4-dien-3-one
Authors: Arif Tawfeeq Nabeel , Kwong Huey Chong , Mohamed Tahir Mohamed Ibrahim , Ravoof Thahira B. S. A.
Published: May 2019

In the title bischalcone, C17H12Br2O, the olefinic double bonds are almost coplanar with their attached 4-bromophenyl rings [torsion angles = −10.2 (4) and −6.2 (4)°], while the carbonyl double bond is in an s-trans conformation with with respect to one of the C=C bonds and an s-cis conformation with respect to the other [C=C—C=O = 160.7 (3) and −15.2 (4)°, respectively]. The dihedral angle between the 4-bromophenyl rings is 51.56 (2)°. In the crystal, molecules are linked into a zigzag chain propagating along [001] by weak C—H...π interactions. The conformations of related bischalcones are surveyed and a Hirshfeld surface analysis is used to investigate and quantify the intermolecular contacts.
2-Amino-6-chloropyridinium 3-carboxy-4-hydroxybenzenesulfonate
Authors: Manickam R. , Rajakannan V. , Prabhaharan M. , Srinivasan G.
Published: May 2019

In the 3-carboxy-4-hydroxybenzenesulfonate anion of the title salt, C5H6ClN2
+·C7H5O6S−, an intramolecular O—H...O hydrogen bond with an S(6) ring motif is observed. In the crystal, the anions are linked into a chain structure running along [1\overline{1}0] via an O—H...O hydrogen bond formed between the carboxy and sulfonate groups. The 2-amino-6-chloropyridinium cations bridge the anion chains via N—H...O and C—H...O hydrogen bonds, forming a sheet parallel to the ab plane. In the sheet, a C—H...Cl interaction between the cations is also observed.
μ-Carbonyl-bis(carbonyl{η5-[tricarbonyl(η6-2-methylindenyl)chromium(0)]rhodium(III)})(Rh—Rh)
Authors: Werlé Christophe , Bailly Corinne , Karmazin Lydia , Djukic Jean-Pierre
Published: May 2019

The structure of the title complex, [Cr2Rh2(C10H9)2(CO)9], was solved by single-crystal X-ray diffraction analysis in the P21/c space group. The crystal shows two units of the tetrametallic complex in the asymmetric unit. The most remarkable features of this new compound are the asymmetric bonding of the RhIII atom to the indenyl ligand, which can be formulated in terms of an η2;η3 coordination rather than η5, and the Rh—Rh distances of 2.6756 (6) and 2.6737 (6) Å that are characteristic of an intermetallic interaction supported by a bridging carbonyl ligand. The infrared spectroscopic signature informs of its clear bridging feature characterized by a significantly elongated C=O bond length compared to those in the two Rh-bound `terminal' carbonyl ligands.
The influence of platform incentives on actual carriers’ continuous participation intention of non-vehicle operating carrier platform
Authors: Xiao Liang , Ke Tongping
Published: May 2019

Purpose

Non-vehicle operating carrier platform is a typical crowdsourcing logistics platform that has achieved rapid development in China in recent years, and the sustainable development of non-vehicle operating carrier platform is underpinned by a large and stable professional user group. The purpose of this paper is to understand what platform incentives are available and to explore the influence mechanism of these incentives on actual carriers’ continuous intention to participate in non-vehicle operating carrier platform.

Design/methodology/approach

Based on organizational institution theory and behavioral motivation theory, the paper established the influence mechanism model of platform incentives on actual carriers’ continuous participation intention of non-vehicle operating carrier platform. A total of 300 questionnaires were distributed by Road Transportation Management Bureau of Zhejiang Province and a third-party questionnaire survey platform, and 176 valid questionnaires were collected. The partial least squares structural equation modeling (PLS-SEM) method based on PLS estimation was used to analyze the data.

Findings

The results revealed that the platform incentives have a significant influence on actual carriers’ continuous participation intention. The influence of the reputation incentive is the most profound, ranking first. The influence of the resource incentive is second to that of reputation incentive, ranking second. The influence of the bonus incentive ranks third. The operating cost perception, social value perception and functional value perception have significantly mediating effect. Furthermore, the mediating effect of social value perception and functional value perception is significantly higher than that of operating cost perception.

Originality/value

This study revealed the influence mechanism of platform incentives on actual carriers’ continuous participation intention of non-vehicle operating carrier platform. The relevant research results provided references for the establishment of platform incentive mechanism.
The impact of nostalgic emotion on brand trust and brand attachment
Authors: Wen Tao , Qin Tong , Liu Raymond R.
Published: May 2019

Purpose

The purpose of this paper is to make up the deficiency of theoretical research in nostalgic marketing and is helpful for the original theories of brand marketing and experiential marketing to deepen further.

Design/methodology/approach

The paper uses the approach of the empirical study. Based on the literature review, a theoretical model of the impact of nostalgic emotion (NE) on brand trust and brand attachment is constructed and corresponding research hypotheses are proposed. Then nostalgia-themed restaurants are selected to complete a questionnaire survey, and SPSS22.0 and LISREL8.70 are used for data analysis and hypothesis testing.

Findings

The results of the paper show that NE consists of four dimensions in the context of China: atmosphere nostalgia, interpersonal nostalgia, family nostalgia and personal nostalgia. Among these, NE has a significant positive impact on brand trust and brand attachment; further, brand trust has a significant positive impact on brand attachment and plays a partial mediating role in the impact of NE on the latter.

Research limitations/implications

As the nostalgic restaurant industry is the research object, the theoretical model described here may be limited to this specific industry. The potential applicability of the theoretical model to other service industries requires further study.

Practical implications

The results of the paper are helpful in building a good nostalgic experience, increasing consumer trust in restaurant brands, and strengthening the connection between NE and restaurant brand reconstruction.

Social implications

The results of the paper on the impact of NE on brand trust and brand attachment provide a referential basis and guide for services’ companies (e.g. restaurants) to revitalize the services’ brands.

Originality/value

The first contribution is that NE scale is constructed for the nostalgia-themed restaurants. The second contribution is that the paper reveals the mechanism of the impact of NE on brand trust and brand attachment.
E-commerce brand
Authors: Chiu Weisheng , Cho Heetae
Published: May 2019

Purpose

The purpose of this paper is to investigate the influence of perceived brand leadership of an e-commerce website on satisfaction and repurchase intention. Moreover, the different roles of gender and age were explored in the proposed model.

Design/methodology/approach

An online survey was administered to Chinese consumers (n=476) who have purchased products on e-commerce websites. Using SmartPLS 3.0 software, a partial least squares structural equation modeling analysis was conducted in this study.

Findings

The results showed that all factors of perceived brand leadership (i.e. quality, value, innovativeness and popularity) have positive influences on satisfaction, and in turn satisfaction significantly affects repurchase intention. Also, value and popularity have positive influences on repurchase intention. In addition, gender differences were found in the proposed model. More specifically, the influence of quality on satisfaction was stronger for male consumers, while the impact of popularity on satisfaction was stronger for female. In terms of age differences, the influence of quality on satisfaction was stronger for the consumers over 40 years old as compared to the younger consumers (i.e. the 20s). Moreover, the influence of innovativeness on satisfaction and repurchase intention was stronger for the 20s consumers as compared to the consumers who are over 40 years old.

Originality/value

This study attempts to apply the concept of brand leadership to the e-commerce setting by addressing differential consumption decision-making process. In addition, different gender and age groups reveal unique preferences and consumption patterns.