bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractExercise 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

ABSTRACTCooperative 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

AbstractThe 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

ABSTRACTGlutamate 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

AbstractSignal 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

AbstractPneumococcal 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

AbstractThe 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

AbstractIntroductionVestibular Myogenic Evoked Potential (VEMP) evaluates vestibulo-ocular and vestibulospinal reflexes associated with posture.PurposeTo compare cervical and ocular VEMP in individuals with HTLV-1 associated myelopathy (HAM) and with HTLV-1-asymptomatic infection.Materials and MethodsThis 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.ResultsCervical 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.ConclusionNeurological 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’ summaryHuman 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

AbstractULK1-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

AbstractGene 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

AbstractCervical 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 SignificanceMultiple 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 SummaryCervical 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
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.