bluuebunny/crossref_metadata_2025 huggingface dataset:
Secure Computing Resource Allocation Framework For Open Fog Computing
Authors: Jiang Jiafu , Tang Linyu , Gu Ke , Jia WeiJia
Published: September 2019

Fog computing has become an emerging environment that provides data storage, computing and some other services on the edge of network. It not only can acquire data from terminal devices, but also can provide computing services to users by opening computing resources. Compared with cloud computing, fog devices can collaborate to provide users with powerful computing services through resource allocation. However, as many of fog devices are not monitored, there are some security problems. For example, since fog server processes and maintains user information, device information, task parameters and so on, fog server is easy to perform illegal resource allocation for extra benefits. In this paper, we propose a secure computing resource allocation framework for open fog computing. In our scheme, the fog server is responsible for processing computing requests and resource allocations, and the cloud audit center is responsible for auditing the behaviors of the fog servers and fog nodes. Based on the proposed security framework, our proposed scheme can resist the attack of single malicious node and the collusion attack of fog server and computing devices. Furthermore, the experiments show our proposed scheme is efficient. For example, when the number of initial idle service devices is 40, the rejection rate of allocated tasks is 10% and the total number of sub-tasks is changed from 150 to 200, the total allocation time of our scheme is only changed from 15 ms to 25 ms; additionally, when the task of 5000 order matrix multiplication is tested on 10 service devices, the total computing time of our scheme is $\sim$250 s, which is better than that of single computer (where single computer needs more than 1500 s). Therefore, our proposed scheme has obvious advantages when it faces some tasks that require more computational cost, such as complex scientific computing, distributed massive data query, distributed image processing and so on.
Long-term prognostic value of morphological plaque features on coronary computed tomography angiography
Authors: Finck Tom , Stojanovic Antonija , Will Albrecht , Hendrich Eva , Martinoff Stefan , Hausleiter Jörg , Hadamitzky Martin
Published: September 2019

Aims

To investigate the incremental prognostic value of morphological plaque features beyond clinical risk and coronary stenosis levels. Although associated with the degree of coronary stenosis, most cardiac events occur on the basis of ruptured non-obstructive plaques and consecutive vessel thrombosis. As such, identification of vulnerable plaques is paramount for cardiovascular risk prediction and treatment decisions.

Methods and results

A total of 1615 patients with suspected but not previously diagnosed coronary artery disease (CAD) were examined by coronary computed tomography angiography and morphological plaque features were assessed. Mean follow-up was 10.5 (interquartile range 9.2–11.4) years. Cox proportional hazards analysis was used for the composite endpoint of cardiac death and non-fatal myocardial infarction. The study endpoint was reached in 51 patients (36 cardiac deaths, 15 non-fatal myocardial infarctions). In addition to quantitative parameters (presence of any calcified/non-calcified plaque or elevated plaque load), morphologic plaque features such as a spotty or gross calcification pattern and napkin-ring sign (NRS) were predictive for events. However, only spotty calcified plaques and NRS could confer additive prognostic value beyond clinical risk and coronary stenosis level. In a stepwise approach, endpoint prediction beyond clinical risk (Morise score) could be improved by inclusion of CAD severity (χ2 of 27.5, P < 0.001) and further discrimination for spotty calcified plaques (χ2 of 3.89, P = 0.049).

Conclusion

Improved cardiovascular risk prediction beyond clinical risk and coronary stenosis levels can be made by discriminating for the presence of spotty calcified plaques. Thus, an intensified prophylactic anti-atherosclerotic treatment appears to be warranted in patients with coronary plaques that show spotty calcifications.
Association of human papillomavirus infection and inflammation in cervical cancer
Authors: Hemmat Nima , Bannazadeh Baghi Hossein
Published: September 2019

Human papillomavirus (HPV) associated cancers, and in particular cervical cancer, are considered to be directly stimulated by HPV oncogenes. Alternatively, these types of cancers could also be indirectly stimulated by HPV-induced chronic inflammations, which in turn are also caused by HPV oncogenes activity. Chronic inflammation is associated with repeated tissue injury and development of mutations in the vital tumor suppressor genes. Thus, it is important to understand that the persistent HPV infection and its associated chronic inflammation is responsible for the progression of HPV-induced cancers. HPV E5, E6 and E7 could upregulate the expression of cyclooxygenase (COX)-2 and prostaglandin (PG) E2 followed by the activation of the COX-PG pathway. This pathway is assumed to be the main cause of HPV-induced inflammation. Additionally, HPV oncogenes could have an impact on the upregulation of pro-inflammatory cytokines in HPV-positive patients. The upregulation of such cytokines accelerates the incidence of inflammation following HPV infection. Other factors such as microRNAs, which are involved in the inflammation pathways and aging, give rise to the increased level of pro-inflammatory cytokines and could also be responsible for the acceleration of HPV-induced inflammation and consequent cervical cancer. In this review, the exact roles of HPV oncogenes in the occurrence of inflammation in cervical tissue, and the effects of other factors in this event are evaluated.
Molecular Evolution in Small Steps under Prevailing Negative Selection: A Nearly Universal Rule of Codon Substitution
Authors: Chen Qingjian , Lan Ao , Shen Xu , Wu Chung-I
Published: September 2019

The widely accepted view that evolution proceeds in small steps is based on two premises: 1) negative selection acts strongly against large differences and 2) positive selection favors small-step changes. The two premises are not biologically connected and should be evaluated separately. We now extend a previous approach to studying codon evolution in the entire genome. Codon substitution rate is a function of the physicochemical distance between amino acids (AAs), equated with the step size of evolution. Between nine pairs of closely related species of plants, invertebrates, and vertebrates, the evolutionary rate is strongly and negatively correlated with a set of AA distances (ΔU, scaled to [0, 1]). ΔU, a composite measure of evolutionary rates across diverse taxa, is influenced by almost all of the 48 physicochemical properties used here. The new analyses reveal a crucial trend hidden from previous studies: ΔU is strongly correlated with the evolutionary rate (R2 > 0.8) only when the genes are predominantly under negative selection. Because most genes in most taxa are strongly constrained by negative selection, ΔU has indeed appeared to be a nearly universal measure of codon evolution. In conclusion, molecular evolution at the codon level generally takes small steps due to the prevailing negative selection. Whether positive selection may, or may not, follow the small-step rule is addressed in a companion study.
Uniform Bound for the Number of Rational Points on a Pencil of Curves
Authors: Dimitrov Vesselin , Gao Ziyang , Habegger Philipp
Published: September 2019

Consider a one-parameter family of smooth, irreducible, projective curves of genus $g\ge 2$ defined over a number field. Each fiber contains at most finitely many rational points by the Mordell conjecture, a theorem of Faltings. We show that the number of rational points is bounded only in terms of the family and the Mordell–Weil rank of the fiber’s Jacobian. Our proof uses Vojta’s approach to the Mordell Conjecture furnished with a height inequality due to the 2nd- and 3rd-named authors. In addition we obtain uniform bounds for the number of torsion points in the Jacobian that lie in each fiber of the family.
Producing a BOSS CMASS sample with DES imaging
Authors: Lee S , Huff E M , Ross A J , Choi A , Hirata C , Honscheid K , MacCrann N , Troxel M A , Davis C , Eifler T F , Cawthon R , Elvin-Poole J , Annis J , Avila S , Bertin E , Brooks D , Carnero Rosell A , Carrasco Kind M , Carretero J , da Costa L N , De Vicente J , Desai S , Flaugher B , Fosalba P , García-Bellido J , Gaztanaga E , Gerdes D W , Gruen D , Gruendl R A , Gschwend J , Gutierrez G , Hollowood D L , James D J , Jeltema T , Kuehn K , Lima M , Maia M A G , Marshall J L , Martini P , Melchior P , Menanteau F , Miller C J , Miquel R , Ogando R L C , Palmese A , Plazas A A , Sanchez E , Scarpine V , Schubnell M , Serrano S , Sevilla-Noarbe I , Smith M , Soares-Santos M , Sobreira F , Suchyta E , Swanson M E C , Tarle G , Thomas D , Weller J , Zuntz J ,   (DES Collaboration)
Published: September 2019

We present a sample of galaxies with the Dark Energy Survey (DES) photometry that replicates the properties of the BOSS CMASS sample. The CMASS galaxy sample has been well characterized by the Sloan Digital Sky Survey (SDSS) collaboration and was used to obtain the most powerful redshift-space galaxy clustering measurements to date. A joint analysis of redshift-space distortions (such as those probed by CMASS from SDSS) and a galaxy–galaxy lensing measurement for an equivalent sample from DES can provide powerful cosmological constraints. Unfortunately, the DES and SDSS-BOSS footprints have only minimal overlap, primarily on the celestial equator near the SDSS Stripe 82 region. Using this overlap, we build a robust Bayesian model to select CMASS-like galaxies in the remainder of the DES footprint. The newly defined DES-CMASS (DMASS) sample consists of 117 293 effective galaxies covering $1244\,\deg ^2$. Through various validation tests, we show that the DMASS sample selected by this model matches well with the BOSS CMASS sample, specifically in the South Galactic cap (SGC) region that includes Stripe 82. Combining measurements of the angular correlation function and the clustering-z distribution of DMASS, we constrain the difference in mean galaxy bias and mean redshift between the BOSS CMASS and DMASS samples to be $\Delta b = 0.010^{+0.045}_{-0.052}$ and $\Delta z = \left(3.46^{+5.48}_{-5.55} \right) \times 10^{-3}$ for the SGC portion of CMASS, and $\Delta b = 0.044^{+0.044}_{-0.043}$ and $\Delta z= (3.51^{+4.93}_{-5.91}) \times 10^{-3}$ for the full CMASS sample. These values indicate that the mean bias of galaxies and mean redshift in the DMASS sample are consistent with both CMASS samples within 1σ.
Infrared-excess white dwarfs in the Gaia 100 pc sample
Authors: Rebassa-Mansergas A , Solano E , Xu(#x8BB8;#x5072;#x827A;) S , Rodrigo C , Jiménez-Esteban F M , Torres S
Published: September 2019

We analyse the 100 pc Gaia white dwarf volume-limited sample by means of VOSA (Virtual Observatory SED Analyser) with the aim of identifying candidates for displaying infrared excesses. Our search focuses on the study of the spectral energy distribution (SED) of 3,733 white dwarfs with reliable infrared photometry and GBP − GRP colours below 0.8 mag, a sample which seems to be nearly representative of the overall white dwarf population. Our search results in 77 selected candidates, 52 of which are new identifications. For each target we apply a two-component SED fitting implemented in VOSA to derive the effective temperatures of both the white dwarf and the object causing the excess. We calculate a fraction of infrared-excess white dwarfs due to the presence of a circumstellar disk of 1.6±0.2%, a value which increases to 2.6±0.3% if we take into account incompleteness issues. Our results are in agreement with the drop in the percentage of infrared excess detections for cool (<8,000 K) and hot (>20,000 K) white dwarfs obtained in previous analyses. The fraction of white dwarfs with brown dwarf companions we derive is ≃0.1–0.2%.
Cell-type-specific analysis of alternative polyadenylation using single-cell transcriptomics data
Authors: Shulman Eldad David , Elkon Ran
Published: September 2019

Alternative polyadenylation (APA) is emerging as an important layer of gene regulation because the majority of mammalian protein-coding genes contain multiple polyadenylation (pA) sites in their 3′ UTR. By alteration of 3′ UTR length, APA can considerably affect post-transcriptional gene regulation. Yet, our understanding of APA remains rudimentary. Novel single-cell RNA sequencing (scRNA-seq) techniques allow molecular characterization of different cell types to an unprecedented degree. Notably, the most popular scRNA-seq protocols specifically sequence the 3′ end of transcripts. Building on this property, we implemented a method for analysing patterns of APA regulation from such data. Analyzing multiple datasets from diverse tissues, we identified widespread modulation of APA in different cell types resulting in global 3′ UTR shortening/lengthening and enhanced cleavage at intronic pA sites. Our results provide a proof-of-concept demonstration that the huge volume of scRNA-seq data that accumulates in the public domain offers a unique resource for the exploration of APA based on a very broad collection of cell types and biological conditions.
Patients with end-stage kidney disease have markedly abnormal cortical hip parameters by dual-energy X-ray absorptiometry
Authors: Aleksova Jasna , Milat Frances , Kotowicz Mark A , Pasco Julie A , Schultz Chris , Wong Phillip , Ebeling Peter R , Elder Grahame J
Published: September 2019

Background

Patients with end-stage kidney disease (ESKD) have higher fracture rates and post-fracture mortality than the general population, but bone mineral density by dual-energy X-ray absorptiometry (DXA) is less predictive of fracture in this patient group. Bone biopsy and high-resolution imaging indicate that cortical thickness (CT) is reduced and cortical porosity is increased in ESKD. The aim of this study was to assess cortical parameters using DXA in patients with ESKD. It was hypothesized that these parameters would show deterioration and be associated with fracture.

Methods

Using advanced hip analysis, normal age-related ranges were determined from 752 female and 861 male femur scans and were compared with scans of 226 patients with ESKD at the time of transplantation.

Results

Compared with controls, female patients had lower mean±SD CT (mms) at the femoral neck (FN) (2.59 ± 1.42 versus 5.23 ± 1.85), calcar (3.46 ± 1.07 versus 5.09 ± 1.30) and shaft (4.42 ± 1.21 versus 7.44 ± 2.07; P < 0.001 for each), and buckling ratios were higher (8.21 ± 4.6 versus 3.63 ± 1.42; P < 0.001), indicating greater FN instability. All findings were similar for men. Prevalent fracture was documented in 28.8% of patients; 12.4% vertebral only, 8.4% non-vertebral only and 8% vertebral plus non-vertebral. In adjusted models, each 1 SD reduction in FN CT and increase in the buckling ratio was associated with a respective 1.73 (1.22–2.46)- and 1.82 (1.49–2.86)-fold increase in the risk of prevalent vertebral fracture.

Conclusions

In patients with ESKD, DXA-derived cortical parameters are markedly abnormal compared with age- and sex-matched controls. These parameters should be assessed for incident fracture prediction and targeting treatment.
Giant elephant trunks from giant molecular clouds
Authors: Sofue Yoshiaki
Published: September 2019

We report the discovery of large elephant trunk (ET)-like objects, named giant elephant trunks (GETs), of molecular gas in star-forming complexes in the Scutum and Norma arms using the $^{12}$CO(J = 1–0)-line survey data with the Nobeyama 45 m telescope. In comparison with the CO maps of ETs in M$\, 16$ as derived from the same data, we discuss physical properties of the GETs. Their lengths are $\sim\!\! 20$ to $50\:$pc, an order of magnitude larger than ETs. GETs show a cometary structure coherently aligned parallel to the galactic plane, and emerge from the bow-shaped concave surface of giant molecular clouds (GMC) facing the H$\,$ ii regions, and point down-stream of the gas flow in the spiral arms. The molecular masses of the head clumps are $\sim 10^{3}$–$10^{4}\, M_{\odot}$, about three to four times the virial masses, indicating that the clumps are gravitationally stable. Jeans masses calculated for the derived density and assumed kinetic temperature are commonly sub-solar. We suggest that the GET heads are possible birth sites of stellar clusters, similarly to ET globules, but at much greater scale. We discuss the origin of the GETs by Rayleigh–Taylor instability due to deceleration of GMCs by low-density gas stagnated in the galactic shock waves as well as by pressure of the H$\,$ ii regions.
The Development of Kraepelin’s Mature Diagnostic Concept of Catatonic Dementia Praecox: A Close Reading of Relevant Texts
Authors: Kendler Kenneth S
Published: September 2019

Through a close reading of texts, this essay traces the development of catatonia from its origination in Kahlbaum’s 1874 monograph to Kraepelin’s catatonic subtype of his new category of Dementia Praecox (DP) in 1899. In addition to Kraepelin’s second to sixth textbook editions, I examine the six articles referenced by Kraepelin: Kahlbaum 1874, Brosius 1877, Neisser 1887, Behr 1891, Schüle 1897, and Aschaffenburg 1897 (Behr and Aschaffenburg worked under Kraepelin). While Brosius and Neisser confirmed Kahlbaum’s descriptions, Behr, Schüle, and Aschaffenburg concluded that his catatonic syndrome was nonspecific and only more narrowly defined forms, especially those with deteriorating course, might be diagnostically valid. Catatonia is first described by Kraepelin as a subform of Verrücktheit (chronic nonaffective delusional insanity) in his second to fourth editions. In his third edition, he adds a catatonic form of Wahnsinn (acute delusional-affective insanity). His fourth and fifth editions contain, respectively, catatonic forms of his two proto-DP concepts: Psychischen Entartungsprocesse and Die Verblödungsprocesse. Kahlbaum’s catatonia required a sequential phasic course. Positive psychotic symptoms were rarely noted, and outcome was frequently good. While agreeing on the importance of key catatonic signs (stupor, muteness, posturing, verbigeration, and excitement), Kraepelin narrowed Kahlbaum’s concept, dropping the phasic course, emphasizing positive psychotic symptoms and poor outcome. In his fourth to sixth editions, as he tried to integrate his three DP subtypes, he stressed, as suggested by Aschaffenburg and Schüle, the close clinical relationship between catatonia and hebephrenia and emphasized the bizarre and passivity delusions seen in catatonia, typical of paranoid DP.
Toward a Neural Model of the Openness-Psychoticism Dimension: Functional Connectivity in the Default and Frontoparietal Control Networks
Authors: Blain Scott D , Grazioplene Rachael G , Ma Yizhou , DeYoung Colin G
Published: September 2019

Psychosis proneness has been linked to heightened Openness to Experience and to cognitive deficits. Openness and psychotic disorders are associated with the default and frontoparietal networks, and the latter network is also robustly associated with intelligence. We tested the hypothesis that functional connectivity of the default and frontoparietal networks is a neural correlate of the openness-psychoticism dimension. Participants in the Human Connectome Project (N = 1003) completed measures of psychoticism, openness, and intelligence. Resting state functional magnetic resonance imaging was used to identify intrinsic connectivity networks. Structural equation modeling revealed relations among personality, intelligence, and network coherence. Psychoticism, openness, and especially their shared variance were related positively to default network coherence and negatively to frontoparietal coherence. These associations remained after controlling for intelligence. Intelligence was positively related to frontoparietal coherence. Research suggests that psychoticism and openness are linked in part through their association with connectivity in networks involving experiential simulation and cognitive control. We propose a model of psychosis risk that highlights roles of the default and frontoparietal networks. Findings echo research on functional connectivity in psychosis patients, suggesting shared mechanisms across the personality–psychopathology continuum.
Triclosan-Selected Host-Associated Microbiota Perform Xenobiotic Biotransformations in Larval Zebrafish
Authors: Weitekamp Chelsea A , Phelps Drake , Swank Adam , McCord James , Sobus Jon R , Catron Tara , Keely Scott , Brinkman Nichole , Zurlinden Todd , Wheaton Emily , Strynar Mark , McQueen Charlene , Wood Charles E , Tal Tamara
Published: September 2019

Microbiota regulate important physiologic processes during early host development. They also biotransform xenobiotics and serve as key intermediaries for chemical exposure. Antimicrobial agents in the environment may disrupt these complex interactions and alter key metabolic functions provided by host-associated microbiota. To examine the role of microbiota in xenobiotic metabolism, we exposed zebrafish larvae to the antimicrobial agent triclosan. Conventionally colonized (CC), microbe-free axenic (AX), or axenic colonized on day 1 (AC1) zebrafish were exposed to 0.16–0.30 µM triclosan or vehicle on days 1, 6, 7, 8, and 9 days post fertilization (dpf). After 6 and 10 dpf, host-associated microbial community structure and putative function were assessed by 16S rRNA gene sequencing. At 10 dpf, triclosan exposure selected for bacterial taxa, including Rheinheimera. Triclosan-selected microbes were predicted to be enriched in pathways related to mechanisms of antibiotic resistance, sulfonation, oxidative stress, and drug metabolism. Furthermore, at 10 dpf, colonized zebrafish contained 2.5–3 times more triclosan relative to AX larvae. Nontargeted chemical analysis revealed that, relative to AX larvae, both cohorts of colonized larvae showed elevations in 23 chemical features, including parent triclosan and putative triclosan sulfate. Taken together, these data suggest that triclosan exposure selects for microbes that harbor the capacity to biotransform triclosan into chemical metabolites with unknown toxicity profiles. More broadly, these data support the concept that microbiota modify the toxicokinetics of xenobiotic exposure.
Impact of spectrograms on the classification of wheezes and crackles in an educational setting. An interrater study
Authors: Aviles-Solis JC. , Storvoll I , Sophie Vanbelle , Melbye H.
Published: September 2019

Background

Chest auscultation is a widely used method in the diagnosis of lung diseases. However, the interpretation of lung sounds is a subjective task and disagreements arise. New technological developments like the use of visual representation of sounds through spectrograms could improve the agreement when classifying lung sounds, but this is not yet known.

Aims

To test if the use of spectrograms improves the agreement when classifying wheezes and crackles.

Methods

We used 30 lung sounds recordings. The sample contained 15 normal recordings and 15 with wheezes or crackles. We produced spectrograms of the recordings. Twenty-three third to fifth-year medical students at UiT the Arctic University of Norway classified the recordings using an online questionnaire. We first showed the students examples of how wheezes and crackles looked in the spectrogram. Then, we played the recordings in a random order two times, first without the spectrogram, then with live spectrograms displayed. We asked them to classify the sounds for the presence of wheezes and crackles. We calculated kappa values for the agreement between each student and the expert classification with and without display of spectrograms and tested for significant improvement. We also calculated Fleiss kappa for the 23 observers with and without the spectrogram.

Results

When classifying wheezes 13/23 (1 with p<.05) students had a positive change in k, and 16/23 (2 with p<.05). All the statistically significant changes were in the direction of improved kappa values (.52 - .75). Fleiss kappa values were k=.51 and k=.56 (p=.63) for wheezes without and with spectrograms. For crackles, these values were k=.22 and k=.40 (p=<0.01) in the same order.

Conclusions

The use of spectrograms had a positive impact on the inter-rater agreement and the agreement with experts. We observed a higher improvement in the classification of crackles compared to wheezes.
Mobile Brain/Body Imaging of cognitive-motor impairment in multiple sclerosis: deriving EEG-based neuro-markers during a dual-task walking study
Authors: Sanctis Pierfilippo De , Malcolm Brenda R. , Mabie Peter C. , Francisco Ana A. , Mowrey Wenzhu B. , Joshi Sonja , Molholm Sophie , Foxe John J.
Published: September 2019

Individuals with a diagnosis of multiple sclerosis (MS) often present with deficits in the cognitive as well as the motor domain. The ability to perform tasks that rely on both domains may therefore be particularly impaired. Yet, behavioral studies designed to measure costs associated with performing two tasks at the same time such as dual-task walking have yielded mixed results. Patients may mobilize additional brain resources to sustain good levels of performance. To test this hypothesis, we acquired event-related potentials (ERP) in thirteen individuals with MS and fifteen healthy control (HC) participants performing a Go/NoGo response inhibition task while sitting (i.e., single task) or walking on a treadmill (i.e., dual-task). In previous work, we showed that the nogo-N2 elicited by the cognitive task was reduced when healthy adults are also asked to walk, and that nogo-N2 reduction was accompanied by sustained dual-task performance. We predicted that some MS patients, similar to their healthy peers, may mobilize N2-indexed brain resources and thereby reduce costs. Somewhat to our surprise, the HC group performed the Go/NoGo task more accurately while walking, thus showing a dual-task benefit, whereas, in line with expectation, the MS group showed a trend towards dual-task costs. The expected nogo-N2 reduction during dual-task walking was found in the HC group, but was not present at the group level in the MS group, suggesting that this group did not modulate the nogo-N2 process in response to higher task load. Regression analysis for the pooled sample revealed a robust link between nogo-N2 reduction and better dual-task performance. We conclude that impaired nogo-N2 adaptation reflects a neurophysiological marker of cognitive-motor dysfunction in MS.
Generation of fluorescent cell-derived-matrix to study 3D cell migration
Authors: Godeau Amélie Luise , Delanoë-Ayari Hélène , Riveline Daniel
Published: September 2019

Abstract

Cell migration is involved in key phenomena in biology, ranging from development to cancer. Fibroblasts move between organs in 3D polymeric networks. So far, motile cells were mainly tracked in vitro on Petri dishes or on coverslips, i.e. 2D flat surfaces, which made the extrapolation to 3D physiological environments difficult. We therefore prepared 3D Cell Derived Matrix (CDM) with specific characteristics with the goal of extracting the main readouts required to measure and characterise cell motion: cell specific matrix deformation through the tracking of fluorescent fibronectin within CDM, focal contacts as the cell anchor and acto-myosin cytoskeleton which applies cellular forces. We report our method for generating this assay of physiological-like gel with relevant readouts together with its potential impact in explaining cell motility in vivo.
Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study
Authors: Kokkinou Michelle , Irvine Elaine E. , Bonsall David R. , Natesan Sridhar , Wells Lisa A. , Smith Mark , Glegola Justyna , Paul Eleanor J. , Tossell Kyoko , Veronese Mattia , Khadayate Sanjay , Dedic Nina , Hopkins Seth C. , Ungless Mark A. , Withers Dominic J. , Howes Oliver D.
Published: September 2019

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. However, the mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we test this in a translational mouse imaging study using a ketamine model. Mice were treated with sub-chronic ketamine (30mg/kg) or saline followed byin-vivopositron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open field test.In-vivocell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d=2.5,P<0.001)and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of cortical and ventral subiculum PV interneurons. Sub-chronic ketamine reduced PV expression in these neurons. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1), significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, and suggest an underlying neurocircuit involving PV interneuron hypofunction in frontal cortex and hippocampus as well as activation of midbrain dopamine neurons. A novel TAAR1 agonist reversed the dopaminergic alterations suggesting a therapeutic mechanism for targeting presynaptic dopamine dysfunction in patients.
Real brains in virtual worlds: Validating a novel oddball paradigm in virtual reality
Authors: Kuziek Jonathan W. P. , Tayem Abdel R. , Burrell Jennifer I. , Redman Eden X. , Murray Jeff , Reinen Jenna , Sipolins Aldis , Mathewson Kyle E.
Published: September 2019

Electroencephalography (EEG) research is typically conducted in controlled laboratory settings. This limits the generalizability to real-world situations. Virtual reality (VR) sits as a transitional tool that provides tight experimental control with more realistic stimuli. To test the validity of using VR for event-related potential (ERP) research we used a well-established paradigm, the oddball task. For our first study, we compared VR to traditional, monitor-based stimulus presentation using visual and auditory oddball tasks while EEG data was recorded. We were able to measure ERP waveforms typically associated with such oddball tasks, namely the P3 and earlier N2 components, in both conditions. Our results suggest that ERPs collected using VR head mounted displays and typical monitors were comparable on measures of latency, amplitude, and spectral composition. In a second study, we implemented a novel depth-based oddball task and we were able to measure the typical oddball-related ERPs elicited by the presentation of near and far stimuli. Interestingly, we observed significant differences in early ERPs components between near and far stimuli, even after controlling for the effects of the oddball task. Current results suggest that VR can serve as a valid means of stimulus presentation in novel or otherwise inaccessible environments for EEG experimentation. We demonstrated the capability of a depth-based oddball in reliably eliciting a P3 waveform. We also found an interaction between the depth at which objects are presented and early ERP responses. Further research is warranted to better explain this influence of depth on the EEG and ERP activity.
Wasting food is disgusting: Evidence from behavioral and neuroimaging study of moral judgment of food-wasting behavior
Authors: Marczak Michalina , Marchewka Artur , Wypych Marek , Misiak Michał , Droździel Dawid , Sorokowski Piotr , Sorokowska Agnieszka
Published: September 2019

Food-wasting has a profound negative social and environmental impact. Acknowledging that referring to moral judgment can motivate behavior change, the present study aimed to determine moral intuitions underlying the perception of food-wasting behavior. We developed a set of affective standardized scenarios and we used them to collect behavioral and neuroimaging data. In the main study, 50 participants made moral judgments regarding food-wasting, disgusting, harmful, dishonest, or neutral behaviors presented in these scenarios. We found that wasting food was considered morally wrong and it was associated with moral disgust. Neuroimaging data revealed that food-wasting stimuli elicited an increased activity in structures associated with moral judgment, as well as in regions involved in the processing of moral, but also physical disgust. We discuss our results in the context of the evolutionary significance of food that might have led to seeing food-wasting as a moral transgression.
Undulating changes in human plasma proteome across lifespan are linked to disease
Authors: Lehallier Benoit , Gate David , Schaum Nicholas , Nanasi Tibor , Lee Song Eun , Yousef Hanadie , Losada Patricia Moran , Berdnik Daniela , Keller Andreas , Verghese Joe , Sathyan Sanish , Franceschi Claudio , Milman Sofiya , Barzilai Nir , Wyss-Coray Tony
Published: September 2019

Aging is the predominant risk factor for numerous chronic diseases that limit healthspan. Mechanisms of aging are thus increasingly recognized as therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues, pointing to the intriguing possibility that age-related molecular changes in blood can provide novel insight into disease biology. We measured 2,925 plasma proteins from 4,331 young adults to nonagenarians and developed a novel bioinformatics approach which uncovered profound non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh, and eighth decades of life reflected distinct biological pathways, and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways of aging and disease and offers potential pathways for aging interventions.
Mathematical model shows how sleep may affect amyloid β fibrillization
Authors: Hoore Masoud , Khailaie Sahamoddin , Montaseri Ghazal , Mitra Tanmay , Meyer-Hermann Michael
Published: September 2019

Deposition of amyloid β (Aβ) fibers in extra-cellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimer’s disease (AD). While many of the biological aspects that contribute to the formation of Aβ plaques are well addressed at the intra- and inter-cellular level in short timescales, an understanding of how Aβ fibrillization usually starts to dominate at a longer timescale in spite of the presence of mechanisms dedicated to Aβ clearance, is still lacking. Furthermore, no existing mathematical model integrates the impact of diurnal neural activity as emanated from circadian regulation to predict disease progression due to a disruption in sleep-wake cycle. In this study, we develop a minimal model of Aβ fibrillization to investigate the onset of AD over a long time-scale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble Aβ (sAβ) to fibrillar Aβ (fAβ) domination upon surpassing a threshold in the production rate of soluble Aβ. By incorporating the circadian rhythm into our model, we reveal that fAβ accumulation is crucially dependent on the regulation of sleep-wake cycle, thereby indicating the importance of a good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fAβ accumulation in the brain by modification of the critical sAβ production rate.
Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice
Authors: Grandjean Joanes , Buehlmann David , Buerge Michaela , Sigrist Hannes , Seifritz Erich , Vollenweider Franz X. , Pryce Christopher R. , Rudin Markus
Published: September 2019

Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that is involved in self-reference and displays altered FC in depressive disorders. In this study we investigated the effects of psilocybin on FC in the analogue of the DMN in mouse, with a view to establishing an experimental animal model to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin-relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interaction between 5-HT- and DA-regulated neural networks contributes to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.
Singular manifolds of proteomic drivers to model the evolution of inflammatory bowel disease status
Authors: Morilla Ian , Léger Thibaut , Marah Assiya , Pic Isabelle , Zaag Hatem , Ogier-Denis Eric
Published: September 2019

The conditions who denotes the presence of an immune disease are often represented by interaction graphs. These informative, but complex structures are susceptible to being perturbed at different levels. The mode in which that perturbation occurs is still of utmost importance in areas such as reprogramming therapeutics. In this sense, the overall graph architecture is well characterise by module identification. Topological overlap-related measures make possible the localisation of highly specific module regulators that can perturb other nodes, potentially causing the entire system to change behaviour or collapse. We provide a geometric framework explaining such situations in the context of inflammatory bowel diseases (IBD). IBD are important chronic disorders of the gastrointestinal tract which incidence is dramatically increasing worldwide. Our approach models different IBD status as Riemannian manifolds defined by the graph Laplacian of two high throughput proteome screenings. Identifies module regulators as singularities within the manifolds (the so-called singular manifolds). And reinterprets the characteristic IBD nonlinear dynamics as compensatory responses to perturbations on those singularities. Thus, we could control the evolution of the disease status by reconfiguring particular setups of immune system to an innocuous target state.
SMN-primed ribosomes modulate the translation of transcripts related to Spinal Muscular Atrophy
Authors: Lauria F , Bernabò P , Tebaldi T , Groen EJN , Perenthaler E , Clamer M , Maniscalco F , Marchioretto M , Orri Julia , Dalla Serra M , Inga A , Quattrone A , Gillingwater TH , Viero G
Published: September 2019

The contribution of ribosome heterogeneity and ribosome-associated factors to the molecular control of proteomes in health and disease remains enigmatic. We demonstrate that Survival Motor Neuron (SMN) protein, loss of which causes the neuromuscular disease spinal muscular atrophy (SMA), binds to ribosomes and that this interaction is tissue-dependent. SMN-primed ribosomes are positioned within the first five codons of a set of mRNAs which are enriched in IRES-like sequences in the 5’UTR and rare codons at the beginning of their coding sequence. Loss of SMN at early-stages of SMA induces translational defectsin vivo,characterized by ribosome depletion in rare codons at the third and fifth position of the coding sequence. These positional defects cause ribosome depletion from mRNAs bound by SMN-primed ribosomes and translational impairment of proteins involved in motor neuron function and stability, including acetylcholinesterase. Thus, SMN plays a crucial role in the regulation of ribosome fluxes along mRNAs which encode proteins relevant to SMA pathogenesis.
A neuroendocrine feedback loop inC. elegansmales integrates food detection and biological sex to modulate chemoreceptor expression and behavioral flexibility
Authors: Wexler Leigh R. , Miller Renee M. , Portman Douglas S.
Published: September 2019

Dynamic integration of internal and external cues is essential for flexible, adaptive animal behavior. InC. elegans, biological sex and feeding state regulate expression of the food-associated chemoreceptorodr-10, contributing to plasticity in food detection and the decision between feeding and exploration. In adult hermaphrodites,odr-10expression is high; in well-fed adult males,odr-10expression is low, promoting exploratory mate-searching behavior. Food-deprivation transiently activates maleodr-10expression, heightening food sensitivity and reducing food-leaving. Here, we identify a neuroendocrine feedback loop that sex-specifically regulatesodr-10in response to food deprivation. In well-fed males, insulin-like (IIS) and TGFβ signaling repressodr-10expression. Upon food deprivation,odr-10is directly activated by DAF-16/FoxO, the canonicalC. elegansIIS effector. The TGFβ ligand DAF-7 acts upstream of IIS, and, likely because of its sexually dimorphic expression in the nervous system, links feeding toodr-10only in males. Surprisingly, these responses to food deprivation are not triggered by internal metabolic cues, but rather by the loss of sensory signals from food. In the presence of inedible food, males become metabolically starved but express levels ofodr-10anddaf-7comparable to those of well-fed males. Further, exposing food-deprived males to inedible food is sufficient to restore lowodr-10expression. Food signals are detected by a small number of sensory neurons whose activity non-autonomously regulatesdaf-7expression, IIS, andodr-10. Thus, adultC. elegansmales employ a neuroendocrine feedback loop that integrates food detection and genetic sex to dynamically modulate chemoreceptor expression and sensory behavior.
The versican-hyaluronan complex provides an essential extracellular matrix niche for Flk1+ hematoendothelial progenitors
Authors: Nandadasa Sumeda , O’Donnell Anna , Murao Ayako , Yamaguchi Yu , Midura Ronald J. , Olson Lorin , Apte Suneel S.
Published: September 2019

Little is known about extracellular matrix (ECM) contributions to formation of the earliest cell lineages in the embryo. Here, we show that the proteoglycan versican and glycosaminoglycan hyaluronan are associated with emerging Flk1+hematoendothelial progenitors at gastrulation. The mouse versican mutantVcanhdflacks yolk sac vasculature, with attenuated yolk sac hematopoiesis. CRISPR/Cas9-mediatedVcaninactivation in mouse embryonic stem cells reduced vascular endothelial and hematopoietic differentiation in embryoid bodies, which generated fewer blood colonies, and had an impaired angiogenic response to VEGF165. HA was severely depleted inVcanhdfembryos, with corresponding increase in the HA-depolymerase TMEM2. Conversely, HA-deficient mouse embryos also had vasculogenic suppression but with increased versican proteolysis. VEGF165and Indian hedgehog, crucial vasculogenic factors, utilized the versican-HA matrix, specifically versican chondroitin sulfate chains, for binding. Versican-HA ECM is an obligate requirement for vasculogenesis and primitive hematopoiesis, acts as an vasculogenic factor-enriching microniche for Flk1+progenitors from their origin at gastrulation.
Interspecies transcriptome analyses identify genes that control the development and evolution of limb skeletal proportion
Authors: Saxena Aditya , Sharma Virag , Neufeld Stanley J. , Tran Mai P. , Gutierrez Haydee L. , Erberich Joel M. , Birmingham Amanda , Cobb John , Hiller Michael , Cooper Kimberly L.
Published: September 2019

Despite the great diversity of vertebrate limb proportion and our deep understanding of the genetic mechanisms that drive skeletal elongation, little is known about how individual bones reach different lengths in any species. Here, we directly compare the transcriptomes of homologous growth cartilages of the mouse (Mus musculus) and bipedal jerboa (Jaculus jaculus), which has extremely long metatarsals of the feet and ‘mouse-like’ arms. When we intersected gene expression differences in metatarsals of the two species with expression differences in forearms, we found that about 10% of all orthologous genes are associated with disproportionate elongation of jerboa feet. Among these,Shox2, has gained expression in jerboa metatarsals where it is not expressed in other vertebrates that have been assessed. This transcription factor is necessary for proximal limb elongation, and we show that it is sufficient to increase mouse distal limb length. Unexpectedly, we also found evidence that jerboa foot elongation occurs in part by releasing latent growth potential that is repressed in mouse feet. In jerboa metatarsals, we observed higher expression ofCrabp1, an antagonist of growth inhibitory retinoic acid, lower expression ofGdf10, an inhibitory TGFβ ligand, and lower expression ofMab21L2, a BMP signaling inhibitor that we show is sufficient to reduce limb bone elongation. By intersecting our data with prior expression analyses in other systems, we identify mechanisms that may both establish limb proportion during development and diversify proportion during evolution. The genes we identified here therefore provide a framework to understand the modular genetic control of skeletal growth and the remarkable malleability of vertebrate limb proportion.
The Role of Hvem and its Interaction with Btla and Cd160 in b-Cell Lymphoma Progression
Authors: de Juan Carla Yago-Diez
Published: September 2019

Despite the fact that the cell surface receptor HVEM (TNFRSF14) appears to be implicated in the development and progression of B-cell lymphomas, its specific role in these tumours is still unclear. On the one hand, HVEM over-expression is related to worse prognosis in some types of B-cell lymphoma and other solid tumours. On the other hand, most mutations of HVEM in B-cell lymphomas are thought to promote tumour growth through the loss of function. Here, we used a CRISPR-Cas9 system to study the effect of HVEM loss on gene expression in a murine model of A20 B-cell lymphoma (belonging to the diffuse large B-cell lymphoma group). We show that loss of HVEM does not affect the doubling rate of A20 tumour cells in culture, but leads to a decrease in BTLA expression. HVEM-deficient A20 cells do not present a different pattern of metastatic dissemination to lymphoid organs compared with unmodified A20 cells. However, we observed a significant expansion of endogenous B-cells as a result of A20 tumour implantation in the thymus. Although we found no differences in the dissemination or progression of HVEM-deficient A20 cells, our results reveal that loss of HVEM alters the leukocyte recruitment capacity of A20 cells in hepatic tumour nodules at the intermediate stage of tumour development, which may be of relevance as a mechanism of immune evasion.