bluuebunny/crossref_metadata_2025_split huggingface dataset:
The migraine eye: distinct rod-driven retinal pathways' response to dim light challenges the visual cortex hyperexcitability theory
Authors: Bernstein Carolyn A. , Nir Rony-Reuven , Noseda Rodrigo , Fulton Anne B. , Huntington Shaelah , Lee Alice J. , Bertisch Suzanne M. , Hovaguimian Alexandra , Buettner Catherine , Borsook David , Burstein Rami 
Published: November 2018

Abstract
Migraine-type photophobia, most commonly described as exacerbation of headache by light, affects nearly 90% of the patients. It is the most bothersome symptom accompanying an attack. Using subjective psychophysical assessments, we showed that migraine patients are more sensitive to all colors of light during ictal than during interictal phase and that control subjects do not experience pain when exposed to different colors of light. Based on these findings, we suggested that color preference is unique to migraineurs (as it was not found in control subjects) rather than migraine phase (as it was found in both phases). To identify the origin of this photophobia in migraineurs, we compared the electrical waveforms that were generated in the retina and visual cortex of 46 interictal migraineurs to those generated in 42 healthy controls using color-based electroretinography and visual-evoked potential paradigms. Unexpectedly, it was the amplitude of the retinal rod-driven b wave, which was consistently larger (by 14%-19% in the light-adapted and 18%-34% in the dark-adapted flash ERG) in the migraineurs than in the controls, rather than the retinal cone-driven a wave or the visual-evoked potentials that differs most strikingly between the 2 groups. Mechanistically, these findings suggest that the inherent hypersensitivity to light among migraine patients may originate in the retinal rods rather than retinal cones or the visual cortex. Clinically, the findings may explain why migraineurs complain that the light is too bright even when it is dim to the extent that nonmigraineurs feel as if they are in a cave.
The association between obesity and outcomes in acute pancreatitis: an individual patient data meta-analysis
Authors: Smeets Xavier J.N.M. , Knoester Iris , Grooteman Karina V. , Singh Vikesh K. , Banks Peter A. , Papachristou Georgios I. , Duarte-Rojo Andres , Robles-Diaz Guillermo , Kievit Wietske , Besselink Marc G.H. , Verdonk Robert C. , Van Santvoort Hjalmar C. , Drenth Joost P.H. , Belias Michael , Van Geenen Erwin J.M. 
Published: November 2018

Objectives
There are data to suggest that obesity is associated with local and systemic complications as well as mortality in acute pancreatitis (AP). Cohort studies to date, however, have shown conflicting results from mostly unadjusted analyses. Therefore, we performed an individual patient data meta-analysis with the primary aim to investigate the association between obesity and mortality in AP. Our secondary aim was to investigate the association between obesity and necrosis, organ failure, multiple organ failure, and invasive intervention.

Patients and methods
We systematically searched four electronic databases for prospective studies on obesity and outcomes in AP. Researchers of eligible studies were invited to share individual patient data using a standardized data collection form. All end points were investigated with a one-stage mixed effects Poisson model with random intercepts and forced entry of relevant confounders.

Results
We included five databases with 1302 patients, of whom 418 (32%) were obese. In total, 466 (36%) patients had necrosis, 328 (25%) had organ failure, 188 (14%) had multiple organ failure, 210 (16%) had an intervention, and 84 (7%) patients died. We found no significant association between obesity and mortality [relative risk (RR) 1.40, 95% confidence interval (CI): 0.89–2.20], necrosis (RR: 1.08, 95% CI: 0.90–1.31) or invasive intervention (RR: 1.10, 95% CI: 0.83–1.47) after adjustment for confounders. However, obesity was independently associated with the development of organ failure (RR: 1.38, 95% CI: 1.11–1.73) and multiple organ failure (RR: 1.81, 95% CI: 1.35–2.42).

Conclusion
Obesity is independently associated with the development of organ failure and multiple organ failure in AP. However, there is no association between obesity and mortality, necrosis, and an intervention.
Classical-contextual interactions in V1 may rely on dendritic computations
Authors: Jin Lei , Behabadi Bardia F. , Jadi Monica P. , Ramachandra Chaithanya A. , Mel Bartlett W. 
Published: November 2018

AbstractA signature feature of the neocortex is the dense network of horizontal connections (HCs) through which pyramidal neurons (PNs) exchange “contextual” information. In primary visual cortex (V1), HCs are thought to facilitate boundary detection, a crucial operation for object recognition, but how HCs modulate PN responses to boundary cues within their classical receptive fields (CRF) remains unknown. We began by “asking” natural images, through a structured data collection and ground truth labeling process, what function a V1 cell should use to compute boundary probability from aligned edge cues within and outside its CRF. The “answer” was an asymmetric 2-D sigmoidal function, whose nonlinear form provides the first normative account for the “multiplicative” center-flanker interactions previously reported in V1 neurons (Kapadia et al. 1995, 2000; Polat et al. 1998). Using a detailed compartmental model, we then show that this boundary-detecting classical-contextual interaction function can be computed with near perfect accuracy by NMDAR-dependent spatial synaptic interactions within PN dendrites – the site where classical and contextual inputs first converge in the cortex. In additional simulations, we show that local interneuron circuitry activated by HCs can powerfully leverage the nonlinear spatial computing capabilities of PN dendrites, providing the cortex with a highly flexible substrate for integration of classical and contextual information.Significance StatementIn addition to the driver inputs that establish their classical receptive fields, cortical pyramidal neurons (PN) receive a much larger number of “contextual” inputs from other PNs through a dense plexus of horizontal connections (HCs). However by what mechanisms, and for what behavioral purposes, HC’s modulate PN responses remains unclear. We pursued these questions in the context of object boundary detection in visual cortex, by combining an analysis of natural boundary statistics with detailed modeling PNs and local circuits. We found that nonlinear synaptic interactions in PN dendrites are ideally suited to solve the boundary detection problem. We propose that PN dendrites provide the core computing substrate through which cortical neurons modulate each other’s responses depending on context.
Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease
Authors: Özen Ayşegül , Lin Kuan-Hung , Romano Keith P , Tavella Davide , Newton Alicia , Petropoulos Christos J. , Huang Wei , Aydin Cihan , Schiffer Celia A. 
Published: November 2018

AbstractHepatitis C virus rapidly evolves, conferring resistance to direct acting antivirals. While resistance via active site mutations in the viral NS3/4A protease has been well characterized, the mechanism for resistance of non-active site mutations is unclear. R155K and V36M often co-evolve and while R155K alters the electrostatic network at the binding site, V36M is more than 13 Å away. In this study the mechanism by which V36M confers resistance, in the context of R155K, is elucidated with drug susceptibility assays, crystal structures, and molecular dynamics (MD) simulations for three protease inhibitors: telaprevir, boceprevir and danoprevir. The R155K and R155K/V36M crystal structures differ in the α-2 helix and E2 strand near the active site, with alternative conformations at M36 and side chains of active site residues D168 and R123, revealing an allosteric coupling, which persists dynamically in MD simulations, between the distal mutation and the active site. This allosteric modulation validates the network hypothesis and elucidates how distal mutations confer resistance through propagation of conformational changes to the active site.
A High-Resolution Luminescent Assay for Rapid and Continuous Monitoring of Protein Translocation Across Biological Membranes
Authors: Pereira Gonçalo C. , Allen William J. , Watkins Daniel W. , Buddrus Lisa , Noone Dylan , Liu Xia , Richardson Andrew , Chacinska Agnieszka , Collinson Ian 
Published: November 2018

ABSTRACTProtein translocation is a fundamental process in biology. Major gaps in our understanding of this process arises due the poor sensitivity, low time-resolution and irreproducibility of translocation assays. To address this, we applied NanoLuc split-luciferase to produce a new strategy for measuring protein transport. The system reduces the timescale of data collection from days to minutes, and allows continuous acquisition with a time-resolution in the order of seconds – yielding kinetics parameters suitable for mechanistic elucidation and mathematical fitting. To demonstrate its versatility, we implemented and validated the assayin vitroandin vivofor the bacterial Sec system, and the mitochondrial protein import apparatus. Overall, this technology represents a major step forward, providing a powerful new tool for fundamental mechanistic enquiry of protein translocation and for inhibitor (drug) screening, with an intensity and rigour unattainable through classical methods.
AMPK-Fyn signaling promotes Notch1 stability to potentiate hypoxia-induced breast cancer stemness and drug resistance
Authors: Lahiry Mohini , Kumar Saurav , Hari Kishore , Chedere Adithya , Jolly Mohit Kumar , Rangarajan Annapoorni 
Published: November 2018

SummaryHypoxia is a hall mark of solid tumor microenvironment and contributes to tumor progression and therapy failure. The developmentally important Notch pathway is implicated in cellular response of cancer cells to hypoxia. Yet, the mechanisms that potentiate Notch signaling under hypoxia are not fully understood. Hypoxia is also a stimulus for AMP-activated protein kinase (AMPK), a major cellular energy sensor. In this study, we investigated if AMPK interacts with the Notch pathway and influences the hypoxia-response of breast cancer cells. Activating AMPK with pharmacological agent or genetic approaches led to an increase in the levels of cleaved Notch1 and elevated Notch signaling in invasive breast cancer cell lines. In contrast, inhibition or depletion of AMPK reduced the amount of cleaved Notch1. Significantly, we show that the hypoxia-induced increase in cleaved Notch1 levels requires AMPK activation. Probing into the mechanism, we demonstrate that AMPK activation impairs the interaction between cleaved Notch1 and its ubiquitin ligase, Itch/AIP4 through the tyrosine kinase Fyn. Under hypoxia, the AMPK-Fyn axis promotes inhibitory phosphorylation of Itch which abrogates its interaction with substrates, thus stabilizing cleaved Notch1 by reducing its ubiquitination and degradation. We further show that inhibition of AMPK alleviates the hypoxia-triggered, Notch-mediated stemness and drug resistance phenotype. Breast cancer patient samples also showed co-expression of hypoxia/AMPK/Notch gene signature. Our work thus establishes AMPK as a key component in the adaptation of breast cancer cells to hypoxia, and proposes therapeutic inhibition of AMPK to mitigate the hypoxia-triggered aggressiveness.
Dedicated acetic acid preference coded by broad spectrum ionotropic receptors in a moth species
Authors: Tang Rui , Jiang Nan-Ji , Ning Chao , Huang Ling-Qiao , Wang Chen-Zhu 
Published: November 2018

AbstractAcetic acid as one of the food related odorant cues attracts many insect species. In the moth Mythimna separata, the olfaction of acid was coded via multiple pathways including 3 sensilla types on the antennae and 3 glomeruli in the antennal lobes. Among, suitable dosages of acetic acid exclusively activated DC3 glomerulus that receives integrated projections across sensilla types, which drives attractiveness and feeding attempts of the moth. This circuit encodes broad spectrum ionotropic receptors 8a, 75q1 and 75q2 which were sufficient to confer acid responsiveness in Xenopus oocytes. Ir75q2 was expressed in vivo with Ir75q1 and it enhanced sensitivity of the receptor functional group toward acids. Furthermore, Ir75q1 and Ir75q2 are both necessary for the moth to conduct acetic acid induced reactions of sensilla, DC3 glomerulus as well as attractiveness. Together, it reveals that an indispensable tetramer IR-based unit is employed to fulfill acetic acid specialized preference under suitable dosages through balancing of transcription and peripheral coding. Understanding of the Ir75q1/2 olfactory pathway provides insights into investigations on acid sensory process in insects.Author SummaryThe preference to acids are common in various organisms, and it may involve both olfactory and gustatory reception. In particular, airborne acidity volatiles can be sensed through antennae of insects and later assessed to help locating foraging, mating, and egg laying sites. However, these stimulatory processes can only be delivered by suitable dosages of acids, as we all know that, high acidity could be fatal in most circumstances. To date, avoidance to acids has been well explained in insects, but attractiveness and its basis remain uncharted. In the brain of oriental armyworm Mythimna separata, we have located 3 olfactory pathways which may play roles in acetic acid reception. Fortunately, when acetic acid was applied at attractive dosages, it only activated 1 dedicated pathway among the three. Later we found that this attractiveness pathway employed two ionotropic receptor genes namely Ir75q1 and Ir75q2, to successfully deliver this trait. Both genes were necessary for the moth to conduct acetic acid preference, but their roles are different. Ir75q1 recognized the acetic acid ligand and Ir75q2 later amplify the sensitivity. By comparing with evidences from electrophysiology and brain imaging tests, we found that the expression bias of either of the two genes has caused the separation of the pathways. It has been revealed in this moth that a smart decision system for olfactory reception exists, and this system may extrapolate to other insect species, as Ir75q1 and Ir75q2 are commonly expressed in many insect families.
Intracellular anti-leishmanial effect of Spergulin-A, a triterpenoid saponin of Glinus oppositifolius
Authors: Banerjee Saswati , Mukherjee Niladri , Gajbhiye Rahul L. , Jaisankar Parasuraman , Datta Sriparna , Das Saha Krishna 
Published: November 2018

ABSTRACTMany of present chemotherapeutics are inadequate and also resistant against visceral leishmaniasis (VL) an immunosuppressive ailment caused by Leishmania donovani. Despite the interest in plant-based drug development, very few number of antileishmanial drugs from plant source is available. Glinus oppositifolius had been reported in favor of being immunomodulators along with other traditional uses. Novel anti-VL therapies can rely on host immune-modulation with associated leishmanicidal action. With this rationale, an n-BuOH fraction of the methanolic extract of the plant and obtained triterpenoid saponin Spergulin-A were evaluated against acellular and intracellular L. donovani. Immunostimulatory activity of them was confirmed by elevated TNF-α and extracellular NO production from treated MФs and was found nontoxic to the host cells. Identification and structure confirmation for isolated Spergulin-A was performed by ESI-MS, 13C, and 1H NMR. Spergulin-A was found ineffective against the acellular forms while, against the intracellular parasites at 30μg/ml, the reduction was 92.6% after 72h. Spergulin-A enhanced ROS and nitric oxide (NO) release and changes in Gp91-phox, i-NOS, and pro and anti-inflammatory cytokines elaborated its intracellular anti-leishmanial activity. The results supported that G. oppositifolius and Spergulin-A can potentiate new lead molecules for the development of alternative drugs against VL.
RNA-DNA hybrids support recombination-based telomere maintenance in fission yeast
Authors: Hu Yan , Bennett Henrietta W. , Liu Na , Moravec Martin , Williams Jessica F. , Azzalin Claus M. , King Megan C. 
Published: November 2018

ABSTRACTA subset of cancers rely on telomerase-independent mechanisms to maintain their chromosome ends. The predominant “alternative lengthening of telomeres” pathway appears dependent on homology-directed repair (HDR) to maintain telomeric DNA. However, the molecular changes needed for cells to productively engage in telomeric HDR are poorly understood. To gain new insights into this transition, we monitored the state of telomeres during serial culture of fission yeast (Schizosaccharomyces pombe) lacking the telomerase recruitment factor Ccq1. Rad52 is loaded onto critically short telomeres shortly after germination despite continued telomere erosion, suggesting that recruitment of recombination factors is not sufficient to maintain telomeres in the absence of telomerase function. Instead, survivor formation coincides with the derepression of telomeric repeat-containing RNA (TERRA). In this context, degradation of TERRA associated with the telomere in the form of R-loops drives a severe growth crisis, ultimately leading to a novel type of survivor with linear chromosomes and altered cytological telomere characteristics, including the loss of the shelterin component Rap1 (but not the TRF1/TRF2 orthologue, Taz1) from the telomere. We demonstrate that deletion of Rap1 is protective in this context, preventing the growth crisis that is otherwise triggered by degradation of telomeric R-loops in survivors with linear chromosomes. These findings suggest that up-regulation of telomere-engaged TERRA or altered recruitment of shelterin components can support telomerase-independent telomere maintenance.
High interictal connectivity within the resection zone is associated with favorable post-surgical outcomes in focal epilepsy patients
Authors: Shah Preya , Bernabei John , Kini Lohith , Ashourvan Arian , Boccanfuso Jacqueline , Archer Ryan , Oechsel Kelly , Lucas Timothy H. , Bassett Danielle S. , Davis Kathryn A. , Litt Brian 
Published: November 2018

AbstractObjectivePatients with drug-resistant focal epilepsy are often candidates for invasive surgical therapies. In these patients, it is necessary to accurately localize seizure-generators to ensure seizure freedom following intervention. While intracranial electroencephalography (iEEG) is the gold standard for mapping networks for surgery, this approach requires inducing and recording seizures, which may cause patient morbidity. The goal of this study is to evaluate the utility of mapping interictal (non-seizure) iEEG networks to identify targets for surgical treatment.MethodsWe analyze interictal iEEG recordings and neuroimaging from 27 focal epilepsy patients treated via surgical resection. We generate interictal functional networks by calculating pairwise correlation of iEEG signals across different frequency bands. We identify electrodes falling within surgically resected tissue (i.e. the resection zone), and compute node-level and edge-level synchrony in relation to the resection zone. We associate these metrics with post-surgical outcomes.ResultsGreater overlap between resected electrodes and highly synchronous electrodes is associated with favorable post-surgical outcomes. Additionally, good outcome patients have significantly higher connectivity localized within the resection zone compared to those with poorer postoperative seizure control. This finding persists following normalization by a spatially-constrained null model.ConclusionsThis study suggests that spatially-informed interictal network synchrony measures can distinguish between good and poor post-surgical outcomes. By capturing clinically relevant information during interictal periods, our method may ultimately reduce the need for prolonged invasive implants and provide insights into the pathophysiology of an epileptic brain. We discuss next steps for translating these findings into a prospectively useful clinical tool.
Multiplexed Profiling of Single-cell Extracellular Vesicles Secretion
Authors: Ji Yahui , Qi Dongyuan , Li Linmei , Su Haoran , Li Xiaojie , Luo Yong , Sun Bo , Zhang Fuyin , Lin Bingcheng , Liu Tingjiao , Lu Yao 
Published: November 2018

AbstractExtracellular vesicles (EVs) are important intercellular mediators regulating health and disease. Conventional EVs surface marker profiling, which was based on population measurements, masked the cell-to-cell heterogeneity in the quantity and phenotypes of EVs secretion. Herein, by using spatially patterned antibodies barcode, we realized multiplexed profiling of single-cell EVs secretion from more than 1000 single cells simultaneously. Applying this platform to profile human oral squamous cell carcinoma (OSCC) cell lines led to deep understanding of previously undifferentiated single cell heterogeneity underlying EVs secretion. Notably, we observed the decrement of certain EV phenotypes (e.g. CD63+EVs) were associated with the invasive feature of both OSCC cell lines and primary OSCC cells. We also realized multiplexed detection of EVs secretion and cytokines secretion simultaneously from the same single cells to investigate multidimensional spectrum of intercellular communications, from which we resolved three functional subgroups with distinct secretion profiles by visualized clustering. In particular, we found EVs secretion and cytokines secretion were generally dominated by different cell subgroups. The technology introduced here enables comprehensive evaluation of EVs secretion heterogeneity at single cell level, which may become an indispensable tool to complement current single cell analysis and EV research.SignificanceExtracellular vesicles (EVs) are cell derived nano-sized particles medicating cell-cell communication and transferring biology information molecules like nucleic acids to regulate human health and disease. Conventional methods for EV surface markers profiling can’t tell the differences in the quantity and phenotypes of EVs secretion between cells. To address this need, we developed a platform for profiling an array of surface markers on EVs from large numbers of single cells, enabling more comprehensive monitoring of cellular communications. Single cell EVs secretion assay led to previously unobserved cell heterogeneity underlying EVs secretion, which might open up new avenues for studying cell communication and cell microenvironment in both basic and clinical research.