bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced critical care demand with early CPAP and proning in COVID-19 at Bradford: a single centre cohort
Authors: Lawton T , Wilkinson K , Corp A , Javid R , MacNally L , McCooe M , Newton E
Published: June 2020

Background

Guidance in COVID-19 respiratory failure has favoured early intubation, with concerns over the use of CPAP. We adopted early CPAP and self-proning, and evaluated the safety and efficacy of this approach.

Methods

This retrospective observational study included all patients with a positive COVID-19 PCR, and others with high clinical suspicion. Our protocol advised early CPAP and self-proning for severe cases, aiming to prevent rather than respond to deterioration. CPAP was provided outside critical care by ward staff supported by physiotherapists and an intensive critical care outreach program. Data were analysed descriptively and compared against a large UK cohort (ISARIC).

Results

559 patients admitted before 1/May/20 were included. 376 were discharged alive, and 183 died. 165 patients (29.5%) received CPAP, 40 (7.2%) were admitted to critical care and 28 (5.0%) were ventilated. Hospital mortality was 32.7%, and 50% for critical care. Following CPAP, 62% of patients with S:F or P:F ratios indicating moderate or severe ARDS, who were candidates for escalation, avoided intubation. Figures for critical care admission, intubation and hospital mortality are lower than ISARIC, whilst critical care mortality is similar. Following ISARIC proportions we would have admitted 92 patients to critical care and intubated 55. Using the described protocol, we intubated 28 patients from 40 admissions, and remained within our expanded critical care capacity.

Conclusion

Bradford’s protocol produced good results despite our population having high levels of co-morbidity and ethnicities associated with poor outcomes. In particular we avoided overloading critical care capacity. We advocate this approach as both effective and safe.

Social media summary

The use of early CPAP and proning in COVID-19 was associated with lower critical care admissions, intubation, and mortality at Bradford compared to a large UK cohort (ISARIC WHO CCP-UK).
Fentanyl-induced antinociception, reward, reinforcement, and withdrawal inHnrnph1mutant mice
Authors: Bryant Camron D. , Healy Aidan F. , Ruan Qiu T. , Coehlo Michal A. , Lustig Elijah , Yazdani Neema , Luttik Kimberly P. , Tran Tori , Swancy Isaiah , Brewin Lindsey W. , Chen Melanie M. , Szumlinski Karen K.
Published: June 2020

Opioid Use Disorder (OUD) and opioid-related deaths remain a major public health concern in the United States. Both environmental and genetic factors influence risk for OUD. We previously identifiedHnrnph1as a quantitative trait gene underlying the stimulant, rewarding, and reinforcing properties of methamphetamine. Prior work demonstrates that hnRNP H1, the RNA-binding protein encoded byHnrnph1,post-transcriptionally regulatesOprm1(mu opioid receptor gene) – the primary molecular target for the therapeutic and addictive properties of opioids. Because genetic variants can exert pleiotropic effects on behaviors induced by multiple drugs of abuse, in the current study, we tested the hypothesis thatHnrnph1mutants would show reduced behavioral sensitivity to the mu opioid receptor agonist fentanyl.Hnrnph1mutants showed reduced sensitivity to fentanyl-induced locomotor activity, along with a female-specific reduction in, and a male-specific induction of, locomotor sensitization following three, daily injections (0.2 mg/kg, i.p.).Hnrnph1mutants also required a higher dose of fentanyl to exhibit opioid reward as measured via conditioned place preference. MaleHnrnph1mutants showed reduced fentanyl reinforcement.Hnrnph1mutants also showed reduced sucrose motivation, suggesting a reward deficit. No genotypic differences were observed in baseline thermal nociception, fentanyl-induced antinociception, physical or negative affective signs of opioid dependence, or in sensorimotor gating. In the context of our prior work, these findings suggest thatHnrnph1dysfunction exerts a selective role in reducing the addiction liability to drugs of abuse (opioids and psychostimulants), which could provide new biological pathways to improve their therapeutic profiles.
The production of within-family inequality: Insights and implications of integrating genetic data
Authors: Fletcher Jason M. , Wu Yuchang , Zhao Zijie , Lu Qiongshi
Published: June 2020

The integration of genetic data within large-scale social and health surveys provides new opportunities to test long standing theories of parental investments in children and within-family inequality. Genetic predictors, called polygenic scores, allow novel assessments of young children’s abilities that are uncontaminated by parental investments, and family-based samples allow indirect tests of whether children’s abilities are reinforced or compensated. We use over 16,000 sibling pairs from the UK Biobank to test whether the relative ranking of siblings’ polygenic scores for educational attainment is consequential for actual attainments. We find strong evidence of compensatory processes, on average, where the association between genotype and phenotype of educational attainment is reduced by over 20% for the higher-ranked sibling compared to the lower-ranked sibling. These effects are most pronounced in high socioeconomic status areas. We find no evidence that similar processes hold in the case of height or for relatives who are not full biological siblings (e.g. cousins). Our results provide a new use of polygenic scores to understand processes that generate within-family inequalities and also suggest important caveats to causal interpretations the effects of polygenic scores using siblingdifference designs.
WITHDRAWN: Excitatory effects of dentate gyrus mossy cells on granule cells and area CA3: an vitro and in vivo study in adult mice
Authors: Bernstein Hannah L , Lu Yi-Ling , Leary Paige , Jain Swati , LaFrancois John J. , Lacefield Clay O. , Botterill Justin J. , Scharfman Helen E
Published: June 2020

Withdrawal statement

The authors have withdrawn this manuscript because it has been divided into several papers. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Latent motives guide structure learning during adaptive social choice
Authors: van Baar Jeroen M. , Nassar Matthew R. , Deng Wenning , FeldmanHall Oriel
Published: June 2020

Predicting the behavior of others is an essential part of human cognition that enables strategic social behavior (e.g., cooperation), and is impaired in multiple clinical populations. Despite its ubiquity, social prediction poses a generalization problem that remains poorly understood: We can neither assume that others will simply repeat their past behavior in new settings, nor that their future actions are entirely unrelated to the past. Here we demonstrate that humans solve this challenge using a structure learning mechanism that uncovers other people’s latent, unobservable motives, such as greed and risk aversion. In three studies, participants were tasked with predicting the decisions of another player in multiple unique economic games such as the Prisoner’s Dilemma. Participants achieved accurate social prediction by learning the hidden motivational structure underlying the player’s actions to cooperate or defect (e.g., that greed led to defecting in some cases but cooperation in others). This motive-based abstraction enabled participants to attend to information diagnostic of the player’s next move and disregard irrelevant contextual cues. Moreover, participants who successfully learned another’s motives were more strategic in a subsequent competitive interaction with that player, reflecting that accurate social structure learning can lead to more optimal social behaviors. These findings demonstrate that advantageous social behavior hinges on parsimonious and generalizable mental models that leverage others’ latent intentions.

Significance statement

A hallmark of human cognition is being able to predict the behavior of others. How do we achieve social prediction given that we routinely encounter others in a dizzying array of social situations? We find people achieve accurate social prediction by inferring another’s hidden motives—motives that do not necessarily have a one-to-one correspondence with observable behaviors. Participants were able to infer another’s motives using a structure learning mechanism that enabled generalization. Individuals used what they learned about others in one setting to predict their actions in an entirely new setting. This cognitive process can explain a wealth of social behaviors, ranging from strategic economic decisions to stereotyping and racial bias.
Comparison between traditional FFT and marginal spectra using the Hilbert-Huang transform method for the broadband spectral analysis of the EEG in healthy humans
Authors: Arrufat-Pié Eduardo , Báez Mario Estévez , Carreras José Mario Estévez , Curbelo Calixto Machado , Leisman Gerry , Beltrán Carlos
Published: June 2020

The fast Fourier transform (FFT), has been the main tool for the EEG spectral analysis (SPA). However, as the EEG dynamics shows nonlinear and non-stationary behavior, results using the FFT approach may result meaningless. A novel method has been developed for the analysis of nonlinear and non-stationary signals known as the Hilbert-Huang transform method. In this study we describe and compare the spectral analyses of the EEG using the traditional FFT approach with those calculated with the Hilbert marginal spectra (HMS) after decomposition of the EEG with a multivariate empirical mode decomposition algorithm. Segments of continuous 60-seconds EEG recorded from 19 leads of 47 healthy volunteers were studied. Although the spectral indices calculated for the explored EEG bands showed significant statistical differences for different leads and bands, a detailed analysis showed that for practical purposes both methods performed substantially similar. The HMS showed a reduction of the alpha activity (−5.64%), with increment in the beta-1 (+1.67%), and gamma (+1.38%) fast activity bands, and also an increment in the theta band (+2.14%), and in the delta (+0.45%) band, and vice versa for the FFT method. For the weighted mean frequencies insignificant mean differences (lower than 1Hz) were observed between both methods for the delta, theta, alpha, beta-1 and beta-2 bands, and only for the gamma band values for the HMS were 3 Hz higher than with the FFT method. The HMS may be considered a good alternative for the SPA of the EEG when nonlinearity or non-stationarity may be present.
Analysis in the frequency domain of multicomponent oscillatory modes of the human electroencephalogram extracted with multivariate empirical mode decomposition
Authors: Arrufat-Pié Eduardo , Estévez-Báez Mario , Estévez-Carreras José Mario , Curbelo Calixto Machado , Leisman Gerry , Beltrán León Carlos
Published: June 2020

Considering the properties of the empirical mode decomposition to extract from a signal its natural oscillatory components known as intrinsic mode functions (IMFs), the spectral analysis of these IMFs could provide a novel alternative for the quantitative EEG analysis without a priori establish more or less arbitrary band limits. This approach has begun to be used in the last years for studies of EEG records of patients included in database repositories or including a low number of individuals or of limited EEG leads, but a detailed study in healthy humans has not yet been reported. Therefore, in this study the aims were to explore and describe the main spectral indices of the IMFs of the EEG in healthy humans using a method based on the FFT and another on the Hilbert-Huang transform (HHT). The EEG of 34 healthy volunteers was recorded and decomposed using a recently developed multivariate empirical mode decomposition algorithm. Extracted IMFs were submitted to spectral analysis with, and the results were compared with an ANOVA test. The first six decomposed IMFs from the EEG showed frequency values in the range of the classical bands of the EEG (1.5 to 56 Hz). Both methods showed in general similar results for mean weighted frequencies and estimations of power spectral density, although the HHT is recommended because of its better frequency resolution. It was shown the presence of the mode-mixing problem producing a slight overlapping of spectral frequencies mainly between the IMF3 and IMF4 modes.
ICON (Ivermectin in COvid Nineteen) study: Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with COVID19
Authors: Rajter Juliana Cepelowicz , Sherman Michael S. , Fatteh Naaz , Vogel Fabio , Sacks Jamie , Rajter Jean-Jacques
Published: June 2020

Importance

No therapy to date has been shown to improve survival for patients infected with SARS-CoV-2. Ivermectin has been shown to inhibit the replication of SARS-CoV-2 in vitro but clinical response has not been previously evaluated.

Objective

To determine whether Ivermectin is associated with lower mortality rate in patients hospitalized with COVID-19.

Design and Setting

Retrospective cohort study of consecutive patients hospitalized at four Broward Health hospitals in South Florida with confirmed SARS-CoV-2. Enrollment dates were March 15, 2020 through May 11, 2020. Follow up data for all outcomes was May 19, 2020.

Participants

280 patients with confirmed SARS-CoV-2 infection (mean age 59.6 years [standard deviation 17.9], 45.4% female), of whom 173 were treated with ivermectin and 107 were usual care were reviewed. 27 identified patients were not reviewed due to multiple admissions, lack of confirmed COVID results during hospitalization, age less than 18, pregnancy, or incarceration.

Exposure

Patients were categorized into two treatment groups based on whether they received at least one dose of ivermectin at any time during the hospitalization. Treatment decisions were at the discretion of the treating physicians. Severe pulmonary involvement at study entry was characterized as need for either FiO2 ≥50%, or noninvasive or invasive mechanical ventilation.

Main Outcomes and Measures

The primary outcome was all-cause in-hospital mortality. Secondary outcomes included subgroup mortality in patients with severe pulmonary involvement and extubation rates for patients requiring invasive ventilation.

Results

Univariate analysis showed lower mortality in the ivermectin group (15.0% versus 25.2%, OR 0.52, 95% CI 0.29-0.96, P=.03). Mortality was also lower among 75 patients with severe pulmonary disease treated with ivermectin (38.8% vs 80.7%, OR 0.15, CI 0.05-0.47, P=.001), but there was no significant difference in successful extubation rates (36.1% vs 15.4%, OR 3.11 (0.88-11.00), p=.07). After adjustment for between-group differences and mortality risks, the mortality difference remained significant for the entire cohort (OR 0.27, CI 0.09-0.85, p=.03; HR 0.37, CI 0.19-0.71, p=.03).

Conclusions and Relevance

Ivermectin was associated with lower mortality during treatment of COVID-19, especially in patients who required higher inspired oxygen or ventilatory support. These findings should be further evaluated with randomized controlled trials.
Lipidomic profiling of plasma extracellular vesicles as an effective means to evaluate the risk of preterm birth
Authors: Zhao Qianqian , Ma Zhen , Wang Xinran , Liang Minling , Wang Wenjing , Su Fengxia , Yang Huanming , Gao Ya , Ren Yan
Published: June 2020

Preterm birth is the main cause of infant death worldwide and results in a high societal economic burden associated with newborn care. Recent studies have shown that extracellular vesicles play an important role in fetal development during pregnancy. Here, we fully investigated differences in lipids in plasma, microvesicles and exosomes between 27 preterm and 66 full-term pregnant women in the early second trimester (12-24 weeks) using an untargeted lipidomics approach. Independent of other characteristics of samples, we detected 97, 58 and 10 differential features (retention time (RT) and m/z) with identification by multivariate and univariate statistical analyses in plasma, microvesicles and exosomes, respectively. These altered lipids were involved in the formation of the bacterial cell wall and chronic low-level inflammation and oxidative stress. Furthermore, lipids in microvesicles could distinguish patients who experienced preterm labor from controls better than lipids in plasma and exosomes. The candidate lipid biomarkers in microvesicles were also validated by the pseudotargeted lipidomics method. The validation set included 41 preterm and 42 healthy pregnant women. PS (34:0) in microvesicles was able to distinguish preterm birth from healthy pregnancy with higher accuracy. Our study shows that differences in lipids in plasma, microvesicles and exosomes are useful for understanding the underlying mechanisms, early clinical diagnosis and intervention of preterm birth.
Closed-loop fMRI neurofeedback to reduce negative attentional bias in depression
Authors: Mennen Anne C. , Turk-Browne Nicholas B. , Wallace Grant , Seok Darsol , Jaganjac Adna , Stock Janet , deBettencourt Megan T. , Cohen Jonathan D. , Norman Kenneth A. , Sheline Yvette I.
Published: June 2020

Depressed individuals show an attentional bias toward negatively valenced stimuli and thoughts. Here we present a novel closed-loop neurofeedback procedure that seeks to remediate this bias. Internal attentional states were detected by applying machine learning techniques to fMRI data in real-time, and externalized using a visually presented stimulus that the participant could learn to control. We trained 15 depressed and 12 healthy control participants over three fMRI sessions, preceded and followed by behavioral and clinical assessments. Initially, depressed participants were more likely than non-depressed participants to get “stuck” in negative attentional states, but this diminished with neurofeedback training relative to controls. Depression severity also decreased from pre- to post-training. These results demonstrate that our method is sensitive to the negative attentional bias in depressed individuals, and its reduction after training showcases the potential of this method as a treatment in the future.
scASK: A novel ensemble framework for classifying cell types based on single-cell RNA-seq data
Authors: Liu Bo , Wu Fang-Xiang , Zou Xiufen
Published: June 2020

The Human Cell Atlas (HCA) is a large project that aims to identify all cell types in the human body. The dimension reduction and clustering for identification of cell types from single-cell RNA-sequencing (scRNA-seq) data have become foundational approaches to HCA. The major challenges of current computational analyses are of poor performance on large scale data and sensitive to initial data. We present a new ensemble framework called Adaptive Slice KNNs (scASK) to address the challenges for analysing scRNA-seq data with high dimensionality. scASK consists of three innovational modules, called DAS (Data Adaptive Slicing), MCS (Meta Classifiers Selecting) and EMS (Ensemble Mode Switching), respectively, which facilitate scASK to approximate a bias-variance tradeoff beyond classification. Thirteen real scRNA-seq datasets are used to evaluate the performance of scASK. Compared with five popular classification algorithms, our experimental results indicate that scASK achieves the best accuracy and robustness among all competing methods. In conclusion, adaptive slicing is an effective structural reduction procedure, and meanwhile scASK provides novel and robust ensemble framework especially for classifying cell types based on scRNA-seq data. scASK is publically available athttps://github.com/liubo2358/scASKcmd.
Mixture model investigation of the inner-outer asymmetry in visual crowding reveals a heavier weight towards the visual periphery
Authors: Shechter Adi , Yashar Amit
Published: June 2020

Crowding, the failure to identify a peripheral item in clutter, is an essential bottleneck in visual information processing. A hallmark characteristic of crowding is the inner-outer asymmetry in which the outer flanker (more eccentric) produces stronger interference than the inner one (closer to the fovea). We tested the contribution of the inner-outer asymmetry to the pattern of crowding errors in a typical radial crowding display in which both flankers are presented simultaneously on the horizontal meridian. In two experiments, observers were asked to estimate the orientation of a Gabor target. Instead of the target, observers reported the outer flanker much more frequently than the inner one. When the target was the outer Gabor, crowding was reduced. Furthermore, when there were four flankers, two on each side of the target, observers misreported the outer flanker adjacent to the target, not the outermost flanker. Model comparisons suggested that orientation crowding reflects sampling over a weighted sum of the represented features, in which the outer flanker is more heavily weighted compared to the inner one. Our findings reveal a counterintuitive phenomenon: in a radial arrangement of orientation crowding, within a region of selection, the outer item dominates appearance more than the inner one.
MTSplice predicts effects of genetic variants on tissue-specific splicing
Authors: Cheng Jun , Çelik Muhammed Hasan , Kundaje Anshul , Gagneur Julien
Published: June 2020

Tissue-specific splicing of exons plays an important role in determining tissue identity. However, computational tools predicting tissue-specific effects of variants on splicing are lacking. To address this issue, we developed MTSplice (Multi-tissue Splicing), a neural network which quantitatively predicts effects of human genetic variants on splicing of cassette exons in 56 tissues. MTSplice combines the state-of-the-art predictor MMSplice, which models constitutive regulatory sequences, with a new neural network which models tissue-specific regulatory sequences. MTSplice outperforms MMSplice on predicting effects associated with naturally occurring genetic variants in most tissues of the GTEx dataset. Furthermore, MTSplice predicts that autism-associated de novo mutations are enriched for variants affecting splicing specifically in the brain. MTSplice is provided free of use and open source at the model repository Kipoi. We foresee MTSplice to be useful for functional prediction and prioritization of variants associated with tissue-specific disorders.
Insights into the Binding Mechanism of Ascorbic Acid and Violaxanthin with Violaxanthin De-Epoxidase (VDE) and Chlorophycean Violaxanthin De-Epoxidase (CVDE) Enzymes: Docking, Molecular Dynamics, and Free Energy Analysis
Authors: Biswal Satyaranjan , Sen Gupta Parth Sarthi , Bhat Haamid Rasool , Rana Malay Kumar
Published: June 2020

Photosynthetic organisms have evolved to work under low and high lights in photoprotection, acting as a scavenger of reactive oxygen species. The light dependent xanthophyll cycle involved in this process is performed by a key enzyme (present in the thylakoid lumen) Violaxanthin De-Epoxidase (VDE) in the presence of violaxanthin and ascorbic acid substrates. Phylogenetically, VDE is found to be connected with an ancestral enzyme Chlorophycean Violaxanthin De-Epoxidase (CVDE) present in the green algae on the stromal side of the thylakoid membrane. However, the structure and functions of CVDE were not known. In search of functional similarities involving this cycle, the structure, binding conformation, stability, and interaction mechanism of CVDE are explored with the two substrates in comparison to VDE. The structure of CVDE was determined by homology modeling and validated. In-silico docking (of first-principles-optimized substrates) revealed it has a larger catalytic domain than VDE. A thorough analysis of the binding affinity and stability of four enzyme-substrate complexes are performed by computing free energies and its decomposition, the root-mean-square deviation (RMSD) and fluctuation (RMSF), the radius of gyration, salt-bridge and hydrogen bonding interactions in molecular dynamics. Based on these, violaxanthin interacts with CVDE to the similar extent as that of VDE, hence its role is expected to be the same for both the enzymes. On the contrary, ascorbic acid has a weaker interaction with CVDE than VDE. As these interactions drive epoxidation or de-epoxidation process in the xanthophyll cycle, it immediately discerns that either ascorbic acid does not take part in de-epoxidation or this process requires a different cofactor because of the weaker interaction of ascorbic acid with CVDE in comparison to VDE.
Phylogenetic comparative analyses of the determinants of anti-predator distraction behavior in shorebirds
Authors: Saijo Miki , Kutsukake Nobuyuki
Published: June 2020

Predation risk exerts a strong selective pressure on anti-predator behavior, resulting in behaviors to achieve defense of offspring and the individual. In shorebirds, some species perform distraction behavior that is attracting the attention of a predator. This behavior evolved, and were lost multiple times, independently and the behavioral repertoire varies among species. Although defense of offspring is critical for parents, the determinants of inter-specific variation in the distraction behavior remain unstudied. We surveyed the literature and conducted phylogenetic comparative analyses (n = 169 species) to test predictions regarding nest site, body mass, and coloniality. We found that small species were more likely to perform distraction behavior than large species. Solitary species were more likely to perform distraction behavior than colonial nesting species. Previous studies suggested that colonial nesting and large species commonly perform aggressive anti-predator behavior, implying that distraction behavior is an alternative anti-predator strategy to aggressive ones.
Computational Support, Not Primacy, Distinguishes Compensatory Memory Reorganization in Epilepsy
Authors: Tracy Joseph I. , Chaudhary Kapil , Modi Shilpi , Crow Andrew , Kumar Ashith , Weinstein David , Sperling Michael R.
Published: June 2020

Temporal lobe epilepsy (TLE) is associated with impairment in episodic memory. A substantial sub-group, however, is able to maintain adequate memory despite temporal lobe pathology. What has been missing from prior work in the cognitive reorganization is a direct comparison of TLE patients with intact/compensated status from those who are memory impaired and uncompensated. Little is known about the particular regional activations, functional connectivities (FC’s), and/or network reconfigurations that implement changes in the primary computations or the support functions that drive adaptive plasticity and compensated memory. We utilized task fMRI on 54 unilateral TLE patients and 24 matched healthy controls (HC) during performance of a paired-associate memory (PAM) task to address three questions: 1) what regions implement PAM in TLE, and do such regions vary as a function of good versus poor performance, 2) are there unique FC’s present during memory encoding that accounts for intact status through the preservation of primary memory computations or the supportive computations that allow for compensated memory responses, and 3) what features during memory encoding are most distinctive: is it the magnitude and location of regional activations, or the presence of enhanced functional connections to key structures such as the hippocampus? Results revealed a unique profile of non-ictal, non-dominant hemisphere regions (e.g., right posterior temporal regions) were most important to intact/compensated status in LTLE, involving both increased regional activity and increased modulatory communication with the hippocampi, all feature that was missing in impaired/uncompensated LTLE. The profile involved areas that are neither contralateral homologues to left hemisphere memory areas, nor regions traditionally considered computationally primary for episodic memory. None of these areas of increased activation or functional connectivity were associated with advantaged memory in HC’s. Our emphasis on different performance levels yielded insight into two forms of cognitive reorganization. Computational primacy, where LTLE showed little change relative to HC’s, and computational support where Intact/Compensated LTLE patients showed adaptive abnormalities. The analyses isolated the unique regional activations and mediating FC’s that implement truly compensatory reorganization in LTLE. The results provided a new perspective on memory deficits by making clear that memory deficits arise not just from knockout of a functional hub, but from the failure to instantiate a complex set of reorganization responses. Such responses provided computational support to ensure successful memory. The findings demonstrated that by keeping track of performance levels, we can increase our understanding of adaptive brain responses and neuroplasticity in epilepsy.
Wide-field Fluorescence Lifetime Imaging Microscopy with a High-Speed Mega-pixel SPAD Camera
Authors: Zickus V. , Wu M.-L. , Morimoto K. , Kapitany V. , Fatima A. , Turpin A. , Insall R. , Whitelaw J. , Machesky L. , Bruschini C. , Faccio D. , Charbon E.
Published: June 2020

Fluorescence lifetime imaging microscopy (FLIM) is a key technology that provides direct insight into cell metabolism, cell dynamics and protein activity. However, determining the lifetimes of different fluorescent proteins requires the detection of a relatively large number of photons, hence slowing down total acquisition times. Moreover, there are many cases, for example in studies of cell collectives, where wide-field imaging is desired. We report scan-less wide-field FLIM based on a 0.5 Megapixel resolution, time-gated Single Photon Avalanche Diode (SPAD) camera, with acquisition rates up to 1 Hz. Fluorescence lifetime estimation is performed via a pre-trained artificial neural network with 1000-fold improvement in processing times compared to standard least squares fitting techniques. We utilised our system to image HT1080 – human fibrosarcoma cell line as well as Convallaria. The results show promise for real-time FLIM and a viable route towards multi-megapixel fluorescence lifetime images, with a proof-of-principle mosaic image shown with 3.6 megapixels.
Dispersal evolution diminishes the negative density dependence in dispersal
Authors: Mishra Abhishek , Chakraborty Partha Pratim , Dey Sutirth
Published: June 2020

In many organisms, dispersal varies with the local population density. Such patterns of density-dependent dispersal (DDD) are expected to shape the dynamics, spatial spread and invasiveness of populations. Despite their ecological importance, empirical evidence for the evolution of DDD patterns remains extremely scarce. This is especially relevant because rapid evolution of dispersal traits has now been empirically confirmed in several taxa. Changes in DDD of dispersing populations could help clarify not only the role of DDD in dispersal evolution, but also the possible pattern of subsequent range expansion. Here, we investigate the relationship between dispersal evolution and DDD using a long-term experimental evolution study onDrosophila melanogaster. We compared the DDD patterns of four dispersal-selected populations and their non-selected controls. The control populations showed negative DDD, which was stronger in females than in males. In contrast, the dispersal-selected populations showed density-independent dispersal, where neither males nor females exhibited DDD. We compare our results with previous evolutionary predictions that focused largely on positive DDD, and highlight how the direction of evolutionary change depends on the initial DDD pattern of a population. Finally, we discuss the implications of DDD evolution for spatial ecology and evolution.
Nitric oxide, KATPchannels and endothelin-1 modulate brain pericyte function, vascular tone and neurovascular coupling
Authors: Zambach Stefan Andreas , Cai Changsi , Cederberg Helms Hans Christian , Hald Bjørn Olav , Fordsmann Jonas Christoffer , Nielsen Reena Murmu , Lønstrup Micael , Brodin Birger , Lauritzen Martin Johannes
Published: June 2020

Neurotransmitter-mediated signaling correlates strongly to changes in cerebral blood flow (CBF), and functional neuroimaging relies on the robust coupling between activity and CBF, i.e. neurovascular coupling (NVC). We here reveal that key endothelial signaling molecules, nitric oxide (eNO) and endothelin-1 (ET1), modulate pericyte contractility and that pericyte ATP-sensitive potassium (KATP) channels interact with endothelial factors to modulate vascular tone and NVC. We show that NVC requires local synthesis of cGMP, but not NO derived from endothelial cells. The potent endothelial vasoconstrictor ET1 contracted pericytes by IP3receptor mediated Ca2+release and blocked NVC. In comparison, pericyte KATPchannel openers increased the diameter of capillaries by deactivation of L-type Ca2+channels while KATPblockers shortened the NVC response. All vasoactive stimuli produced the largest diameter changes at the first capillary that branches off from the penetrating arteriole. Our results reveal that three different signaling pathways mediate the effects of NO, ET1 and KATPchannels on brain pericytes and capillary blood flow by mechanisms similar to vascular smooth muscle despite great differences in morphology.
Unsupervised Neural Tracing in Densely Labeled Multispectral Brainbow Images
Authors: Duan Bin , Walker Logan A , Roossien Douglas H , Shen Fred Y , Cai Dawen , Yan Yan
Published: June 2020

Reconstructing neuron morphology is central to uncovering the complexity of the nervous system. That is because the morphology of a neuron essentially provides the physical constraints to its intrinsic electrophysiological properties and its connectivity. Recent advances in imaging technologies generated large quantities of high-resolution 3D images of neurons in the brain. Furthermore, the multispectral labeling technology, Brainbow permits unambiguous differentiation of neighboring neurons in a densely labeled brain, therefore enables for the first time the possibility of studying the connectivity between many neurons from a light microscopy image. However, lack of reliable automated neuron morphology reconstruction makes data analysis the bottleneck of extracting rich informatics in neuroscience. Supervoxel-based neuron segmentation methods have been proposed to solve this problem, however, the use of previous approaches has been impeded by the large numbers of errors which arise in the final segmentation. In this paper, we present a novel unsupervised approach to trace neurons from multispectral Brainbow images, which prevents segmentation errors and tracing continuity errors using two innovations. First, we formulate a Gaussian mixture model-based clustering strategy to improve the separation of segmented color channels that provides accurate skeletonization results for the following steps. Next, a skeleton graph approach is proposed to allow the identification and correction of discontinuities in the neuron tree topology. We find that these innovations allow our approach to outperform current state-of-the-art approaches, which results in more accurate neuron tracing as a tree representation close to human expert annotation.
Genome-wide analysis of the cupin superfamily in cowpea (Vigna unguiculata)
Authors: Rocha Antônio J. , de Oliveira Barsottini Mario Ramos , Paiva Ana Luiza Sobral , Costa José Hélio , Grangeiro Thalles Barbosa
Published: June 2020

Cowpea [Vigna unguiculata(L.)Walp.] is an essential food crop that is cultivated in many important arid and semi-arid regions of the world. In this study the genome-wide database of cowpea genes was accessed in search of genomic sequences coding for globulins, specifically members of the cupin superfamily, a well-documented multigenic family belonging to the globulin protein class. A total of seventy-seven genes belonging to the cupin superfamily were found and divided into six families. We classifyV. unguiculatagenes into two subgroups: classical cupins with one cupin domain (fifty-nine proteins) and bicupins with two cupin domains (eighteen members). In addition, a search for cupin members in other closely related species of the fabaceae family [V. angularis, V. radiatamandPhaseolus vulgaris(common bean)] was performed. Based on those data, a detailed characterization and comparison of the cupin genes on these species was performed with the aim to better understand the connection and functions of cupin proteins from different, but related, plant species. This study was the first attempt to investigate the cupin superfamily inV. unguiculata, allowing the identification of six cupins families and better understand the structural features of those proteins, such as number of domains alternative splicing.
Genomics of OcularChlamydia trachomatisafter 5 years of SAFE interventions for trachoma in Amhara, Ethiopia
Authors: Pickering Harry , Chernet Ambahun , Sata Eshetu , Zerihun Mulat , Williams Charlotte A. , Breuer Judith , Nute Andrew W. , Haile Mahiteme , Zeru Taye , Tadesse Zerihun , Bailey Robin L. , Callahan E. Kelly , Holland Martin J. , Nash Scott D.
Published: June 2020

Background

To eliminate trachoma as a public health problem, the WHO recommends the SAFE strategy. As part of the SAFE strategy in the Amhara Region, Ethiopia, the Trachoma Control Program distributed over 124 million doses of antibiotic between 2007 and 2015. Despite these interventions, trachoma remained hyperendemic in many districts and a considerable level ofChlamydia trachomatis(Ct) infection was evident.

Methods

We utilised residual material from Abbott m2000Ctdiagnostic tests to sequence 99 ocularCtsamples from Amhara and investigated the role ofCtgenomic variation in the continued transmission ofCtfollowing 5 years of SAFE.

Findings

Sequences were typical of ocularCt, at the whole-genome level and in tissue tropism-associated genes. There was no evidence of macrolide-resistance in thisCtpopulation. Polymorphism in a region aroundompAgene was associated with village-level TF prevalence. Additionally, greaterompAdiversity at the district-level was associated with increasedCtinfection prevalence.

Interpretation

We found no evidence forCtgenomic variation contributing to continued transmission ofCtafter treatment, adding to previous evidence that azithromycin does not drive acquisition of macrolide resistance alleles inCt. IncreasedCtinfection in villages and in districts with moreompAvariants requires longitudinal investigation to understand what impact this may have on treatment success and host immunity.

Funding

European Commission; Neglected Tropical Disease Support Center; International Trachoma Initiative
Measuring Neuronal Signals with Microelectrode Arrays: A Finite Element Analysis
Authors: Bestel R , van Rienen U , Thielemann C , Appali R
Published: June 2020

Objective

Measuring neuronal cell activity using microelectrode arrays reveals a great variety of derived signal shapes within extracellular recordings. However, possible mechanisms responsible for this variety have not yet been entirely determined, which might hamper any subsequent analysis of the recorded neuronal data. For an investigation of this issue, we propose a computational model based on the finite element method describing the electrical coupling between an electrically active neuron and an extracellular recording electrode in detail. This allows for a systematic study of possible parameters that may play an essential role in defining or altering the shape of the measured electrode potential. Our results indicate that neuronal geometry and neurite structure, as well as the actual pathways of input potentials that evoke action potential generation, have a significant impact on the shape of the resulting extracellular electrode recording and explain most of the known signal shape variety.
Different protein metabolic strategies for growth during food-induced physiological plasticity
Authors: Ellison Aimee , Pouv Amara , Pace Douglas A.
Published: June 2020

Food-induced morphological plasticity, a type of developmental plasticity, is a well-documented phenomenon in larvae of the echinoid echinoderm,Dendraster excentricus. A recent study in our lab has shown that this morphological plasticity is associated with significant physiological plasticity for growth. The goal of the current study was to measure several aspects of protein metabolism in larvae growing at different rates to understand the mechanistic basis for this physiological growth plasticity. Larvae ofD. excentricuswere fed rations of 1,000 (low-fed) or 10,000 (high-fed) algal cells mL−1. Primary measurements of protein growth, algal ingestion, aerobic metabolism, alanine transport and protein synthesis were used to model growth and protein metabolism. Relative protein growth rates were 6.0 and 12.2 % day−1for low- and high-fed larvae, respectively. The energetic cost of protein synthesis was similar between both treatments at 4.91 J (mg protein synthesized)−1. Larvae in both treatments used about 50% of their metabolic energy production to fuel protein synthesis. Mass-specific rates of protein synthesis were also similar. The most important difference between low- and high-fed larvae were mass-specific rates of protein degradation. Low-fed larvae had relatively low rates of degradation early in development that increased with larval age, surpassing high-fed degradation rates at 20 days post-fertilization. Changes in protein depositional efficiency during development were similar to those of larval growth efficiency, indicating that differences in protein metabolism are largely responsible for whole-organism growth plasticity. Mass-specific alanine transport rates were about 2-times higher in low-fed larvae, demonstrating that the longer arms of low-fed larvae may be a mechanism for acquiring more dissolved nutrients from their environment. In total, these results provide an explanation for the differences in growth efficiency between low- and high-fed larvae and demonstrate the importance of protein degradation pathways in establishing these growth differences. These observations, together with previous studies measuring morphological and physiological plastic responses, allow for a more integrated understanding of developmental plasticity in echinoid larvae.
Morpho-physiological and gene expression responses of wheat byAegilops cylindricaamphidiploids to salt stress
Authors: Kiani Razieh , Arzani Ahmad , Maibody S. A. M. Mirmohammady , Rahimmalek Mehdi , Razavi Khadijeh
Published: June 2020

Aegilops cylindricaHost is one of the most salt-tolerant species in the Triticeae tribe. Amphidiploid plants derived from hybridization of ‘Roshan’ ×Aegilops cylindricaand ‘Chinese Spring’ ×Ae. cylindricagenotypes contrasting in salt tolerance were assessed for their morpho-physiological responses and the expression patterns of three genes related to ion homeostasis under 250 mM NaCl. Results showed that salt stress caused significant declines in both their morphological and phenological traits. Moreover, salt stress reduced not only their chlorophyll content but also their root and shoot K contents and K/Na ratios, while it led to significant enhancements in the remaining traits. Similar toAe. cylindrica, the amphidiploids subjected to salt stress exhibited significantly higher H2O2levels, root and shoot K contents, and root and shoot K/Na ratios accompanied by lower root and shoot Na contents and MDA concentrations when compared with the same traits in the wheat parents. Quantitative Real-Time PCR showed significant differential expression patterns of theHKT1;5, NHX1, andSOS1genes between the amphidiploids and their parents. The transcript level ofHKT1;5was found to be higher in the roots than in the shoots of both the amphidiploids andAe. cylindricawhileNHX1exhibited a higher expression in the shoot tissues. The consistency of these data provides compelling support for the hypothesis that active exclusion of Na from the roots and elevated vacuolar sequestration of Na in the leaves might explain the declining Na levels in the shoots and roots of both the amphidiploids andAe. cylindricarelative to those measured in wheat parents. It is concluded that the hybridized amphiploids are potentially valuable resources for salt improvement in bread wheat through the backcrossing approach.
No modulatory effect of rhythmic visual alpha/gamma stimulation in a bistable motion illusion
Authors: Wälti Michel J. , Bächinger Marc , Wenderoth Nicole
Published: June 2020

The ‘motion quartet’, also called stroboscopic alternative motion (SAM), is a bistable apparent motion paradigm where dots are perceived as moving either horizontally or vertically. These two percepts are known to switch randomly depending on both alpha (8 – 12 Hz) and gamma (30 – 80 Hz) oscillations within and between hemispheres, respectively. However, whether these oscillations play a causal role in triggering perceptual switches remains unknown.

Here, we aimed to entrain brain oscillations in the visual system by presenting flickering stimuli. Two LEDs were flickering either at 10 Hz, 40 Hz or corresponding jittered stimulation frequencies on the left and right sides of the visual field during the presentation of a motion quartet. In our control condition (no stimulation), we show that interhemispheric gamma connectivity (spectral coherence) between the visual cortices of both hemispheres is important for sensory feature integration. On the other hand, alpha power did not predict perceptual switches for the motion quartet. Rhythmic visual stimulation with 10 Hz and 40 Hz evoked resonance-like neural responses but did not alter visual perception.

Thus, although sensory stimuli seem to entrain ongoing brain rhythms, the effect on human behavior differs from the principles observed for endogenous brain oscillations.
Long-range local influenza forecasts via distributed syndromic monitoring: preliminary results
Authors: Dalziel B.D. , Chamberlain S.D. , Ariza C.A. , Daitch A.L. , Philips P.P. , Singh I.
Published: June 2020

Forecasting influenza primes public health systems to respond, reducing transmission, morbidity and mortality. Most influenza forecasts to date have, by necessity, relied on spatially course-grained data (e.g. state-or country-level incidence), and have operated at time horizons of 12 weeks or less. If influenza outbreaks could be predicted farther in advance and with increased spatial precision, then limited public health resources could be adaptively managed to minimize spread and improve health outcomes. Here, we use real-time syndromic data from a distributed network of thermometers to construct city-specific forecasts of influenza-like illness (ILI) with a horizon of 30 weeks. Daily geolocated ILI data from the network allows for estimates of recurrent city-specific patterns in ILI transmission rates. These “transmission templates” are used to parameterize an ensemble of ILI forecasts that differ randomly in three parameters, representing city- and season-specific rates of susceptible depletion and reporting, as well as differences in influenza season onset timing. For nine cities across the US, the best-in-hindsight model matches the observed data, and the best forecast variants can be identified in the early season.