bluuebunny/crossref_metadata_2025 huggingface dataset:
The Omega-3 Index is Inversely Associated with the Neutrophil-Lymphocyte Ratio in Adults
Authors: McBurney Michael I. , Tintle Nathan L. , Harris William S.
Published: October 2021

The neutrophil-lymphocyte ratio (NLR) is a biomarker of systemic inflammation and measures innate-adaptive immune system balance. The omega-3-index (O3I) measures the amount of EPA+DHA in blood. Both a low O3I and an elevated NLR are associated with increased risk for chronic disease and mortality, including cardiovascular diseases and cancer. Hypothesizing that low O3I may partly contribute to systemic chronic inflammation, we asked if a relationship existed between O3I and NLR in healthy adults (≥18y, n=28,871, 51% female) without inflammation [C-reactive protein (CRP) <3mg/mL)] who underwent a routine clinical assessment. NLR was inversely associated with O3I before (p<0.0001) and after adjusting for age, sex, BMI, and CRP (p<0.0001). Pearson correlations of other variables with NLR were r=0.06 (CRP), r=0.14 (age), and r=0.01(BMI). In this healthy population, an O3I <6.6% was associated with increasing NLR whereas NLR remained relatively constant (low) when O3I >6.6%, suggestive of a quiescent, balanced immune system.
Circulating Tumor-Derived Extracellular Vesicles Predict Clinical Outcomes in11C Choline-identified Oligometastatic Castration-Refractory Prostate Cancer Treated with Stereotactic Ablative Radiotherapy
Authors: Lucien F. , Kim Y. , Qian J , Zhang H. , Arafa A , Abraha F. , Thapa I. , Tryggestad E. J. , Harmsen W. S. , Kosti J. , Ali H. , Orme J. J. , Lowe V. J. , Johnson G. B. , Kwon E. D. , Dong H. , Park S. S.
Published: October 2021

Stereotactic ablative radiotherapy (SABR) has demonstrated clinical benefit in oligometastatic prostate cancer patients. However, the risk of developing new distant metastatic lesions remains high and only a minority of patients experience durable progression-free response. Therefore, there is a critical need to identify which subset of oligometastatic patients will benefit from SABR alone versus combination SABR and systemic agents. Herein, we provide the first proof-of-concept for the clinical value of circulating prostate cancer-specific extracellular vesicles (PCEVs) as non-invasive predictor of oncological outcomes in oligometastatic castration-refractory prostate cancer (oCRPC) patients treated with SABR.

We have defined PCEVs and analyzed their kinetics in the peripheral blood of 79 oCRPC patients with nanoscale flow cytometry at baseline and days 1, 7, and 14 post-SABR. High PCEV levels at baseline was predictive of shorter time to distant recurrence (3.5 vs 6.6 months, p=0.0087). Following SABR, PCEV levels reached a peak at day 7 and median overall survival was significantly longer in patients with higher PCEV levels (32.7 vs 27.6 months, p=0.003). This suggests that pre-treatment PCEV levels can be a biomarker of tumor burden while early changes post-treatment can predict response to SABR. In contrast, radiomic analyses of11C-choline PET/CT before and after SABR was not predictive of clinical outcomes. Interestingly, a correlation was noted between PCEV levels and peripheral tumor-reactive CD8 T cells (TTR; CD8+CD11ahigh).

This original study demonstrates that circulating PCEVs can serve as prognostic and predictive marker to SABR in order to identify “true” oCRPC patients. In addition, we provide novel insights in the global crosstalk mediated by PCEVs between tumors and immune cells which leads to systemic suppression of immunity against CRPC. This work lays the foundation for future studies that investigate the underpinnings of metastatic progression and providing new therapeutic targets (e.g PCEVs) to improve SABR efficacy and clinical outcomes in treatment resistant CRPC.
Severity of Illness Caused by Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern in Children: A Single-Center Retrospective Cohort Study
Authors: Edward Priya R. , Lorenzo-Redondo Ramon , Reyna Megan E. , Simons Lacy M. , Hultquist Judd F. , Patel Ami B. , Ozer Egon A. , Muller William J. , Heald-Sargent Taylor , McHugh Matthew , Dean Taylor J. , Dalal Raj M. , John Jordan , Manz Shannon C. , Kociolek Larry K.
Published: October 2021

Background

Recent surges in coronavirus 2019 disease (COVID-19) is attributed to the emergence of more transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs). However, the relative severity of SARS-CoV-2 VOCs in children is unknown.

Methods

This retrospective single-center cohort study was performed at the Ann & Robert H. Lurie Children’s Hospital of Chicago, academic free-standing children’s hospital. We included all children ≤ 18 years-old diagnosed with COVID-19 between October 15th, 2020 and August 31st, 2021 and whose SARS-CoV-2 isolate was sequenced using the Illumina platform. For each patient sample, we identified the SARS-CoV-2 lineage, which was assigned to one of the following groups: Non-VOC, alpha VOC, beta VOC, gamma VOC, or delta VOC. We measured frequency of 5 markers of COVID-19 severity: hospitalization; COVID-19 pharmacologic treatment; respiratory support; intensive care unit admission; and severe disease as classified by the COVID-19 World Health Organization (WHO) Clinical Progression Scale (severe disease; score ≥ 6). A series of logistic regression models were fitted to estimate odds of each severity marker with each VOC (in comparison to non-VOCs), adjusting for COVID-19 community incidence and demographic and clinical co-variates.

Results

During the study period, 2,025 patients tested positive for SARS-CoV-2; 1,422 (70.2%) had sufficient viral load to permit sequencing. Among the 499 (35.1%) patients whose isolate was sequenced, median (inter-quartile range) age was 7 (1,12) years; 256 (51.3%) isolates were a VOC: 96 (37.5%) alpha, 38 (14.8%) gamma, and 119 (46.5%) delta. After adjusting for age, Black race, Hispanic ethnicity, high-risk medical conditions, and COVID-19 community incidence, neither alpha nor delta was associated with severe COVID-19. Gamma was independently associated with hospitalization (OR 5.9, 95% CI 1.6-21.5, p=0.007), respiratory support (OR 8.3, 95% CI 1.5-56.3, p=0.02), and severe disease as classified by the WHO Clinical Progression Scale (OR 7.7, 95% CI 1.0-78.1, p=0.05).

Conclusions

Compared to non-VOC COVID-19 infections, the gamma VOC, but not the alpha or delta VOCs, was associated with increased severity. These data suggest that recent increased in pediatric COVID-19 hospitalizations are related to increased delta COVID-19 incidence rather than increased delta virulence in children.
Interoperability in NHS Acute Trusts within England: a Situation and Capability Analysis using Freedom of Information requests
Authors: Budhdeo Sanjay , Weerasuriya Chathika K , Zhang Joe , Thomas John P , Mariam Neethu , Sharma Nikhil , Cosco Theodore D , Harrison Oliver T , Banerjee Amitava
Published: October 2021

Background

Many central initiatives to improve digital maturity and interoperability in the NHS started after 2015. There are few prior assessments of digital maturity and interoperability.

Methods

Freedom of Information Act requests were sent to all English Acute NHS Trusts and Clinical Commissioning Groups (CCGs) to obtain information regarding digital maturity according to the Healthcare Information and Management Systems Society (HIMSS) Electronic Medical Record Adoption Mode (EMRAM) scale, and interoperability.

Results

One third of Acute NHS Trusts have an EMR that meets requirements for EMRAM stage 6 or above. 17.4% of responding Trusts considered this. 59.1% of responding Trusts stated that their EMR allows for functional interoperability with other (interoperable) EMRs. The majority of responding Trusts had not conferred with other Trusts when making EMR purchasing decisions.

Discussion

In order to realise the benefits of digitisation and interoperability, we discuss policy recommendations including actions for local health economies.
State-of-the-art EEG artifact removal evaluation
Authors: Jin Zhenyu
Published: October 2021

Object

Electroencephalography (EEG) signals suffer from a low signal-to-noise ratio and are very susceptible to muscular, ambient noise, and other artifacts. Many artifact removal algorithms have been proposed to address this problem. However, the evaluation of these algorithms is conventionally too indirect (e.g., black-box comparisons of brain-computer interface performance before and after removal) because it is unclear which part of the signal represents raw EEG and which is noise. This project objectively benchmarks popular artifact removal algorithms and evaluates the fundamental Independent Component Analysis (ICA) approach thanks to a unique dataset where EEG is recorded simultaneously with other physiological signals-facial electromyography (EMG), accelerometers, and gyroscope-while ten subjects perform several repetitions of common artifact-inflicting tasks (blinking, speaking, etc.).

Approach

I have compared the correlation between EEG signals and the artifact-representing channels before and after applying an artifact removal algorithm across the different artifact-inflicting tasks. The extent to which an artifact removal method can reduce this correlation objectively quantifies its effectiveness for the different artifacts. In the same direction, I have determined to what extent ICA successfully detects artefactual components in EEG by comparing the corresponding correlations for independent components that are labelled as artifacts with those labeled as EEG.

Main result

The FORCe was found to be the most effective and generic artifact removal method, cleaning almost 40% of artifacts. ICA is shown to be able to isolate almost 70% of artefactual components.

Significance

This work alleviates the problem of unreliable evaluation of EEG artifact removal frameworks and provides the first reliable benchmark for the most popular algorithms in this literature.
Predicting willingness to be vaccinated for Covid-19: evidence from New Zealand
Authors: Kaine Geoff , Wright Vic , Greenhalgh Suzie
Published: October 2021

Governments around the world are seeking to slow the spread of Covid-19 and reduce hospitalisations by encouraging mass vaccinations for Covid-19. The success of this policy depends on most of the population accepting the vaccine and then being vaccinated. Understanding and predicting the motivation of individuals to be vaccinated is, therefore, critical in assessing the likely effectiveness of a mass vaccination programme in slowing the spread of the virus.

In this paper we draw on the I3Response Framework to understand and predict the willingness of New Zealanders to be vaccinated for Covid-19. The Framework differs from most studies predicting willingness to be vaccinated because it is based on the idea that the willingness to adopt a behaviour depends on both involvement (a measure of motivational strength) with the behaviour and attitudes towards the behaviour. We show that predictions of individuals’ willingness to be vaccinated are improved using involvement and attitudes together, compared to attitudes alone. This result has important implications for the implementation of mass vaccination programmes for Covid-19.
Comparing adaptive coding of reward in bipolar I disorder and schizophrenia
Authors: Kaliuzhna Mariia , Kirschner Matthias , Tobler Philippe N. , Kaiser Stefan
Published: October 2021

Background

Deficits in neural processing of reward have been described in both bipolar disorder (BD) and schizophrenia (SZ), but it remains unclear to what extent these deficits are caused by similar mechanisms. Efficient reward processing relies on adaptive coding which allows representing large input spans by limited neuronal encoding ranges. Deficits in adaptive coding of reward have previously been observed across the SZ spectrum and correlated with total symptom severity. In the present work we sought to establish whether adaptive coding is similarly affected in patients with BD.

Methods

25 patients with BD, 27 patients with SZ and 25 healthy controls performed a variant of the Monetary Incentive Delay task during functional magnetic resonance imaging in two reward range conditions.

Results

Adaptive coding was impaired in BD and SZ in the posterior part of the right caudate. In contrast, BD did not show impaired adaptive coding in the anterior caudate and right precentral gyrus/insula, where SZ showed deficits compared to healthy controls.

Conclusions

BD patients show adaptive coding deficits, that are similar to those observed in SZ in the right posterior caudate. Adaptive coding in BD appeared more preserved as compared to SZ participants especially in the more anterior part of the right caudate and to a lesser extent also in the right precentral gyrus. Thus, dysfunctional adaptive coding could constitute a fundamental deficit in severe mental illnesses that extends beyond the schizophrenia spectrum.
Hyaluronan and Elastin-Like Protein (HELP) Gels Significantly Improve Cargo Retention in the Myocardium
Authors: Suhar Riley A. , Doulames Vanessa M. , Liu Yueming , Hefferon Meghan E. , Figueroa Oscar , Buabbas Hana , Heilshorn Sarah C.
Published: October 2021

Heart disease is the leading cause of death globally, and delivery of therapeutic cargo (e.g.cells, proteins, drugs) through direct injection into the myocardium is a promising clinical intervention. However, retention of deliverables to the contracting myocardium is low, with as much as 60 - 90% of payload being lost within 24 hours. Commercially-available injectable hydrogels, including Matrigel, have been hypothesized to increase payload retention, but have not yielded significant improvements in quantified analyses. Here, we assess a recombinant hydrogel composed of chemically modified hyaluronan and elastin-like protein (HELP) as an alternative injectable carrier to increase cargo retention. HELP is crosslinked using dynamic covalent bonds, and tuning the hyaluronan chemistry significantly alters hydrogel mechanical properties including stiffness, stress-relaxation rate, and ease of injectability through a needle or catheter. These materials can be injected even after complete crosslinking, extending the time window for surgical delivery. We show that HELP gels significantly improvein vivoretention of microsphere cargo compared to Matrigel, both 1 day and 7 days post-injection directly into the rat myocardium. These data suggest that HELP gels may assist with the clinical translation of therapeutic cargo designed for delivery into the contracting myocardium by preventing acute cargo loss.
Neural basis of learning to perceive speech through touch using an acoustic-to-vibrotactile speech sensory substitution
Authors: Malone Patrick S. , Eberhardt Silvio P. , Auer Edward T. , Klein Richard , Bernstein Lynne E. , Riesenhuber Maximilian
Published: October 2021

The goal of sensory substitution is to convey the information transduced by one sensory system through a novel sensory modality. One example is vibrotactile (VT) speech, for which acoustic speech is transformed into vibrotactile patterns. Despite an almost century-long history of studying vibrotactile speech, there has been no study of the neural bases of VT speech learning. We here trained hearing adult participants to recognize VT speech syllables. Using fMRI, we showed that both somatosensory (left post-central gyrus) and auditory (right temporal lobe) regions acquire selectivity for VT speech stimuli following training. The right planum temporale in particular was selective for both VT and auditory speech. EEG source-estimated activity revealed temporal dynamics consistent with direct, low-latency engagement of right temporal lobe following activation of the left post-central gyrus. Our results suggest that VT speech learning achieves integration with the auditory speech system by “piggybacking” onto corresponding auditory speech representations.

Significance statement

In sensory substitution, the information conveyed by one sensory system is used to replace the function of another. Blind individuals, for example, can learn to use a visual-to-acoustic sensory substitution device to navigate the world. We tested the hypothesis that sensory substitution can more generally occur in typical individuals, by exploiting the existence of multi-sensory convergence areas in the brain. We trained hearing participants to recognize speech syllables presented as vibrotactile stimulation patterns. Using fMRI and EEG, we show that vibrotactile speech learning integrates with the auditory speech system by “piggybacking” onto corresponding auditory speech representations. These results suggest that the human brain can bootstrap new senses by leveraging one sensory system to process information normally processed by another.
Preservation of neural synchrony at peak alpha frequency via global synaptic scaling compensates for white matter structural decline over adult lifespan
Authors: Pathak Anagh , Sharma Vivek , Roy Dipanjan , Banerjee Arpan
Published: October 2021

We propose that preservation of functional integration, estimated from measures of neural synchrony, is a key neurocompensatory mechanism associated with healthy human ageing. To support this proposal, we demonstrate how phase-locking at peak alpha frequency from Magnetoencephalography (MEG) data is invariant over lifespan in a large cohort of human participants, aged 18-88 years. Using empirically derived connection topologies from diffusion tensor imaging (DTI) data, we create an in-silico model of whole-brain alpha dynamics. We show that enhancing inter-areal coupling can cancel the effect of increased axonal transmission delay associated with age-related degeneration of white matter tracts and thus, preserve neural synchrony. Together with analytical solutions for non-biological all-to-all connection scenarios, our model establishes the theoretical principles by which frequency slowing with age, frequently observed in the alpha band in diverse populations, can be viewed as an epiphenomenon of the underlying neurocompensatory mechanisms.
Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers
Authors: Mao Qiyan , Acharya Achyuth , Rodríguez-delaRosa Alejandra , Marchiano Fabio , Dehapiot Benoit , Tanoury Ziad Al , Rao Jyoti , Díaz-Cuadros Margarete , Mansur Arian , Wagner Erica , Chardes Claire , Gupta Vandana A. , Lenne Pierre-François , Habermann Bianca H. , Theodoly Olivier , Pourquie Olivier , Schnorrer Frank
Published: October 2021

Human muscle is a hierarchically organised tissue with its contractile cells called myofibers packed into large myofiber bundles. Each myofiber contains periodic myofibrils built by hundreds of contractile sarcomeres that generate large mechanical forces. To better understand the mechanisms that coordinate human muscle morphogenesis from tissue to molecular scales, we adopted a simple in vitro system using induced pluripotent stem cell-derived human myogenic precursors. When grown on an unrestricted two-dimensional substrate, developing myofibers spontaneously align and self-organise into higher-order myofiber bundles, which grow and consolidate to stable sizes. Following a transcriptional boost of sarcomeric components, myofibrils assemble into chains of periodic sarcomeres that emerge across the entire myofiber. By directly probing tension we found that tension build-up precedes sarcomere assembly and increases within each assembling myofibril. Furthermore, we found that myofiber ends stably attach to other myofibers using integrin-based attachments and thus myofiber bundling coincides with stable myofiber bundle attachment in vitro. A failure in stable myofiber attachment results in a collapse of the myofibrils. Overall, our results strongly suggest that mechanical tension across sarcomeric components as well as between differentiating myofibers is key to coordinate the multi-scale self-organisation of muscle morphogenesis.
Aggregation pheromone 4-vinylanisole promotes the synchrony of sexual maturation in female locusts
Authors: Chen Dafeng , Hou Li , Wei Jianing , Guo Siyuan , Cui Weichan , Yang Pengcheng , Kang Le , Wang Xianhui
Published: October 2021

Reproductive synchrony generally occurs in various group-living animals; however, the underlying mechanisms remain largely unexplored. Here, we report that aggregation pheromone, 4-vinylanisole, plays a key role in promoting sexual maturation synchrony of female adults in the migratory locust,Locusta migratoria, a worldwide agricultural pest species that can form huge swarms with millions of individuals. Gregarious female locusts display significant synchrony of sexual maturation and oviposition whereas solitarious females and olfactory deficiency mutants do not. Only the presence of gregarious male adults can stimulate sexual maturation synchrony of female adults. Of the volatiles emitted abundantly by gregarious male adults, only 4-vinylanisole induces female sexual maturation synchrony, whereas this effect is abolished in mutants of 4- vinylanisole receptor. Interestingly, 4-vinylanisole mainly accelerates oocyte maturation of young females aged at middle developmental stages (3-4 days post adult eclosion). Juvenile hormone/vitellogenin pathway mediates female sexual maturation triggered by 4-vinylanisole. Our results highlight a “catch-up” strategy by which gregarious females synchronize their oocyte maturation and oviposition by time-dependent endocrinal response to 4-vinylanisole.
Radical pairs may explain reactive oxygen species-mediated effects of hypomagnetic field on neurogenesis
Authors: Rishabh  , Zadeh-Haghighi Hadi , Salahub Dennis , Simon Christoph
Published: October 2021

Exposures to a hypomagnetic field can affect biological processes. Recently, it has been observed that hypomagnetic field exposure can adversely affect adult hippocampal neurogenesis and hippocampus-dependent cognition in mice. In the same study, the role of reactive oxygen species (ROS) in hypomagnetic field effects has been demonstrated. However, the mechanistic reasons behind this effect are not clear. This study proposes a radical pair mechanism based on a flavin-superoxide radical pair to explain the modulation of ROS production and the attenuation of adult hippocampal neurogenesis in a hypomagnetic field. The results of our calculations favor a singlet-born radical pair over a triplet-born radical pair. Our model predicts hypomagnetic field effects on the triplet/singlet yield of comparable strength as the effects observed in experimental studies on adult hippocampal neurogenesis. Our predictions are also in qualitative agreement with experimental results on superoxide concentration and other observed ROS effects. We also predict the effects of applied magnetic fields and oxygen isotopic substitution on adult hippocampal neurogenesis. Our findings strengthen the idea that nature might harness quantum resources in the context of the brain.

Author summary

Exposure to magnetic fields influences many neurobiological processes. The formation of new neurons (neurogenesis) in the hippocampal region of the adult brain plays a crucial role in learning and memory. It can be adversely affected by shielding the earth’s magnetic field, and this effect is intimately related to ROS concentration. In this study, we have developed a quantum mechanical model to explain this magnetic field dependence of adult hippocampal neurogenesis. Our model is also consistent with the observed ROS effects.
Outbreak of SARS-CoV-2 B.1.617.2 (Delta) variant in a Nursing Home 28 weeks after two doses of mRNA anti-Covid-19 vaccines: evidence of a waning immunity
Authors: Pierobon Alice , Dal Zotto Alessandra , Antico Antonio , Ernesto De Antoni Mario , Vianello Liviano , Gennari Monica , Di Caprio Antonio , Russo Francesca , Brambilla Gianfranco , Saugo Mario
Published: October 2021

Objectives

Description of a SARS-CoV-2 B.1.617.2 (Delta) variant outbreak among residents (N=69) and Health Workers (HWs: N=69) of a small Nursing Home in Northern-East Italy, with full vaccination coverage of 91 and 82%, respectively. Evaluation of the Anti-Spike IgG titers 28 weeks after the mRNA vaccine boosts against SARS-COV-2 infection and severe Covid-19.

Materials and methods

A timely collection of sera within 48h from the index case; anti-Spike IgG determination (expressed as Binding Antibody Units – BAU/mL) through a commercial quantitative assay; SARS-CoV-2 diagnostics via RT-PCR, and full-genome sequencing for lineage characterization. Residents were grouped according to anti-Spike IgG titers (≤ 50, 51-1000, and > 1000 BAU/mL) and resulting protection against the infection and the severe disease was measured.

Results

0/20 HWs and 14/59 (24%) residents fully vaccinated and without a previous SARS-CoV-2 infection showed anti-Spike IgG lower/equal to 50 BAU/mL (1-sided Fisher exact p=0.011). Among these residents, a level of anti-Spike IgG ≤50 BAU/mL resulted in a higher risk of SARS-CoV-2 infection (RR=1.55, CI95% 1.17-2.05) and severe Covid-19 disease (RR=5.33, CI95% 1.83-15.57). Conclusion Low levels of SARS-CoV-2 neutralizing anti-Spike IgG in serum 28 weeks after the administration of the second dose parallels the waning of vaccine protection.
Domestic violence, mental health, and repeat self-harm in Sri Lanka
Authors: Bandara Piumee , Page Andrew , Rajapakse Thilini , Knipe Duleeka
Published: October 2021

Background

Evidence on the risk factors for repeat self-harm from low- and middle-income countries is scarce and requires urgent attention.

Aims

We sought to examine psychosocial correlates of repeat self-harm in Kandy, Sri Lanka.

Methods

Logistic regression models (adjusting for age and sex) were used to examine associations between study factors and repeat self-harm among adult patients (N=292) admitted for self-poisoning.

Results

Depression (OR 2.8 95% CI 1.7-4.7), prior psychiatric diagnosis (OR 4.8 95% CI 2.2-10.2), past-year exposure to suicidal behaviour (OR 1.9 95% 1.1-3.3), physical/sexual abuse (OR 3.0 95% CI 1.3-6.9), and psychological abuse (OR 2.3 95% CI 1.3-4.2) were strongly associated with repeat self-harm.

Conclusions

Identification and management of domestic violence and psychiatric morbidity should be part of routine clinical assessments of patients presenting with self-harm.
Modeling the impact of vaccination strategies for nursing homes in the context of increased SARS-CoV-2 community transmission and variants
Authors: Holmdahl Inga , Kahn Rebecca , Slifka Kara Jacobs , Dooling Kathleen , Slayton Rachel B.
Published: October 2021

Nursing homes (NH) were among the first settings to receive COVID-19 vaccines in the United States, but staff vaccination coverage remains low at an average of 64%. Using an agent-based model, we examined the impact of community prevalence, the Delta variant, staff vaccination coverage, and boosters for residents on outbreak dynamics in nursing homes. We found that increased staff primary series coverage and high booster vaccine effectiveness (VE) in residents leads to fewer infections and that the cumulative incidence is highly dependent on community transmission. Despite high VE, high community transmission resulted in continued symptomatic infections in NHs.
A Crowdsourcing Approach to Develop Machine Learning Models to Quantify Radiographic Joint Damage in Rheumatoid Arthritis
Authors: Sun Dongmei , Nguyen Thanh M. , Allaway Robert J. , Wang Jelai , Chung Verena , Yu Thomas V , Mason Michael , Dimitrovsky Isaac , Ericson Lars , Li Hongyang , Guan Yuanfang , Israel Ariel , Olar Alex , Pataki Balint Armin ,   RA2 DREAM Challenge Community, Stolovitzky Gustavo , Guinney Justin , Gulko Percio S. , Frazier Mason B. , Costello James C. , Chen Jake Y. , Bridges S. Louis
Published: October 2021

To develop machine learning methods to quantify joint damage in patients with rheumatoid arthritis (RA), we developed the RA2 DREAM Challenge, a crowdsourced competition that utilized existing radiographic images and “gold-standard” scores on 674 sets of films from 562 patients. Training and leaderboard sets were provided to participants to develop methods to quantify joint space narrowing and erosions. In the final round, participants submitted containerized codes on a test set; algorithms were evaluated using weighted root mean square error (RMSE). In the leaderboard round, there were 173 submissions from 26 teams in 7 countries. Of the 13 submissions in the final round, four top-performing teams were identified. Robustness of results was assessed using Bayes factor and validated using an independent set of radiographs. The top-performing algorithms, which consisted of different styles of deep learning models, provided accurate and robust quantification of joint damage in RA. Ultimately, these methods lay the groundwork to accelerate research and help clinicians to optimize treatments to minimize joint damage.
Molecular identification of rhizobacterial isolates from Prosopis limensis and their effect on the growth of Raphanus sativus under salt stress
Authors: Clavo Rene Flores , Valladolid Suyón Esteban A , Reinoza Farroñan Karin , Ortega Cristian Asmat , Zuñiga Valdera Gabriel , Garboggini Fabiana Fantinatti , Iglesias-Osores Sebastian , Carreño Farfán Carmen Rosa
Published: October 2021

Soil salinity negatively affects the development of agricultural crops. The utilization of plant growth-promoting rhizobacteria is a biotechnological alternative to mitigate this problem. Rhizobacteria were isolated from the roots and rhizosphere of Prosopis limensis Bentham “carob” to identify them and determine their potential as plant growth-promoters under salt stress. First, ACC deaminase activity was determined in Dworkin & Foster (DF) minimum medium with 3.0 mM ACC as a source of nitrogen; besides, tolerance to sodium chloride was determined in Nutrient Broth (NB) supplemented with 10% NaCI. Then, bacteria displaying ACC deaminase activity and a 10% NaCI tolerance were selected, identified through genomic analysis targeting the 16s rRNA gene, and inoculated into Raphanus sativus L. “radish” seeds to determine the effect on germination percentage under salt stress (80 mM NaCI) and, also on indole production and phosphate solubilization. Isolates were also utilized to evaluate their effect on the growth of radish in saline soils. Genomic analysis showed two bacterial isolates from the genus Pseudomonas and one from the genus Bordetella: Isolate MW604823 was identified as Pseudomonas sp.; isolate MW604824, as Pseudomonas hunanensis; and isolate MW604826 as Bordetella muralis. Thee isolates demonstrated ACC deaminase activity and tolerance to 10% NaCI. Inoculation of the isolates on radish seeds increased germination percentage compared to the control. The isolates displayed in vitro indole production and phosphate solubilization capacity. Moreover, the isolates promoted the growth of radish under salt stress conditions, increasing, leave number, root number, aerial, and root biomass, demonstrating their potential as a biofertilizers.
Epidermal Stratification Requires Retromer-Mediated Desmoglein-1 Recycling
Authors: Hegazy Marihan , Koetsier Jennifer L. , Huffine Amber L. , Broussard Joshua A. , Godsel Brendan M. , Godsel Lisa M. , Green Kathleen J.
Published: October 2021

Sorting and trafficking transmembrane cargo is essential for tissue development and homeostasis. However, the importance of intracellular trafficking in the development and regeneration of stratified epidermis has not been investigated. Here we identify the interaction between VPS35, an essential component of the retromer endosomal trafficking complex, and the desmosomal cadherin, Desmoglein 1 (Dsg1). Dsg1 is specifically expressed in stratified tissues and when properly localized on the plasma membrane, promotes epidermal stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support keratinocyte stratification and differentiation. The retromer enhancing chaperone, R55 promotes the plasma membrane localization of Dsg1 and a Dsg1 mutant associated with Severe dermatitis, multiple Allergies, and Metabolic wasting (SAM) syndrome, enhancing the ability of SAM-Dsg1 to promote stratification. Our work provides the first evidence for retromer function in epidermal regeneration and identifies it as a potential therapeutic skin disease target.
Vaccinia E5 is a major inhibitor of the DNA sensor cGAS
Authors: Yang Ning , Wang Yi , Dai Peihong , Li Tuo , Zierhut Christian , Tan Adrian , Zhang Tuo , Pan Heng , Li Zhuoning , Ordureau Alban , Xiang Jenny Zhaoying , Hendrickson Ronald C. , Funabiki Hironori , Chen Zhijian , Deng Liang
Published: October 2021

The DNA sensor cyclic GMP-AMP synthase (cGAS) is critical in host antiviral immunity. Vaccinia virus (VACV) is a large cytoplasmic DNA virus that belongs to the poxvirus family. How vaccinia virus antagonizes the cGAS-mediated cytosolic DNA-sensing pathway is largely unknown. In this study, we screened 82 vaccinia viral genes to identify potential viral inhibitors of the cGAS/Stimulator of interferon gene (STING) pathway. We discovered that vaccinia E5 is a virulence factor and a major inhibitor of cGAS that elicits proteasome-dependent cGAS degradation. E5 localizes to the cytoplasm and nuclei of infected cells. Cytosolic E5 triggers K48-linked ubiquitination of cGAS and proteasome-dependent degradation via interacting with cGAS. E5 itself also undergoes ubiquitination and degradation. Deleting the E5R gene from the Modified vaccinia virus Ankara (MVA) genome strongly induces type I IFN production by dendritic cells (DCs) and promotes DC maturation, thereby improving the immunogenicity of the viral vector.
Adipocyte autophagy limits gut inflammation by controlling oxylipin levels
Authors: Richter Felix Clemens , Friedrich Matthias , Kampschulte Nadja , Pohin Mathilde , Alsaleh Ghada , Guschina Irina , Wideman Sarah Karin , Johnson Errin , Borsa Mariana , Piletic Klara , Hahn Paula , Schipper Henk Simon , Edwards Claire M. , Zechner Rudolf , Schebb Nils Helge , Powrie Fiona , Simon Anna Katharina
Published: October 2021

Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, through their use as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti- inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an altered oxylipin balance, driven through an NRF2-mediated upregulation of Ephx1. This was accompanied by a shift in adipose tissue macrophage polarization with reduced secretion of IL-10, leading to lower circulating levels of IL-10. These results suggest an underappreciated fat-gut crosstalk through an autophagy- dependent regulation of anti-inflammatory oxylipins, indicating a protective effect of adipose tissues for distant inflammation.
Spinning sugars in antigen biosynthesis: a direct study of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases
Authors: Cross Alice R. , Roy Sumita , Vega Mirella Vivoli , Rejzek Martin , Nepogodiev Sergey A. , Cliff Matthew , Salmon Debbie , Isupov Michail N. , Field Robert A. , Prior Joann L. , Harmer Nicholas J.
Published: October 2021

The sugars streptose and dihydrohydroxystreptose (DHHS) are unique to the bacteria Streptomyces griseus and Coxiella burnetii respectively. Streptose forms the central moiety of the antibiotic streptomycin, whilst DHHS is found in the O-antigen of the zoonotic pathogen C. burnetii. Biosynthesis of these sugars has been proposed to follow a similar path to that of TDP-rhamnose, catalysed by the enzymes RmlA/RmlB/RmlC/RmlD. Streptose and DHHS biosynthesis unusually require a ring contraction step that might be performed by the orthologues of RmlC or RmlD. Genome sequencing of S. griseus and C. burnetii proposed the StrM and CBU1838 proteins respectively as RmlC orthologues. Here, we demonstrate through both coupled and direct observation studies that both enzymes can perform the RmlC 3’’,5’’ double epimerisation activity; and that this activity supports TDP-rhamnose biosynthesis in vivo. We demonstrate that proton exchange is faster at the 3’’ position than the 5’’ position, in contrast to a previously studied orthologue. We solved the crystal structures of CBU1838 and StrM in complex with TDP and show that they form an active site highly similar to previously characterised enzymes. These results further support the hypothesis that streptose and DHHS are biosynthesised using the TDP pathway and are consistent with the ring contraction step being performed on a double epimerised substrate, most likely by the RmlD paralogue. This work will support the determination of the full pathways for streptose and DHHS biosynthesis.
Deep neural networks and visuo-semantic models explain complementary components of human ventral-stream representational dynamics
Authors: Jozwik Kamila M , Kietzmann Tim C , Cichy Radoslaw M , Kriegeskorte Nikolaus , Mur Marieke
Published: October 2021

Deep neural networks (DNNs) are promising models of the cortical computations supporting human object recognition. However, despite their ability to explain a significant portion of variance in neural data, the agreement between models and brain representational dynamics is far from perfect. We address this issue by asking which representational features are currently unaccounted for in neural timeseries data, estimated for multiple areas of the ventral stream via source-reconstructed magnetoencephalography (MEG) data acquired in human participants (9 females, 6 males) during object viewing. We focus on the ability of visuo-semantic models, consisting of human-generated labels of object features and categories, to explain variance beyond the explanatory power of DNNs alone. We report a gradual reversal in the relative importance of DNN versus visuo-semantic features as ventral-stream object rep-resentations unfold over space and time. While lower-level visual areas are better explained by DNN features, especially during the early phase of the response (< 128 ms after stimulus onset), higher-level cortical dynamics are best accounted for by visuo-semantic features during a later time window (starting 146 ms after stimulus onset). Among the visuo-semantic features, object parts and basic categories drive the advantage over DNNs. These results show that a significant component of the variance unexplained by DNNs in higher-level cortical dynamics is structured, and can be explained by readily nameable aspects of the objects. We conclude that current DNNs fail to fully capture dynamic representations in higher-level human visual cortex and suggest a path toward more accurate models of ventral stream computations.

SIGNIFICANCE STATEMENT

When we view objects such as faces and cars in our visual environment, their neural representations dynamically unfold over time at a millisecond scale. These dynamics reflect the cortical computations that support fast and robust object recognition. Deep neural networks (DNNs) have emerged as a promising framework for modeling these computations but cannot yet fully account for the neural dynamics. Using magnetoencephalography data acquired in human observers during object viewing, we show that readily nameable aspects of objects, such as “eye”, “wheel”, and “face”, can account for variance in the neural dynamics over and above DNNs. These findings suggest that DNNs and humans may in part rely on different object features for visual recognition and provide guidelines for model improvement.
Autotaxin is a Potential Link between Genetic Risk Factors and Pathogenesis of Systematic Lupus Erythematosus in Plasmacytoid Dendritic Cells
Authors: Tsuchida Yumi , Shoda Hirofumi , Nakano Masahiro , Ota Mineto , Okamura Tomohisa , Yamamoto Kazuhiko , Kurano Makoto , Yatomi Yutaka , Fujio Keishi , Sawada Tetsuji
Published: October 2021

Background

The importance of autotaxin, an enzyme that catalyzes lysophospholipid production, has recently been recognized in various diseases, including cancer and autoimmune diseases. Herein, we examined the role of autotaxin in systemic lupus erythematosus (SLE), utilizing data from ImmuNexUT, a comprehensive database consisting of transcriptome data and expression quantitative trait locus (eQTL) data of immune cells from patients with immune-mediated disorders.

Methods

Serum autotaxin concentrations in patients with SLE and healthy controls (HCs) were compared. The transcriptome data of patients with SLE and age-and sex-matched HCs were obtained from ImmuNexUT. The expression of ENPP2, the gene encoding autotaxin, was examined in peripheral blood immune cells. Next, weighted gene correlation network analysis (WGCNA) was performed to identify genes with expression patterns similar to ENPP2. The ImmuNexUT eQTL database and public epigenomic databases were used to infer the relationship between autotaxin and pathogenesis of SLE.

Results

Autotaxin levels were elevated in the serum of patients with SLE compared to HCs. Furthermore, the expression of ENPP2 was higher in plasmacytoid dendritic cells (pDCs) than in other immune cell subsets, and its expression was elevated in pDCs of patients with SLE compared to HCs. In WGCNA, ENPP2 belonged to a module that correlated with disease activity. This module was enriched in interferon-associated genes and included genes whose expression was influenced by single-nucleotide polymorphisms associated with SLE, suggesting that it is a key module connecting genetic risk factors of SLE with disease pathogenesis. Analysis utilizing the ImmuNexUT eQTL database and public epigenomic databases suggested that the increased expression of ENPP2 in pDCs from patients with SLE may be caused by increased expression of interferon-associated genes and increased binding of STAT3 complexes to the regulatory region of ENPP2.

Conclusions

Autotaxin may play a critical role in connecting genetic risk factors of SLE to disease pathogenesis in pDCs.
Urinary bladder enlargement across nine rodent models of diabetes: correlations with glucose and insulin levels
Authors: Yesilyurt Zeynep E. , Matthes Jan , Hintermann Edith , Castañeda Tamara R. , Elvert Ralf , Beltran-Ornelas Jesus H. , Silva-Velasco Diana L. , Xia Ning , Kannt Aimo , Christen Urs , Centurion David , Li Huige , Pautz Andrea , Arioglu-Inan Ebru , Michel Martin C.
Published: October 2021

The urinary bladder is markedly enlarged in the type 1 diabetes mellitus model of streptozotocin (STZ)-injected rats, but much less data exist for models of type 2 diabetes (T2DM). Diabetic polyuria has been proposed to explain bladder enlargement. We have collected data on bladder weight and blood glucose from 16 studies representing 9 distinct rodent diabetes (7 T2DM) and obesity models; some included arms with diets and/or pharmacological treatments. Data were analyzed for bladder enlargement and for correlations between bladder weight on the one and glucose levels on the other hand. Our data confirm major bladder enlargements in STZ rats, minor if any enlargement in fructose-fed rats, db/db mice and mice on a high-fat diet. For the first time we report bladder weight data on 5 other models with presence and degree of bladder enlargement being heterogeneous across models. Bladder weight was correlated with plasma glucose in some but not other models, but correlations were moderate to weak except for RIP-LMCV mice. We conclude that the presence and extent of bladder enlargement varies markedly across diabetes models, particularly TD2M models; our data do not support the idea that bladder enlargement is primarily driven by glucose levels/glucosuria.
The Isl1/Shh/Wnt5a cascade controls the invasion of myoblasts by tuning the CXCL12/CXCR4 axis during tongue morphogenesis
Authors: Zhang Wei , Yu Jiaojiao , Fu Guoquan , Huang Ruiqi , Li Jianying , Huang Huarong , Liu Jing , Yu Dongliang , Gan Lin , Qiu Mengsheng , Zhang Zunyi , Li Feixue
Published: October 2021

The migration and invasion of myoblast cells derive from the occipital somites is critical for tongue morphogenesis. However, the molecular mechanisms underlying myoblast migration and invasion remain elusive. In this study, we report that transcription factor Isl1 is required for tongue development. Loss of Isl1 in the distal mandibular epithelium results in aglossia due to the defect of myoblast cells invasion. In the absence of Isl1 expression, myoblast cells in the first branchial arch fail to migrate into the presumptive tongue primordium. Down-regulation of Shh was detected in the distal mandibular epithelium after Isl1 deletion. As a downstream target gene of Shh, Wnt5a attracts the migration of mesenchymal cells expressing chemokine ligand 12 (CXCL12). CXCL12+ mesenchymal cells in the Isl1 mutant embryo fail to migrate to the distal region but accumulate in a relatively small proximal domain of the first branchial arch. CXCL12 serves as a bidirectional cue for myoblasts that express its receptor CXCR4, attracting CXCR4+ myoblasts invasion at low concentration but repelling at high concentration. The defect in the distal migration of CXCL12+ mesenchymal cells leads to a high local concentration of CXCL12, thereby preventing the invasion of CXCR4+ myoblasts. In addition, transgenic activation of Ihh alleviates the defect in tongue development and rescues the invasion of myoblasts, corroborating the functional involvement of Hedgehog signaling in tongue development. In summary, this study provides the first line of genetic evidence for the Isl1/Shh/Wnt5a cascade to regulate myoblasts invasion by tuning the CXCL12/CXCR4 axis.
Going Beyond the Point Neuron: Active Dendrites and Sparse Representations for Continual Learning
Authors: Grewal Karan , Forest Jeremy , Cohen Benjamin P. , Ahmad Subutai
Published: October 2021

Biological neurons integrate their inputs on dendrites using a diverse range of non-linear functions. However the majority of artificial neural networks (ANNs) ignore biological neurons’ structural complexity and instead use simplified point neurons. Can dendritic properties add value to ANNs? In this paper we investigate this question in the context of continual learning, an area where ANNs suffer fromcatastrophic forgetting(i.e., ANNs are unable to learn new information without erasing what they previously learned). We propose that dendritic properties can help neurons learn context-specific patterns and invoke highly sparse context-specific subnetworks. Within a continual learning scenario, these task-specific subnetworks interfere minimally with each other and, as a result, the network remembers previous tasks significantly better than standard ANNs. We then show that by combining dendritic networks with Synaptic Intelligence (a biologically motivated method for complex weights) we can achieve significant resilience to catastrophic forgetting, more than either technique can achieve on its own. Our neuron model is directly inspired by the biophysics of sustained depolarization following dendritic NMDA spikes. Our research sheds light on how biological properties of neurons can be used to solve scenarios that are typically impossible for traditional ANNs to solve.