bluuebunny/crossref_metadata_2025 huggingface dataset:
DLPFC-tDCS unable to modulate mind-wandering propensity nor underlying functional or effective brain connectivity
Authors: Coulborn Sean , Fernández-Espejo Davinia
Published: May 2022

There is conflicting evidence over the ability to modulate mind-wandering propensity with anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC-tDCS). Here, 20 participants received 20-minutes of anodal and sham DLPFC-tDCS while in the MRI scanner, in two separate sessions (counterbalanced). In each session, they completed two runs of a sustained attention to response task (before and during tDCS), which included probes recording subjective responses of mind-wandering. We assessed the effects of tDCS on behavioural responses as well as functional and effective dynamics, via dynamic functional network connectivity (dFNC) and dynamic causal modelling analyses over regions of the default mode, salience and executive control networks. Behavioural results provided substantial evidence in support of no effect of tDCS on task performance nor mind-wandering propensity. Similarly, we found no effect of tDCS on frequency (how often) or dwell time (time spent) of underlying brain states nor effective connectivity. Overall, our results suggest that DLPFC-tDCS is unable to modulate mind-wandering propensity or influence underlying brain function. This expands previous behavioural replication failures in suggesting that DLPFC-tDCS may not lead to even subtle (i.e., under a behavioural threshold) changes in brain activity during self-generated cognition.
Background modeling, Quality Control and Normalization for GeoMx RNA data with GeoDiff
Authors: Yang Lei , Yang Zhi , Danaher Patrick , Zimmerman Stephanie , Hether Tyler , Henderson David , Beechem Joseph
Published: May 2022

Background

NanoString’s GeoMx Digital Spatial Profiler (DSP) RNA assay can measure mRNA from hundreds of regions of customizable shape and size, yet it gives unique challenge in Quality Control(QC) and normalizating due to the omnipresent background noise incurred by the non-specific probe binding, which could not be addressed by conventional methods.

Results and discussion

Using Poisson Background model, Background Score Test, Negative Binomial threshold model and Poisson threshold model for normalization from the R package GeoDiff, we perform tasks including size factor estimation, QC and normalization on GoeMx RNA assay data. They are shown to outperform conventional methods like Limit of Quantification for QC as to consistency/false positive rate and 75% quantile normalization as to eliminating technical variability and recovering true signal.

Conclusions

We present a statistical model based workflow for QC and normalizing GeoMx RNA data using GeoDiff, justified by statistical theory and validated by real/simulated data.
Peripheral ghrelin administration prevents the behavioral effects of restraint stress in mice: possible implication of PVNCRHneurons
Authors: Dos-Santos Raoni Conceição , Flores Rafael Appel , de Jesus Aline Alves , Rorato Rodrigo , Mecawi André Souza , Antunes-Rodrigues José , Kagohara Elias Lucila Leico
Published: May 2022

Ghrelin is a gut-derived hormone that is secreted during conditions of negative caloric balance and acts as a key modulator of feeding, increasing food intake and affecting several physiological systems such as metabolism, behavior and the control of endocrine and autonomic functions. Previous studies showed that ghrelin participates in the stress response, acting on hypothalamic paraventricular nucleus neurons that express corticotropin-releasing hormone (PVNCRHneurons). In the present study, we investigated the effects of ghrelin administration on the behavioral responses to restraint stress in mice. In their homecage, C57Bl6 mice in basal conditions expressed the behaviors of surveying, walking, rearing, grooming and, to a lesser extent, digging, climbing and freezing. Restraint stress increased the time spent in grooming without significant changes in other behaviors. Ghrelin administration did not affect behavior in control mice, but it reversed the effect of restraint stress on grooming. Chemogenetic activation of PVNCRHneurons by clozapine N-Oxide (CNO) administration in hM3Dq DREADD mice increased grooming, while ghrelin mitigated this effect. In addition, CNO administration decreased walking and rearing, both in the presence or absence of ghrelin. Food intake was increased by ghrelin administration, however, it was not affected by stress or CNO. These results indicate that ghrelin decreases the activity of PVNCRHneurons, partially preventing the behavioral effects of restraint stress. The inhibitory input to PVNCRHneurons probably arrives from other nuclei, since GABAergic neurons were not identified in the PVN neurons of these mice.
Enrichment of hard sweeps on the X chromosome in Drosophila melanogaster
Authors: Harris Mariana , Garud Nandita
Published: May 2022

The characteristic properties of the X chromosome, such as male hemizygosity and its unique inheritance pattern, expose it to natural selection in a way that can be different from the autosomes. Here, we investigate the differences in the tempo and mode of adaptation on the X chromosome and autosomes in a population of Drosophila melanogaster. Specifically, we test the hypothesis that due to hemizygosity and a lower effective population size on the X, the relative proportion of hard sweeps, which are expected when adaptation is gradual, compared to soft sweeps, which are expected when adaptation is rapid, is greater on the X than on the autosomes. We quantify the incidence of hard versus soft sweeps in North American D. melanogaster population genomic data with haplotype homozygosity statistics and find an enrichment of the proportion of hard versus soft sweeps on the X chromosome compared to the autosomes, confirming predictions we make from simulations. Understanding these differences may enable a deeper understanding of how important phenotypes arise as well as the impact of fundamental evolutionary parameters on adaptation, such as dominance, sex-specific selection, and sex-biased demography.
Secretin modulates appetite via brown adipose tissue - brain axis
Authors: Sun Lihua , Laurila Sanna , Lahesmaa Minna , Rebelos Eleni , Virtanen Kirsi A. , Schnabl Katharina , Klingenspor Martin , Nummenmaa Lauri , Nuutila Pirjo
Published: May 2022

Secretin activates brown adipose tissue (BAT) and induces satiation in both mice and humans. However, the exact brain mechanism of this satiety inducing, secretin-mediated gut-BAT-brain axis is unknown. In this placebo-controlled, single-blinded neuroimaging study, firstly using [18F]FDG-PET measures (n = 15), we established that secretin modulated brain glucose consumption through the BAT-brain axis. Predominantly, we found that BAT and caudate glucose uptake levels were negatively correlated (r = −0.54, p = 0.037) during secretin but not placebo condition. Then, using functional magnetic resonance imaging (fMRI; n = 14), we found that secretin down-regulated the brain response to appetizing food images and improved inhibitory control. Finally, in a PET-fMRI fusion analysis (n = 10), we disclosed the patterned correspondence between caudate glucose uptake and neuroactivity to reward and inhibition, showing that the secretin-induced neurometabolic coupling pattern promoted satiation. These findings suggest that secretin modulates the BAT-brain metabolic crosstalk and subsequent neurometabolic coupling to induce satiation, bearing potential clinical benefits for treating eating disorders.

Significance of the study

Secretin activates brown adipose tissue and induces satiation, but the underlying brain mechanisms are still unclear. This placebo-controlled PET-fMRI study uses brain metabolic and BOLD measures to dissect the modulatory effects of secretin on brain functions associative to satiation. Findings show that secretin i) modulates caudate glucose metabolism via the BAT-brain axis, ii) enhances BOLD response in inhibitory control, and iii) reduces reward-related BOLD response. Further evidence shows that these measured effects are tightly linked via the secretin-mediated brain neurometabolic coupling. This study significantly advances our knowledge on how secretin leads to satiation and highlights the potential role of secretin in treating eating disorders and obesity.
Examining Effects of Schizophrenia on EEG with Explainable Deep Learning Models
Authors: Ellis Charles A. , Sattiraju Abhinav , Miller Robyn , Calhoun Vince
Published: May 2022

Schizophrenia (SZ) is a mental disorder that affects millions of people globally. At this time, diagnosis of SZ is based upon symptoms, which can vary from patient to patient and create difficulty with diagnosis. To address this issue, researchers have begun to look for neurological biomarkers of SZ and develop methods for automated diagnosis. In recent years, several studies have applied deep learning to raw EEG for automated SZ diagnosis. However, the use of raw time-series data makes explainability more difficult than it is for traditional machine learning algorithms trained on manually engineered features. As such, none of these studies have sought to explain their models, which is problematic within a healthcare context where explainability is a critical component. In this study, we apply perturbation-based explainability approaches to gain insight into the spectral and spatial features learned by two distinct deep learning models trained on raw EEG for SZ diagnosis for the first time. We develop convolutional neural network (CNN) and CNN long short-term memory network (CNN-LSTM) architectures. Results show that both models prioritize the T8 and C3 electrodes and the δ- and γ-bands, which agrees with previous literature and supports the overall utility of our models. This study represents a step forward in the implementation of deep learning models for clinical SZ diagnosis, and it is our hope that it will inspire the more widespread application of explainability methods for insight into deep learning models trained for SZ diagnosis in the future.
NFYA promotes the malignant behavior of triple-negative breast cancer through the regulation of lipid metabolism
Authors: Okada Nobuhiro , Ueki Chihiro , Shimazaki Masahiro , Tsujimoto Goki , Kohno Susumu , Muranaka Hayato , Yoshikawa Kiyotsugu , Takahashi Chiaki
Published: May 2022

Two splicing variants exist in NFYA, which exhibits high expression in many human tumor types, and their expression balance is known to correlate with prognosis in breast cancer, but functional differences are still unclear. Here, we demonstrate that NFYAv1, the long-form variant, upregulates the transcription of ACACA and FASN, essential lipogenic enzymes, to enhance the malignant behavior of triple-negative breast cancer (TNBC). Loss of the NFYAv1-lipogenesis axis strongly suppresses the malignant behavior in vitro and in vivo, indicating that the NFYAv1-lipogenesis axis is essential for TNBC malignant behavior and that the axis might be a potential therapeutic target for TNBC. Furthermore, mice deficient in lipogenic enzymes such as Acly, Acaca, and Fasn exhibit embryonic lethality, but our Nfyav1-deficient mice have no apparent developmental abnormalities. Taken together, our results elucidate NFYAv1-lipogenesis axis has significant tumor-promoting effects and the potential for NFYAv1 to be a safer therapeutic target for TNBC.
ADAM10 pharmacological inhibition modifies the expression of components of the dopaminergic system
Authors: Maitra Subhamita , Vincent Bruno
Published: May 2022

Dopamine is a primary neurotransmitter associated with memory formation, emotional control, reward processing and other higher order mental functions. Altered dopamine signaling is implied in several neuropsychiatric, neurodevelopmental and neurodegenerative disorders including Alzheimer’s disease. Age-related memory decline often presents itself with spectrum of overtly behavioral responses in patients diagnosed with Alzheimer’s disease, thus suggesting that an alteration of dopaminergic transmission could account for the psychotic symptoms observed along the pathology. Since less sAPPα production due to reduced α-secretase activity is a direct contributor of compromised neuroprotection and can impart higher vulnerability to cellular insults, we explored the impact of specific inhibition of ADAM10, the main neuronal α-secretase, on dopamine system components in cultured human SH-SY5Y neuroblastoma cells. We found that dopamine receptor D4 protein levels were dose-dependently down regulated by GI254023X, but not by the ADAM17-specific inhibitor TAPI-0. We then established that GI254023X operates at a transcriptional levels. Furthermore, we showed that GI254023X treatment also significantly increased the levels of active PKA as well as the transcription of the dopamine-degrading enzymes catechol-O-methyltransferase, monoamine oxidase A and monoamine oxidase B. Altogether, our data propose that ADAM10 inhibition modulates the dopaminergic system to possibly trigger psychosis in Alzheimer’s disease.
Advancing North: White-nosed coati’s Nasua narica Range Expansion in Arizona
Authors: Ragan Kinley , Walker Faith M. , Stevens Lawrence E. , Schipper Jan
Published: May 2022

Over the past century, the white-nosed coati (WNC; Nasua narica) has expanded its northernmost range from the United States-Mexico border into northern Arizona. WNC are medium-sized, opportunistic omnivores that often occur in large groups (“bands”) and forage on insects, fruits, and small vertebrates. We compiled data from iNaturalist, published literature, Arizona Game and Fish records, museum collections, personal communications, and our own camera trap photography to chronicle this range expansion. Historical records documented WNC populations in mountainous areas along the US-Mexican border but rarely north of Tucson, AZ. The popularity of using wildlife cameras in both research and recreation, paired with the advancement of citizen science projects like iNaturalist have generated a vast amount of new data on species distributions. With this new body of information we report the range of WNC now occurs over 400 km farther north, extending north of Flagstaff, Arizona. Recent records include occurrence in ponderosa pine forest that sustain sometimes heavy winter snow – an environment vastly different from the species’ normal range. The northward expansion of this meso-carnivore invites many questions about drivers of range expansion, including climate change, mesopredator release, or simple opportunism. More research into the behavior and ecology of WNC in the northern extent of their range is needed to guide understanding and potential future management of this species, its impacts, and prediction of other such range expansions.
On predicting heterogeneity in nanoparticle dosage
Authors: Dowling Celia V. , Cevaal Paula M. , Faria Matthew , Johnston Stuart T.
Published: May 2022

Nanoparticles are increasingly employed as a vehicle for the targeted delivery of therapeutics to specific cell types. However, much remains to be discovered about the fundamental biology that dictates the interactions between nanoparticles and cells. Accordingly, few nanoparticle-based targeted therapeutics have succeeded in clinical trials. One element that hinders our understanding of nanoparticle-cell interactions is the presence of heterogeneity in nanoparticle dosage data obtained from standard experiments. It is difficult to distinguish between heterogeneity that arises from stochasticity in nanoparticle behaviour, and that which arises from heterogeneity in the cell population. Mathematical investigations have revealed that both sources of heterogeneity contribute meaningfully to the heterogeneity in nanoparticle dosage. However, these investigations have relied on simplified models of nanoparticle internalisation. Here we present a stochastic mathematical model of nanoparticle internalisation that incorporates a suite of relevant biological phenomena such as multistage internalisation, cell division, asymmetric nanoparticle inheritance and nanoparticle saturation. Critically, our model provides information about nanoparticle dosage at an individual cell level. We perform model simulations to examine the influence of specific biological phenomena on the heterogeneity in nanoparticle dosage. Under certain modelling assumptions, we derive analytic approximations of the nanoparticle dosage distribution. We demonstrate that the analytic approximations are accurate, and show that nanoparticle dosage can be described by a Poisson mixture distribution with rate parameters that are a function of Beta-distributed random variables. We discuss the implications of the analytic results with respect to parameter estimation and model identifiability from standard experimental data. Finally, we highlight extensions and directions for future research.
Strange attractor of a narwhal (Monodon monoceros)
Authors: Podolskiy Evgeny A. , Heide-Jørgensen Mads Peter
Published: May 2022

Detecting structures within the continuous diving behavior of marine animals is challenging, and no universal framework is available. We captured such diverse structures using chaos theory. By applying time-delay embedding to exceptionally long dive records (83 d) from the narwhal, we reconstructed the state-space portrait. Using measures of chaos, we detected a diurnal pattern and its seasonal modulation, classified data, and found how sea-ice appearance shifts time budgets. There is more near-surface rest but deeper dives at solar noon, and more intense diving during twilight and at night but to shallower depths (likely following squid); sea-ice appearance reduces rest. The introduced geometrical approach is simple to implement and potentially helpful for mapping and labeling long-term behavioral data, identifying differences between individual animals and species, and detecting perturbations.
Using eDNA metabarcoding to establish targets for freshwater fish composition following river restoration
Authors: Ito Gen , Yamauchi Hiroshi , Shigeyoshi Miwa , Ashino Kousuke , Yonashiro Chie , Asami Maki , Goto Yuko , Duda Jeffrey J. , Yamanaka Hiroki
Published: May 2022

Establishing realistic targets for fish community composition is needed to assess the effectiveness of river restoration projects. We used environmental DNA (eDNA) metabarcoding with MiFish primers to obtain estimates of fish community composition across 17 sites upstream, downstream and within a restoration mitigation project area (Kaihotsu– Kasumi) located in the Shigenobu River system, Ehime Prefecture, Japan. We evaluate the benefits of using eDNA to quickly, sensitively, and extensively gather data to establish existing fish community composition in the restoration area, as well as potential future short-term, medium-term, and long-term targets of species assemblages that could realistically emerge following dispersal into the project area from upstream and downstream populations. We compare results from eDNA metabarcoding with species lists obtained from contemporaneous capture surveys and historical information. Nonmetric multidimensional scaling plots of community composition obtained from eDNA surveys showed that the Kaihotsu–Kasumi restoration area and surrounding river reaches were divided into three clusters: upper reaches, middle and lower reaches, and estuarine reaches. The Kaihotsu– Kasumi restoration area sites were included in the group containing the middle and lower reaches of the inflow and outflow rivers that were near the restoration area. We detected a total of twenty-six species in this group, twenty-one native species and five non-native species. Therefore, these native species were considered suitable as short-term target species with high potential for dispersal into Kaihotsu–Kasumi restoration area. By comparison, only 14 species would have been selected as target species based on capture surveys and historical literature. One factor increasing the resolution of our eDNA surveys was our ability to identify the presence of intraspecific lineages of Misgurnus anguillicaudatus (Clades A and B), which were missed by the capture surveys. These results indicate that the eDNA metabarcoding method can provide more comprehensive and realistic short-term target species estimates than capture surveys, as well as provide higher resolution monitoring through intraspecific lineage detection.
Doublecortin-like kinase 1 is a therapeutic target in squamous cell carcinoma
Authors: Standing David , Arnold Levi , Dandawate Prasad , Ottemann Brendan , Snyder Vusala , Ponnurangam Sivapriya , Sayed Afreen , Subramaniam Dharmalingam , Srinivasan Pugazhendhi , Choudhury Sonali , New Jacob , Kwatra Deep , Ramamoorthy Prabhu , Roy Badal C. , Shadoin Melissa , Al-Rajabi Raed , O’Neil Maura , Gunewardena Sumedha , Ashcraft John , Umar Shahid , Weir Scott J. , Tawfik Ossama , Padhye Subhash B. , Anant Shrikant , Thomas Sufi Mary
Published: May 2022

Doublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck squamous cell carcinoma (HNSCC) and anal squamous cell carcinoma (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in HPV negative cancer tissues, which are typically aggressive with poor responses to radiation therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on non-specific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD [3,5-bis (2,4-difluorobenzylidene)-4-piperidone] binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth.
Whole-exome sequencing study identifies novel rare variants and genes associated with intraocular pressure and glaucoma
Authors: Gao Xiaoyi Raymond , Chiariglione Marion , Arch Alexander J.
Published: May 2022

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, the leading cause of irreversible blindness worldwide. IOP is also the only modifiable risk factor for glaucoma. Previous genome-wide association studies have established the contribution of common genetic variants to IOP. The role of rare variants for IOP was unknown. Using whole exome sequencing data from 454,756 participants in the UK Biobank (UKB), we conducted the largest exome-wide association study of IOP to date. In addition to confirming known IOP genes, we identified 40 novel rare-variant genes for IOP, such as BOD1L1, ACAD10 and HLA-B, demonstrating the power of including and aggregating rare variants in gene discovery. About half of these IOP genes are also associated with glaucoma phenotypes in UKB and the FinnGen cohort. Six of these genes, i.e. ADRB1, PTPRB, RPL26, RPL10A, EGLN2, and MTOR, are drug targets that are either established for clinical treatment or in clinical trials. Furthermore, we constructed a rare-variant polygenic risk score and showed its significant association with glaucoma in independent subjects. We demonstrated the value of rare variants to enhance our understanding of the biological mechanisms regulating IOP, and uncovered potential novel therapeutic targets for glaucoma.
Statistical segmentation and correlation analysis of the EEG between the different phases of general anesthesia
Authors: Sun C. , Longrois D. , Holcman D.
Published: May 2022

Electroencephalography (EEG) is routinely used to monitor general anesthesia (GA). Unanswered questions concern the possibility of using the EEG signal to classify patients as more or less sensitive to anesthetic drugs from the onset of anesthesia. We investigate here possible statistical correlation between different phases of general anesthesia. We test whether it could be possible to predict the speed of return to consciousness from the induction or the maintenance phases. For that goal, we tracked the maximum power of theα−band and follow its time course. Using an optimization procedure, we quantify the characteristic shift of theα−band during recovery and the associated duration. Interestingly, we found no correlation (Pearson coefficient) between these shifts and the amount ofα−band or iso-electric suppressions (flat EEG epochs) present in the maintenance phase or induced by a propofol injection during induction. To quantify the instability of theα−band, we introduce the total variation theα−band that accounts for all possible deviation from a flat line. To conclude, the present analysis shows that it would not be possible to anticipate the duration of recovery of consciousness from previous phases of general anesthesia in children and adults. Possibly the involved neuronal mechanisms during the different phases are not comparable.
Multi-ancestry GWAS deciphers genetic architecture of abdominal aortic aneurysm and highlightsPCSK9as a therapeutic target
Authors: Roychowdhury Tanmoy , Klarin Derek , Levin Michael G , Spin Joshua M , Rhee Yae Hyun , Deng Alicia , Headley Colwyn A , Surakka Ida , Tsao Noah L , Gellatly Corry , Zuber Verena , Shen Fred , Hornsby Whitney E , Laursen Ina Holst , Verma Shefali S , Locke Adam E , Einarsson Gudmundur , Thorleifsson Gudmar , Graham Sarah E , Dikilitas Ozan , Pattee Jack W , Judy Renae L , Pauls-Verges Ferran , Nielsen Jonas B , Wolford Brooke N , Brumpton Ben M , Dilmé Jaume , Peypoch Olga , Juscafresa Laura Calsina , Edwards Todd L , Li Dadong , Banasik Karina , Brunak Søren , Jacobsen Rikke L , Garcia-Barrio Minerva T , Zhang Jifeng , Rasmussen Lars M , Lee Regent , Handa Ashok , Wanhainen Anders , Mani Kevin , Lindholt Jes S , Obel Lasse M , Strauss Ewa , Oszkinis Grzegorz , Nelson Christopher P , Saxby Katie , van Herwaarden Joost A , van der Laan Sander W , van Setten Jessica , Camacho Mercedes , Davis Frank M , Wasikowski Rachael , Tsoi Lam C , Gudjonsson Johann E , Eliason Jonathan L , Coleman Dawn M , Henke Peter K , Ganesh Santhi K , Chen Y Eugene , Guan Weihua , Pankow James S , Pankratz Nathan , Pedersen Ole B , Erikstrup Christian , Tang Weihong , Hveem Kristian , Gudbjartsson Daniel , Gretarsdottir Solveig , Thorsteinsdottir Unnur , Holm Hilma , Stefansson Kari , Ferreira Manuel A , Baras Aris , Kullo Iftikhar J , Ritchie Marylyn D , Christensen Alex H , Iversen Kasper K , Eldrup Nikolaj , Sillesen Henrik , Ostrowski Sisse R , Bundgaard Henning , Ullum Henrik , Burgess Stephen , Gill Dipender , Gallagher Katherine , Sabater-Lleal Maria ,   DiscovEHR,   Regeneron Genetics Center,   UK Aneurysm Growth Study,   DBDS Genomic Consortium,   VA Million Veteran Program, Jones Gregory T , Bown Matthew J , Tsao Philip S , Willer Cristen J , Damrauer Scott M
Published: May 2022

Abdominal aortic aneurysm (AAA) is a common disease with significant heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 144 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis was able to explain AAA beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in the pathogenesis of AAA. We further integrated functional data to elucidate expression of genes associated with AAA. These genes also indicate crossover between the development of AAA and other monogenic aortopathies, particularly via TGF-β signaling pathways. Motivated by the strong evidence for the role of lipid levels in AAA by PheWAS, we identified therapeutic opportunities using Mendelian Randomization and, in pre-clinical studies, we demonstrated thatPCSK9inhibition in mice prevented the development of AAA.
Identifying COVID-19 phenotypes using cluster analysis and assessing their clinical outcomes
Authors: Yamga Eric , Mullie Louis , Durand Madeleine , Cadrin-Chenevert Alexandre , Tang An , Montagnon Emmanuel , Chartrand-Lefebvre Carl , Chassé Michaël
Published: May 2022

Multiple clinical phenotypes have been proposed for COVID-19, but few have stemmed from data-driven methods. We aimed to identify distinct phenotypes in patients admitted with COVID-19 using cluster analysis, and compare their respective characteristics and clinical outcomes.

We analyzed the data from 547 patients hospitalized with COVID-19 in a Canadian academic hospital from January 1, 2020, to January 30, 2021. We compared four clustering algorithms: K-means, PAM (partition around medoids), divisive and agglomerative hierarchical clustering. We used imaging data and 34 clinical variables collected within the first 24 hours of admission to train our algorithm. We then conducted survival analysis to compare clinical outcomes across phenotypes and trained a classification and regression tree (CART) to facilitate phenotype interpretation and phenotype assignment.

We identified three clinical phenotypes, with 61 patients (17%) in Cluster 1, 221 patients (40%) in Cluster 2 and 235 (43%) in Cluster 3. Cluster 2 and Cluster 3 were both characterized by a low-risk respiratory and inflammatory profile, but differed in terms of demographics. Compared with Cluster 3, Cluster 2 comprised older patients with more comorbidities. Cluster 1 represented the group with the most severe clinical presentation, as inferred by the highest rate of hypoxemia and the highest radiological burden. Mortality, mechanical ventilation and ICU admission risk were all significantly different across phenotypes.

We conducted a phenotypic analysis of adult inpatients with COVID-19 and identified three distinct phenotypes associated with different clinical outcomes. Further research is needed to determine how to properly incorporate those phenotypes in the management of patients with COVID-19.
Identification of Disease-Specific Turning Movement Hallmarks: A Systematic Review towards Establishment of Disease Screening Algorithm
Authors: Ogawa Ami , Takeda Takanori , Yoshino Kohei , Iijima Hirotaka
Published: May 2022

Background

Patients with nervous system and musculoskeletal diseases display gait disturbance that is a leading cause of falls. Identification of disease-specific movement hallmarks is therefore an essential first step in preventing falls. Since turning, a common daily activity, is a unique movement that requires inter-limb spatial coordination, turning may be a suitable observational target for the identification of disease-specific movement disorder. However, to date, few comprehensive systematic review regarding disease-specific alterations in turning movement is available.

Research question

This systematic review with meta-analysis summarized the level of knowledge regarding movement disorders during turning in patients with nervous system and musculoskeletal diseases.

Methods

A systematic review was conducted of papers throughout 2021 in accordance with PRISMA guideline. Including criteria were (1) were published in a peer-reviewed journal, (2) were written in English, (3) included adult patients who were diagnosed with musculoskeletal or nervous system diseases, (4) had a control group of age-matched healthy adults, and (5) outcomes included turning parameters.

Results

Meta-analysis revealed a significantly larger step number, longer turn duration, and shorter step length in patients with Parkinson’s disease (PD) than in controls during the 180° turn, suggesting that these biomechanical alterations may be, at least in part, movement disorders associated with PD. Notably, this review identified methodological heterogeneity for turning movement assessments, which limited the identification of disease-specific movement disorders.

Significance

This work serves as a call to action for the establishment of a standard assessment protocol towards the identification of disease-specific turning movement disorders and effective disease screening.
Circular RNA RORβ regulates TGFBR1 by decoying miR-140 in alcohol-exposed lungs and fibroblasts
Authors: Sueblinvong Viranuj , Fan Xian , Williams Raven , Kang Bum-Yong
Published: May 2022

Alcohol ingestion exaggerates transforming growth factor-beta 1 (TGFβ1) expression and signaling leading to fibroproliferation. Inhibition of TGFβ receptor type 1 (TGFβR1) mitigates the effect of TGFβ1 signaling. We showed that alcohol can modulate microRNA (miRNA) expressions. The mechanism by which alcohol modulates microRNA and how it ties to TGFβ1 signaling has not been well elucidated. Circular RNA (circRNAs or circ) emerges as a potential therapeutic target based on its stability, tissue specificity, and its ability to modify miRNAs. In this study, we showed that alcohol upregulates TGFβR1 and circRNA form of retinoic acid receptor-related orphan receptor beta (circ-RORβ) in lung fibroblasts (LF) and the lung. We identified miR-140 to have binding sites for both TGFβR1 3’ UTR and circ-RORβ and alcohol attenuated miR-140 expression in LF and the lung. We demonstrated that inhibition of circ-RORβ upregulated miR-140 and completely abrogated alcohol-induced miR-140 suppression. We further showed that inhibition of circ-RORβ attenuated alcohol-induced TGFβR1, fibronectin (FN1), and α-smooth muscle actin (αSMA) expressions and myofibroblast development as seen by an attenuation of αSMA stress fiber formation in LF. Taken together, these findings identify circ-RORβ-miR-140-TGFβR1 axis as a novel mechanism by which alcohol induces TGFβ1 signaling and promotes FMD.

Highlights

Alcohol induces circ-RORβ expression in lung fibroblasts

Circ-RORβ regulates TGFβR1 by decoying miR-140 in lung fibroblasts

Inhibition of Circ-RORβ restores miR-140 expression

Inhibition of Circ-RORβ mitigates alcohol-mediated myofibroblast differentiation

This is the first description of circ-RORβ functional significance in lung fibroblast
sMAP: An interactive microarray data analysis tool for early-stage researchers
Authors: Bharti Samuel , Krishnan Nikita , Veyssi Arian , Momeni Maryam , Raj Sneha
Published: May 2022

Microarray data enables biologists to extract differentially expressed genes (DEGs) across multiple phenotypes. While several pipelines and tools exist to perform microarray data analysis, they are targeted to users with moderate to advanced computational understanding and lack an easy-to-use, interactive and dynamic methodology to perform analysis assisted with comprehensive learning resources. In this study, we developed an interactive application “sMAP” (Standard Microarray Analysis Pipeline) to make transcriptome microarray data analysis more accessible in learning environments and to enable the identification of significant pathological biomarkers. In a case study of colorectal cancer, we showed that sMAP enabled us to reproduce previous findings and discover relevant pathways. sMAP provides a comprehensive set of tutorials and learning documentation to help early-stage researchers. The latest URLs of sMAP’s hosting, tutorial, and frequently updated documentation can be found at https://github.com/BI-STEM-Away/sMAP.
Peritoneal autoantibody landscape in endometriosis
Authors: Harden Sarah , Tan Tse Yeun , Ku Chee Wai , Zhou Jieliang , Chen Qingfeng , Chan Jerry Kok Yen , Brosens Jan , Lee Yie Hou
Published: May 2022

Women with endometriosis have a profound association with autoimmunity. An excess of autoantigens in the peritoneal cavity resulting from retrograde menstruation could lead to inflammation and pathologic autoimmunity. Using a native-conformation protein array, proteome-wide analysis of autoantibodies (AAbs) against 1623 proteins were profiled in peritoneal fluids (PF) of 25 women with endometriosis and 25 endometriosis-negative women. 46% of endometriotic women have five or more AAbs. Diverse cognate autoantigens were identified and corresponding AAbs against proteins involved in implantation, B-cell activation/development, and aberrant migration and mitogenicity. AAbs recognizing tumour suppressor protein p53 were the most frequent at 35% and were targeted against native and citrullinated p53 forms. Further, unsupervised hierarchical clustering and integrative pathway analysis, we observed clusters of endometriosis-associated infertile women with 60% positive for two or more AAbs which are involved in PDGF, TGF-β, RAC1/PAK1/p38/MMP2 signaling, LAT2/NTAL/LAB-mediated calcium mobilisation and integrin-mediated cell adhesion. Together, our data identifies peritoneal autoimmunity in a significant subset of women with endometriosis, with diverse impact on infertility and disease pathophysiology.
Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I
Authors: Rodríguez-Nuevo Aida , Torres-Sanchez Ariadna , Duran Juan M , De Guirior Cristian , Martínez-Zamora Maria Angeles , Böke Elvan
Published: May 2022

Oocytes form before birth and remain viable for several decades before fertilisation. Although poor oocyte quality accounts for the majority of female fertility problems, little is known about how oocytes maintain cellular fitness, nor why they eventually decline with age. Reactive oxygen species (ROS) produced as by-products of mitochondrial activity are associated with lower rates of fertilisation and embryo survival. Yet, how healthy oocytes balance essential mitochondrial activity with the production of ROS is unknown. Here, we show that oocytes evade ROS by remodelling the mitochondrial electron transport chain (ETC) through elimination of complex I. Combining live-cell imaging and proteomics in human and Xenopus oocytes, we find that early oocytes exhibit greatly reduced levels of complex I. This is accompanied by a highly active mitochondrial unfolded protein response, which is indicative of an imbalanced ETC. Biochemical and functional assays confirm that complex I is neither assembled nor active in early oocytes. Thus, we report the first physiological cell type without complex I in animals. Our findings clarify why patients suffering from complex I related hereditary mitochondrial diseases do not experience subfertility, in contrast to diseases involving other mitochondrial complexes. Complex I suppression represents an evolutionary-conserved strategy that allows longevity while maintaining biological activity in long-lived oocytes.
Adgrg6/Gpr126 is required for myocardial Notch activity and N-cadherin localization to attain trabecular identity
Authors: Srivastava Swati , Gunawan Felix , Gentile Alessandra , Petersen Sarah C. , Stainier Didier Y.R. , Engel Felix B.
Published: May 2022

How adhesion G protein-coupled receptors (aGPCRs) control development remains unclear. The aGPCR Adgrg6/Gpr126 has been associated with heart trabeculation. Defects in this process cause cardiomyopathies and embryonic lethality. Yet, how cardiomyocytes attain trabecular identity is poorly understood. Here, we show that Gpr126 regulates Notch activity and N-cadherin localization that are necessary for attaining trabecular identity in zebrafish. Maternal zygotic gpr126stl47 early truncation mutants exhibit hypotrabeculation whereby N-cadherin distributes randomly at apical/basal membranes of compact layer cardiomyocytes. In contrast, gpr126st49 mutants expressing a N-terminal fragment lacking the GPS motif (NTFΔGPS) exhibit a multilayered ventricular wall consisting of polarized cardiomyocytes with normal N-cadherin expression and increased Notch signaling. Notably, endocardially expressed C-terminal fragment (CTF) reinstates trabeculation in gpr126st49 mutants. Collectively, our data indicate domain-specific roles of Gpr126 during trabeculation whereby the NTF maintains cell-cell adhesion and is required for compact wall integrity, while the CTF is essential to provide trabecular identity
A Role for Nup153 in Nuclear Assembly Reveals Differential Requirements for Targeting of Nuclear Envelope Constituents
Authors: LaJoie Dollie , Turkmen Ayse M. , Mackay Douglas R. , Jensen Christopher C. , Aksenova Vasilisa , Niwa Maho , Dasso Mary , Ullman Katharine S.
Published: May 2022

Assembly of the nucleus following mitosis requires rapid and coordinate recruitment of diverse constituents to the inner nuclear membrane. We have identified an unexpected role for the nucleoporin Nup153 in promoting the continued addition of a subset of nuclear envelope proteins during initial expansion of nascent nuclei. Specifically, disrupting the function of Nup153 interferes with ongoing addition of B-type lamins, lamin B receptor (LBR), and SUN1 early in telophase, after the nuclear envelope (NE) has initially enclosed chromatin. In contrast, effects on lamin A and SUN2 were minimal, pointing to differential requirements for the ongoing targeting of nuclear envelope proteins. Further, distinct mis-targeting phenotypes arose among the proteins that require Nup153 for NE targeting. Thus, disrupting the function of Nup153 in nuclear formation reveals several previously undescribed features important for establishing nuclear architecture: 1) a role for a nuclear basket constituent in ongoing recruitment of nuclear envelope components, 2) two functionally separable phases of nuclear envelope formation in mammalian cells, and 3) distinct requirements of individual nuclear envelope residents for continued targeting during the expansion phase of NE reformation.
Mapping Structural Drivers of Insulin Analogs Using Molecular Dynamics and Free Energy Calculations at Insulin Receptor
Authors: Sena Mohan Maruthi , Ramakrishnan C , Gromiha M. Michael , Chatterji Monalisa , Khedkar Anand , Ranganathan Anirudh
Published: May 2022

A century on from the discovery of insulin, a complete understanding of insulin interactions with the insulin receptor (IR) at atomic level remains elusive. In this work, we have leveraged recent advancements in structural biology that have resulted in multiple high-resolution structures of the insulin-IR complex. As a first step, we employed molecular dynamics (MD) simulations to unravel atomic insights into the interactions between insulin-IR complexes in order to better understand ligand recognition at the receptor. The MD simulations were followed up with free energy perturbation (FEP) calculations to discriminate between and elucidate the drivers for ligand association for various natural and man-made insulin analogs. As an example, these calculations were utilized to understand the molecular mechanisms that characterized the loss-of-function seen in disease-associated insulin mutations seen in different populations. Further, multiple man-made insulin analogs spanning a range of potencies, mutations, and sequence lengths were studied using FEP and a comprehensive molecular level map of potency determinants were established. ∼85% of FEP calculations captured the direction of shift of potency, and in ∼53% of cases the predictions were within 1 kcal/mol of experiment. The impressive accuracy of FEP in recapitulating functional profiles across such a span of insulin analogs and potency profiles provided clear evidence of its utility in computational mutagenesis. In addition to the impressive accuracy, the ability of FEP to provide a dissected understanding of protein residue, solvent and solvent-mediated contributions to binding energy clearly establishes its utility in the design of novel insulins and peptides in general.
The histone H3.3 K27M mutation found in diffuse midline gliomas coordinately disrupts adjacent H3.3 Ser31 phosphorylation and the fidelity of chromosome segregation
Authors: Day Charles A. , Grigore Florina , Hakkim Faruck L. , Langfald Alyssa , Fadness Sela , Schwab Paiton , Sepaniac Leslie , Stumpff Jason , Daniels David J. , Vaughan Kevin T. , Robinson James P. , Hinchcliffe Edward H.
Published: May 2022

During the cell cycle, differential phosphorylation of select histone H3 serine/threonine residues regulates chromatin structure, necessary for both dynamic transcriptional control and proper chromosome segregation1-2. Histone H3.3 contains a highly conserved serine residue (Ser31) within its N-terminal tail that is unique to this variant. During interphase phosphorylation of Ser31 amplifies stimulation-induced transcription and is required for early metazoan development3-6. During mitosis Ser31 phosphorylation at the pericentromere supports proper chromosome segregation, albeit by unknown mechanisms7-10. H3.3 Ser31 is flanked by mutational sites that drive several human cancers, including pediatric gliomas5-8. This is typified by the H3.3K27M mutation found in ∼80% of diffuse midline gliomas, which undergo epigenetic reprogramming in proliferative cells coordinate with loss of global H3 lysine 27 trimethylation (H3K27Me3)11-14. However, whether the K27M mutation influences the neighboring Ser31 phosphorylation and whether disrupting Ser31 phosphorylation plays a distinct role in driving gliomagenesis has not been tested. Here we show that H3.3K27M mutant cells have reduced capacity for H3.3 Ser31 phosphorylation at the mitotic pericentromere, increased rates of chromosome missegregation, and impaired G1 checkpoint responses to chromosome instability. CRISPR-reversion of K27M to wild-type restores phospho-Ser31 levels and suppresses chromosome segregation defects. CRISPR editing to introduce a non-phosphorylatable H3.3S31A alone is sufficient to increase the frequency of chromosome missegregations. Finally, expression of H3.3S31A in a PDGFβ-driven RCAS/TVA mouse model is sufficient to drive high grade gliomagenesis, generating diffuse tumors morphologically indistinguishable from those generated by H3.3K27M expression. Importantly, this occurs without the loss of H3K27 triple methylation that is the hallmark of K27M tumors. Our results reveal that the H3.3 K27M mutation alters the neighboring Ser31 phosphorylation, and loss of proper H3.3 Ser31 phosphorylation contributes to the formation of diffuse midline gliomas.
Gaze onsets during naturalistic infant-caregiver interaction associate with ‘sender’ but not ‘receiver’ neural responses, and do not lead to changes in inter-brain synchrony
Authors: Marriott Haresign I. , Phillips E.A.M , Whitehorn M. , Lamagna F. , Eliano M. , Goupil L. , Jones E.J.H. , Wass S.V.
Published: May 2022

Temporal coordination during infant-caregiver social interaction is thought to be crucial for supporting early language acquisition and cognitive development. Despite a growing prevalence of theories suggesting that increased inter-brain synchrony associates with many key aspects of social interactions such as mutual gaze, little is known about how this arises during development. Here, we investigated the role of mutual gazeonsetsas a potential driver of inter-brain synchrony. We extracted dual EEG activity around naturally occurring gaze onsets during infant-caregiver social interactions in N=55 dyads (mean age 12 months). We differentiated between two types of gaze onset, depending on each partners’ role. ‘Sender’ gaze onsets were defined at a time when either the adult or the infant made a gaze shift towards their partner at a time when their partner was either already looking at them (mutual) or not looking at them (non-mutual). ‘Receiver’ gaze onsets were defined at a time when their partner made a gaze shift towards them at a time when either the adult or the infant was already looking at their partner (mutual) or not (non-mutual). Contrary to our hypothesis we found that, during a naturalistic interaction, both mutual and non-mutual gaze onsets were associated with changes in the sender, but not the receiver’s brain activity and were not associated with increases in inter-brain synchrony above baseline. Further, we found that mutual, compared to non-mutual gaze onsets were not associated with increased inter brain synchrony. Overall, our results suggest that the effects of mutual gaze are strongest at the intra-brain level, in the ‘sender’ but not the ‘receiver’ of the mutual gaze.