bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting a Positive Antibody Response After 2 SARS-CoV-2 mRNA Vaccines in Transplant Recipients: A Machine Learning Approach With External Validation
Authors: Alejo Jennifer L. , Mitchell Jonathan , Chiang Teresa P.-Y. , Chang Amy , Abedon Aura T. , Werbel William A. , Boyarsky Brian J. , Zeiser Laura B. , Avery Robin K. , Tobian Aaron A.R. , Levan Macey L. , Warren Daniel S. , Massie Allan B. , Moore Linda W. , Guha Ashrith , Huang Howard J. , Knight Richard J. , Gaber Ahmed Osama , Ghobrial Rafik Mark , Garonzik-Wang Jacqueline M. , Segev Dorry L. , Bae Sunjae
Published: July 2022

Background.

Solid organ transplant recipients (SOTRs) are less likely to mount an antibody response to SARS-CoV-2 mRNA vaccines. Understanding risk factors for impaired vaccine response can guide strategies for antibody testing and additional vaccine dose recommendations.

Methods.

Using a nationwide observational cohort of 1031 SOTRs, we created a machine learning model to explore, identify, rank, and quantify the association of 19 clinical factors with antibody responses to 2 doses of SARS-CoV-2 mRNA vaccines. External validation of the model was performed using a cohort of 512 SOTRs at Houston Methodist Hospital.

Results.

Mycophenolate mofetil use, a shorter time since transplant, and older age were the strongest predictors of a negative antibody response, collectively contributing to 76% of the model’s prediction performance. Other clinical factors, including transplanted organ, vaccine type (mRNA-1273 versus BNT162b2), sex, race, and other immunosuppressants, showed comparatively weaker associations with an antibody response. This model showed moderate prediction performance, with an area under the receiver operating characteristic curve of 0.79 in our cohort and 0.67 in the external validation cohort. An online calculator based on our prediction model is available at http://transplantmodels.com/covidvaccine/.

Conclusions.

Our machine learning model helps understand which transplant patients need closer follow-up and additional doses of vaccine to achieve protective immunity. The online calculator based on this model can be incorporated into transplant providers’ practice to facilitate patient-centric, precision risk stratification and inform vaccination strategies among SOTRs.
Class imbalance should not throw you off balance: Choosing the right classifiers and performance metrics for brain decoding with imbalanced data
Authors: Thölke Philipp , Mantilla-Ramos Yorguin-Jose , Abdelhedi Hamza , Maschke Charlotte , Dehgan Arthur , Harel Yann , Kemtur Anirudha , Berrada Loubna Mekki , Sahraoui Myriam , Young Tammy , Bellemare Pépin Antoine , El Khantour Clara , Landry Mathieu , Pascarella Annalisa , Hadid Vanessa , Combrisson Etienne , O’Byrne Jordan , Jerbi Karim
Published: July 2022

Machine learning (ML) is increasingly used in cognitive, computational and clinical neuroscience. The reliable and efficient application of ML requires a sound understanding of its subtleties and limitations. Training ML models on datasets with imbalanced classes is a particularly common problem, and it can have severe consequences if not adequately addressed. With the neuroscience ML user in mind, this paper provides a didactic assessment of the class imbalance problem and illustrates its impact through systematic manipulation of data imbalance ratios in (i) simulated data and (ii) brain data recorded with electroencephalography (EEG) and magnetoencephalography (MEG). Our results illustrate how the widely-used Accuracy (Acc) metric, which measures the overall proportion of successful predictions, yields misleadingly high performances, as class imbalance increases. Because Acc weights the per-class ratios of correct predictions proportionally to class size, it largely disregards the performance on the minority class. A binary classification model that learns to systematically vote for the majority class will yield an artificially high decoding accuracy that directly reflects the imbalance between the two classes, rather than any genuine generalizable ability to discriminate between them. We show that other evaluation metrics such as the Area Under the Curve (AUC) of the Receiver Operating Characteristic (ROC), and the less common Balanced Accuracy (BAcc) metric – defined as the arithmetic mean between sensitivity and specificity, provide more reliable performance evaluations for imbalanced data. Our findings also highlight the robustness of Random Forest (RF), and the benefits of using stratified cross-validation and hyperprameter optimization to tackle data imbalance. Critically, for neuroscience ML applications that seek to minimize overall classification error, we recommend the routine use of BAcc, which in the specific case of balanced data is equivalent to using standard Acc, and readily extends to multi-class settings. Importantly, we present a list of recommendations for dealing with imbalanced data, as well as open-source code to allow the neuroscience community to replicate and extend our observations and explore alternative approaches to coping with imbalanced data.
Regulation of mRNA transcripts, protein isoforms, glycosylation and spatial localization of ACE2 and other SARS-CoV-2-associated molecules in human airway epithelium upon viral infection and type 2 inflammation
Authors: Stocker N , Radzikowska U , Wawrzyniak P , Tan G , Huang M , Ding M , Akdis CA , Sokolowska M
Published: July 2022

SARS-CoV-2 infection continues to pose a significant life threat, especially in patients with comorbidities. It remains unknown, if asthma or allergen- and virus-induced airway inflammation are risk factors or can constitute some forms of protection against COVID-19. ACE2 and other SARS-CoV-2-related host proteins are limiting factors of an infection, expression of which is regulated in a more complex way than previously anticipated. Hence, we studied the expression of ACE2 mRNA and protein isoforms, together with its glycosylation and spatial localization in house dust mite (HDM)-, interleukin-13 (IL-13)- and human rhinovirus (RV)-induced inflammation in the primary human bronchial airway epithelium of healthy subjects and patients with asthma. IL-13 decreased the expression of long ACE2 mRNA and glycosylation of full-length ACE2 protein via alteration of the N-linked glycosylation process, limiting its availability on the apical side of ciliated cells. RV infection increased short ACE2 mRNA, but it did not influence its protein expression. HDM exposure did not affect ACE2 mRNA or protein. IL-13 and RV significantly regulated mRNA, but not protein expression of TMPRSS2 and NRP1. Regulation of ACE2 and other host proteins was similar in healthy and asthmatic epithelium, underlining the lack of intrinsic differences, but rather the dependence on the inflammatory milieu in the airways.
Signatures for Viral Infection and Inflammation in the Proximal Olfactory System in Familial Alzheimer’s Disease
Authors: Bubak Andrew N. , Merle Laetitia , Niemeyer Christy S. , Baxter B. Dnate’ , Polese Arianna Gentile , Ramakrishnan Vijay , Gomez Johana , Madrigal Lucia , Villegas-Lanau Andres , Lopera Francisco , Macklin Wendy , Frietze Seth , Nagel Maria A. , Restrepo Diego
Published: July 2022

Objective

Alzheimer’s disease (AD) is characterized by loss of smell and olfactory system pathology that precedes the diagnosis of dementia. Understanding these early processes can potentially identify diagnostic and therapeutic targets to slow AD progression. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and olfactory tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A paisa mutation and age-matched controls.

Methods

Formalin-fixed, paraffin-embedded sections containing both the OB and OT from 6 FAD individuals and 6 age-matched controls were obtained. Tissue morphology and composition were characterized by immunohistochemistry using antibodies against the myelin marker proteolipid protein (PLP), amyloid-beta (Aβ), and microglia/macrophage markers Iba1 and CD68, respectively. OB and OT were analyzed separately by targeted RNA sequencing of the whole human transcriptome (BioSpyder TempO-Seq); ingenuity pathway analysis and R-computational program were used to identify differentially expressed genes and pathways between groups. The nanoString spatial proteomics assay for 88 proteins, including markers for AD and immune responses, was used to complement gene expression findings.

Results

Compared to control OT, FAD OT had significantly increased immunostaining for Aβ and CD68 in the high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region only; both control and FAD OT samples had similar total area of high and low myelinated regions. In FAD samples, RNA sequencing showed a transcription profile consistent with: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts, indicating dysregulation of myelination. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus.

Conclusions

These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt downstream hippocampal function, contributing to acceleration of FAD progression.
Probabilistic integration of transcriptome-wide association studies and colocalization analysis prioritizes molecular pathways of complex traits
Authors: Okamoto Jeffrey , Wang Lijia , Yin Xianyong , Luca Francesca , Pique-Regi Roger , Helms Adam , Im Hae Kyung , Morrison Jean , Wen Xiaoquan
Published: July 2022

Transcriptome-wide association studies (TWAS) and colocalization analysis are complementary integrative genetic association approaches routinely used to identify functional units underlying complex traits in post-genome-wide association study (post-GWAS) analyses. Recent studies suggest that both approaches are individually imperfect, but joint usage can yield robust and powerful inference results. This paper introduces a new statistical framework, INTACT, to perform probabilistic integration of TWAS and colocalization evidence for implicating putative causal genes. This procedure is flexible and can work with a wide range of existing TWAS and colocalization approaches. It has the unique ability to quantify the uncertainty of implicated genes, enabling rigorous control of false-positive discoveries. Taking advantage of this highly-desirable feature, we describe an efficient algorithm, INTACT-GSE, for gene set enrichment analysis based on the integrated TWAS and colocalization analysis results. We examine the proposed computational methods and illustrate their improved performance over the existing approaches through simulation studies. Finally, we apply the proposed methods to the GTEx data and a variety of GWAS summary statistics derived from complex and molecular traits previously analyzed by Hukku et al. and Sinnott-Armstrong et al. We find empirical evidence that the proposed methods improve and complement existing putative gene implication methods and are advantageous in evaluating and identifying key gene sets and biological pathways.
Oral oxycodone self-administration leads to features of opioid addiction in male and female mice
Authors: Slivicki Richard A. , Earnest Tom , Chang Yu-Hsuan , Pareta Rajesh , Casey Eric , Li Jun-Nan , Tooley Jessica , Abiraman Kavitha , Vachez Yvan M. , Wolfe Drew K. , Sackey Jason T. , Gereau Robert W. , Copits Bryan A. , Kravitz Alexxai V. , Creed Meaghan C.
Published: July 2022

Use of prescription opioids, particularly oxycodone is an initiating factor driving the current opioid epidemic. There are several challenges with modeling oxycodone abuse. First, prescription opioids including oxycodone are orally self-administered and have different pharmacokinetics and dynamics than morphine or fentanyl which have been more commonly used in rodent research. This oral route of administration determines the pharmacokinetic profile, which then influences the establishment of drug-reinforcement associations in animals. Moreover, the pattern of intake and the environment in which addictive drugs are self-administered are critical determinants of the levels of drug intake, of behavioral sensitization, and of propensity to relapse behavior. These are all important considerations when modeling prescription opioid use, which is characterized by continuous drug access in familiar environments. Thus, to model features of prescription opioid use and the transition to abuse, we designed an oral, homecage-based oxycodone self-administration paradigm. Mice voluntarily self-administer oxycodone in this paradigm without any taste modification such as sweeteners, and the majority exhibit preference for oxycodone, escalation of intake, physical signs of dependence, and reinstatement of seeking after withdrawal. In addition, a subset of animals demonstrate drug taking that is resistant to aversive consequences. This model is therefore translationally relevant and useful for studying the neurobiological substrates of prescription opioid abuse.
Sensory neurons safeguard from mutational inheritance by controlling the CEP-1/p53-mediated DNA damage response in primordial germ cells
Authors: Uszkoreit Simon , Meyer David H. , Rechavi Oded , Schumacher Björn
Published: July 2022

The genome integrity control in primordial germ cells (PGCs) is prerequisite for the inheritance of stable genomes. The PGCs inC. elegansare embedded in a somatic niche that regulates its DNA damage response (DDR). Here, we show that the AMPK-like kinases KIN-29 and AAK-2 are required for arresting PGCs carrying persistent DNA damage. We determined that the ASI neurons, which sense environmental conditions such as nutrient availability, secrete the TGF-beta-like ligand DAF-7 that is recognized by the DAF-1 receptor in PGCs. ASI-dependent DAF-7 signaling regulates the induction of CEP-1/p53 in the PGCs amid persistent DNA damage. Using single worm whole genome sequencing, we establish that defective ASI control of the CEP-1/p53-regulated DDR in PGCs ultimately results in the inheritance ofde novogermline mutations. Our results indicate that sensory neurons safeguard from the inheritance of germline mutations suggesting the possibility that perception of the environment could direct genetic inheritance.

One sentence summary

The ASI sensory neurons regulate the CEP-1/p53-dependent DNA damage response of primordial germ cells via TGF-beta signaling and influence inherited mutational burden.
Persistent homology analysis distinguishes pathological bone microstructure in non-linear microscopy images
Authors: Pritchard Ysanne , Sharma Aikta , Clarkin Claire , Ogden Helen , Mahajan Sumeet , Sánchez-García Rubén J.
Published: July 2022

We present a topological method for the detection and quantification of bone microstructure from non-linear microscopy images. Specifically, we analyse second harmonic generation (SHG) and two photon excited autofluorescence (TPaF) images of bone tissue which capture the distribution of matrix (fibrillar collagen) structure and autofluorescent molecules, respectively. Using persistent homology statistics with a signed Euclidean distance transform filtration on binary patches of images, we are able to quantify the number, size, distribution, and crowding of holes within and across samples imaged at the microscale. We apply our methodology to a previously characterized murine model of skeletal pathology whereby vascular endothelial growth factor expression was deleted in osteocalcin-expressing cells (OcnVEGFKO) presenting increased cortical porosity, compared to wild type (WT) littermate controls. We show significant differences in topological statistics between the OcnVEGFKO and WT groups and, when classifying the males, or females respectively, into OcnVEGFKO or WT groups, we obtain high prediction accuracies of 98.7% (74.2%) and 77.8% (65.8%) respectively for SHG (TPaF) images. The persistence statistics that we use are fully interpretable, can highlight regions of abnormality within an image and identify features at different spatial scales.
Cas9+conditionally immortalized neutrophil progenitors as a tool for genome wide CRISPR screening for neutrophil differentiation and function
Authors: Jong Robyn M. , Ching Krystal L. , Garelis Nicholas E. , Zilinskas Alex , Nguyenla Xammy , Rawal Sagar , Hill Bianca C. , Luckie Bridget A. , Shallow Lillian , Cox Jeffery S. , Barton Gregory M. , Stanley Sarah A.
Published: July 2022

Neutrophils are short-lived cells of the innate immune system that play numerous roles in defense against infection, regulation of immune responses, tissue damage and repair, autoimmunity, and other non-communicable diseases. Understanding neutrophil function at a mechanistic level has been hampered by the difficulty of working with primary neutrophils, which die rapidly upon isolation, and the relative paucity of neutrophil cell lines. Murine neutrophil progenitors that are immortalized with estrogen-regulated expression of Hoxb8 differentiate into neutrophils upon withdrawal of estrogen and facilitate the quantitative production of neutrophilsin vitro. Here we report the creation of a Cas9+ER-Hoxb8 neutrophil progenitor cell line that enables both forward and reverse genetic analysis of neutrophils for the first time. By editing progenitors via transduction with sgRNAs, and then withdrawing estrogen, Cas9 edited neutrophils are produced with high efficiency. Importantly, neutrophil differentiation of edited progenitors occurs bothin vitroin cell culture and when transferred into murine recipients. To demonstrate the utility of Cas9+ER-Hoxb8 progenitors for forward genetics, we performed a pooled CRISPR screen to identify factors required for survival during neutrophil differentiation. This screen identified hundreds of genes both negatively and positively selected under differentiation conditions. One of the top hits from this screen wasCebpe, a transcription factor known to be required for neutrophil differentiation from pre-neutrophils to immature neutrophils. Using the progenitor cell line, we also confirmed thatCepbeis required for neutrophil differentiationin vivo, validating the utility of this cell line both for screening and for studyingin vivophenotypes. The genome-wide screen also identified all components of the WASH complex as being required for neutrophil differentiation, a finding that extends the known role of WASH in hematopoietic stem cell differentiation to later stages of neutrophil development. Taken together, we demonstrate that Cas9+ER-Hoxb8 immortalized neutrophils can be used to study neutrophil function bothin vitroandin vivo. This new resource will enable the analysis of the role of neutrophils in numerous disease states using genetics for the first time.
GO Bench: Shared-hub for Universal Benchmarking of Machine Learning-Based Protein Functional Annotations
Authors: Dickson Andrew , Asgari Ehsaneddin , McHardy Alice C. , Mofrad Mohammad R.K.
Published: July 2022

Motivation

Gene annotation is the problem of mapping proteins to their functions represented as Gene Ontology terms, typically inferred based on the primary sequences. Gene annotation is a multi-label multi-class classification problem, which has generated growing interest for its uses in the characterization of millions of proteins with unknown functions. However, there is no standard GO dataset used for benchmarking the newly developed new machine learning models within the bioinformatics community. Thus, the significance of improvements for these models remains unclear.

The Gene Benchmarking database is the first effort to provide an easy-to-use and configurable hub for the learning and evaluation of gene annotation models. It provides easy access to pre-specified datasets and takes the non-trivial steps of preprocessing and filtering all data according to custom presets using a web interface. The GO bench web application can also be used to evaluate and display any trained model on leaderboards for annotation tasks.

Availability and Implementation

The GO Benchmarking dataset is freely available at llp.berkeley.edu/GO_bench/dataset_form, and code is available at http://github.com/amdson/GO_pipeline.

Contact

amdickson@berkeley.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
Safety and biodistribution of Nanoligomers™ targeting SARS-CoV-2 genome for treatment of COVID-19
Authors: McCollum Colleen R. , Courtney Colleen M. , O’Connor Nolan J. , Aunins Thomas R. , Jordan Tristan X. , Rogers Keegan , Brindley Stephen , Brown Jared M. , Nagpal Prashant , Chatterjee Anushree
Published: July 2022

As the world braces to enter its third year in the coronavirus disease 2019 (COVID-19) pandemic, the need for accessible and effective antiviral therapeutics continues to be felt globally. The recent surge of Omicron variant cases has demonstrated that vaccination and prevention alone cannot quell the spread of highly transmissible variants. A safe and nontoxic therapeutic with an adaptable design to respond to the emergence of new variants is critical for transitioning to treatment of COVID-19 as an endemic disease. Here, we present a novel compound, called SBCoV202, that specifically and tightly binds the translation initiation site of RNA-dependent RNA polymerase within the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome, inhibiting viral replication. SBCoV202 is a Nanoligomer,™ a molecule that includes peptide nucleic acid sequences capable of binding viral RNA with single-base-pair specificity to accurately target the viral genome. The compound has been shown to be safe and nontoxic in mice, with favorable biodistribution, and has shown efficacy against SARS-CoV-2 in vitro. Safety and biodistribution were assessed after three separate administration methods, namely intranasal, intravenous, and intraperitoneal. Safety studies showed the Nanoligomer caused no outward distress, immunogenicity, or organ tissue damage, measured through observation of behavior and body weight, serum levels of cytokines, and histopathology of fixed tissue, respectively. SBCoV202 was evenly biodistributed throughout the body, with most tissues measuring Nanoligomer concentrations well above the compound KD of 3.37 nM. In addition to favorable availability to organs such as the lungs, lymph nodes, liver, and spleen, the compound circulated through the blood and was rapidly cleared through the renal and urinary systems. The favorable biodistribution and lack of immunogenicity and toxicity set Nanoligomers apart from other antisense therapies, while the adaptability of the nucleic acid sequence of Nanoligomers provides a defense against future emergence of drug resistance, making these molecules an attractive potential treatment for COVID-19.
Muscle-directed mechanosensory feedback activates egg-laying circuit activity and behavior inC. elegans
Authors: Medrano Emmanuel , Collins Kevin M.
Published: July 2022

Mechanosensory feedback of internal reproductive state drives decisions about when and where to reproduce.1For instance, stretch in theDrosophilareproductive tract produced by artificial distention or from accumulated eggs regulates the attraction to acetic acid to ensure optimal oviposition.2How such mechanosensory feedback modulates neural circuits to coordinate reproductive behaviors is incompletely understood. We previously identified a stretch-dependent homeostat that regulates egg laying inCaenorhabditis elegans. Sterilized animals lacking eggs show reduced Ca2+transient activity in the presynaptic HSN command motoneurons that drive egg-laying behavior while animals forced to accumulate extra eggs show dramatically increased circuit activity that restores egg laying.3Interestingly, genetic ablation or electrical silencing of the HSNs delays, but does not abolish, the onset of egg laying3–5with animals recovering vulval muscle Ca2+transient activity upon egg accumulation.6Using an acute gonad microinjection technique to mimic changes in pressure and stretch resulting from germline activity and egg accumulation, we find that injection rapidly stimulates Ca2+activity in both neurons and muscles of the egg-laying circuit. Injection-induced vulval muscle Ca2+activity requires L-type Ca2+channels but is independent of presynaptic input. Conversely, injection-induced neural activity is disrupted in mutants lacking the vulval muscles, suggesting ‘bottom-up’ feedback from muscles to neurons. Direct mechanical prodding activates the vulval muscles, suggesting they are the proximal targets of the stretch-dependent stimulus. Our results show that egg-laying behavior inC. elegansis regulated by a stretch-dependent homeostat that scales postsynaptic muscle responses with egg accumulation in the uterus.
The Piks allele of the NLR immune receptor Pik breaks the recognition of AvrPik effectors of the rice blast fungus
Authors: Xiao Gui , Wang Wenjuan , Liu Muxing , Li Ya , Liu Jianbin , Franceschetti Marina , Yi Zhaofeng , Zhu Xiaoyuan , Zhang Zhengguang , Lu Guodong , Banfield Mark J. , Wu Jun , Zhou Bo
Published: July 2022

Arms race co-evolution of plant-pathogen interactions evolved sophisticated recognition mechanisms between host immune receptors and pathogen effectors. Different allelic haplotypes of an immune receptor in host mount distinct recognition against sequence or non-sequence related effectors in pathogens. We report the molecular characterization of the Piks allele of the rice immune receptor Pik against rice blast pathogen, which requires two head-to-head arrayed nucleotide binding site and leucine-rich repeat proteins. Like other Pik genes, both Piks-1 and Piks-2 are necessary and sufficient for Piks-mediated resistance. However, unlike other Pik alleles, Piks does not recognize any known AvrPik variants of M. oryzae. Sequence analysis of the genome of an avirulent isolate V86010 further revealed that its cognate avirulence (Avr) gene most likely has no significant sequence similarity to known AvrPik variants. We conclude that Piks breaks the canonical Pik/AvrPik recognition pattern. Piks-1 and Pikm-1 have only two amino acid differences within the integrated heavy metal-associated (HMA) domain. Pikm-1-HMA interact with AvrPik-A, -D and -E in vitro and in vivo, whereas Piks-1-HMA does not bind any AvrPik variants. Reciprocal exchanges of single amino acid residues between Piks-1 and Pikm-1 further reveal a dynamic recognition mechanism between Piks/Pikm alleles and their respective effectors. Piks-1E229Q/Pikm-1V261A can only activate immunity to AvrPik-D but not to other effectors, indicating that the amino acid change of E to Q at position 229 leads to its gain of a partial recognition spectrum of Pikm. By contrast, Piks-1A261V/Pikm-1Q229E confers immunity to the Piks cognate effector, indicating that the amino acid change of Q to E at position 229 leads to its shifts of the recognition from Pikm to Piks. Intriguingly, binding activities in both Y2H and analytical gel filtration assays are illustrated between Piks-1A261V/Pikm-1Q229E and AvrPik-D. However, it is unable to mount immunity against AvrPik-D, suggesting that biochemical activities based on in vitro and in vivo assays could be insufficient for sustaining biological function of receptor and effector pairs.
Improved Cladocopium goreaui genome assembly reveals features of a facultative coral symbiont and the complex evolutionary history of dinoflagellate genes
Authors: Chen Yibi , Shah Sarah , Dougan Katherine E. , van Oppen Madeleine J. H. , Bhattacharya Debashish , Chan Cheong Xin
Published: July 2022

Dinoflagellates of the family Symbiodiniaceae are crucial photosymbionts in corals and other marine organisms. Of these algae, Cladocopium goreaui is one of the most dominant symbiont species in the Indo-Pacific. Here, we present an improved genome assembly of C. goreaui combining new long-read sequence data with earlier generated short-read data. Incorporating new full-length transcripts to guide gene prediction, the C. goreaui genome (1.2 Gb) exhibits a high extent of completeness (82.4% based on BUSCO protein recovery) and better resolution of repetitive sequence regions; 45,322 gene models were predicted, and 327 putative, topologically associated domains of the chromosomes were identified. Comparison with other Symbiodiniaceae genomes revealed a prevalence of repeats and duplicated genes in C. goreaui, and lineage-specific genes indicating functional innovation. Incorporating 2,841,408 protein sequences from 96 broadly sampled eukaryotes and representative prokaryotes in a phylogenomic approach, we assessed the evolutionary history of C. goreaui genes. Of the 5,246 phylogenetic trees inferred from homologous protein sets containing two or more phyla, 35-36% have putatively originated via horizontal gene transfer (HGT), predominantly (19-23%) via an ancestral Archaeplastida lineage implicated in the endosymbiotic origin of plastids: 10-11% are of green algal origin, including genes encoding photosynthetic functions. Our results demonstrate the utility of long-read sequence data in resolving structural features of a dinoflagellate genome and highlight how genetic transfer has shaped genome evolution of a facultative symbiont, and more broadly of dinoflagellates.
High dimensional flow cytometric analysis reveals distinct NK cell subsets but conserved response to cytokine stimulation in umbilical cord blood and adult peripheral blood
Authors: Buckle Irina , Weinert Vicky , Sester David P. , Radford Kristen , Guillerey Camille
Published: July 2022

Adoptive cellular therapies using Natural Killer (NK) cells are of growing interest. NK cells can be obtained from various sources, including umbilical cord blood (UCB) and adult peripheral blood (APB). Understanding the diversity of NK cell populations and their receptor expression in both UCB and APB will guide future therapeutic designs. In this study, we used a 20-colour flow cytometry panel to compare unstimulated and cytokine-activated UCB and APB NK cells. Our analysis showed that UCB NK cells express slightly higher levels of the immune checkpoints PD-1, TIGIT and CD96 compared to their APB counterparts. Unsupervised hierarchical clustering and principal component analyses revealed previously unappreciated differences in NK cell populations from UCB and APB. UCB was characterised by an enrichment in CD56negas well as mature NKp46negand CD56+CD16+NK cell populations whereas CD57+terminally differentiated NK cells with variable expression of KIRs and CD16 were found in APB. These populations were conserved following two-days of IL-15 culture as well as overnight stimulation with IL-12, IL-15, and IL-18. Interestingly, cytokine stimulation was associated with the up-regulation of LAG-3 and DNAM-1 together with the downregulation of NKG2D, TIGIT and CD16 on multiple NK cell subsets in both UCB and APB. TIM-3 was also up-regulated with activation, but only in UCB. Overall, our data indicate that NK cells in UCB have a more immature phenotype than APB NK cells and UCB NK cells might be more amenable to immune checkpoint therapy.
Risk factors for severe COVID-19 among HIV-infected and-uninfected individuals in South Africa, April 2020- March 2022 – data from sentinel surveillance
Authors: Walaza Sibongile , Tempia Stefano , von Gottberg Anne , Wolter Nicole , Bhiman Jinal N. , Buys Amelia , Amoako Daniel , Moosa Fahima , Plessis Mignon du , Moyes Jocelyn , McMorrow Meredith L. , Dawood Halima , Variava Ebrahim , Reubenson Gary , Nel Jeremy , Zar Heather J , Makhasi Mvuyo , Meiring Susan , Quan Vanessa , Cohen Cheryl
Published: July 2022

Background

Data on risk factors for COVID-19-associated hospitalisation and mortality in high HIV prevalence settings are limited.

Methods

Using existing syndromic surveillance programs for influenza-like-illness and severe respiratory illness at sentinel sites in South Africa, we identified factors associated with COVID-19 hospitalisation and mortality.

Results

From April 2020 through March 2022, SARS-CoV-2 was detected in 24.0% (660/2746) of outpatient and 32.5% (2282/7025) of inpatient cases. Factors associated with COVID-19-associated hospitalisation included: older age (25-44 [adjusted odds ratio (aOR) 1.8, 95% confidence interval (CI) 1.1-2.9], 45-64 [aOR 6.8, 95%CI 4.2-11.0] and ≥65 years [aOR 26.6, 95%CI 14.4-49.1] vs 15-24 years); black race (aOR 3.3, 95%CI 2.2-5.0); obesity (aOR 2.3, 95%CI 1.4-3.9); asthma (aOR 3.5, 95%CI 1.4-8.9); diabetes mellitus (aOR 5.3, 95%CI 3.1-9.3); HIV with CD4 ≥200/mm3 (aOR 1.5, 95%CI 1.1-2.2) and CD4<200/mm3 (aOR 10.5, 95%CI 5.1-21.6) or tuberculosis (aOR 12.8, 95%CI 2.8-58.5). Infection with Beta (aOR 0.5, 95%CI 0.3-0.7) vs Delta variant and being fully vaccinated (aOR 0.1, 95%CI 0.1-0.3) were less associated with COVID-19 hospitalisation.

In-hospital mortality was increased in older age (45-64 years [aOR 2.2, 95%CI 1.6-3.2] and ≥65 years [aOR 4.0, 95%CI 2.8-5.8] vs 25-44 years) and male sex (aOR1.3, 95%CI 1.0-1.6) and was lower in Omicron -infected (aOR 0.3, 95%CI 0.2-0.6) vs Delta-infected individuals.

Conclusion

Active syndromic surveillance encompassing clinical, laboratory and genomic data identified setting-specific risk factors associated with COVID-19 severity that will inform prioritization of COVID-19 vaccine distribution. Elderly, people with tuberculosis or people living with HIV, especially severely immunosuppressed should be prioritised for vaccination.

Summary of article’s viewpoint

Compared to the Delta variant, the Omicron variant was associated with reduced risk of mortality and Beta associated with decreased risk of hospitalisation. Active syndromic surveillance combining clinical, laboratory and genomic data can be used to describe the epidemic timing, epidemiological characteristics of cases, early detection of variants of concern and how these impact disease severity and outcomes; and presents a viable surveillance approach in settings where national surveillance is not possible.
The use of artificial intelligence and machine learning methods in first trimester pre-eclampsia screening: a systematic review protocol
Authors: Hedley Paula L. , Hagen Christian M. , Wilstrup Casper , Christiansen Michael
Published: July 2022

Introduction

Pre-eclampsia (PE) is a leading cause of perinatal morbidity and mortality worldwide. Low-dose aspirin can prevent PE in high risk pregnancies if started early. However, despite intense research into the area, first-trimester screening for PE risk is still not a routine part of pregnancy care. Several studies have described the application of artificial intelligence (AI) and machine learning (ML) in risk prediction of PE and its subtypes. A systematic review of available literature is necessary to catalogue the current applications of AI/ML methods in early pregnancy screening for PE, in order to better inform the development of clinically relevant risk prediction algorithms which will enable timely intervention and the development of new treatment strategies. The aim of this systematic review is to identify and assess studies regarding the application of AI/ML methods in first-trimester screening for PE.

Methods

A systematic review of peer-reviewed as well as the grey literature cohort or case-control studies will be conducted. Relevant information will be accessed from the following databases; PubMed, Google Scholar, Web of Science, Arxiv, BioRxiv, and MedRxiv. The studies will be evaluated by two reviewers in a parallel, blind assessment of the literature, a third reviewer will assess any studies in which the first two reviewers did not agree. The free online tool Rayyan, will be used in this literature assessment stage. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist will be used to guide the review process and the methods of the studies will be assessed using the Newcastle-Ottawa scale. Narrative synthesis will be conducted for all included studies. Meta-analysis will also be conducted where data quality and availability allow.

Ethics and dissemination

The review will not require ethical approval and the findings will be published in a peer-reviewed journal using the PRISMA guidelines.
Generation of cardiomyocytes from human induced pluripotent stem cells resembling atrial cells with ability to respond to adrenoceptor agonists
Authors: Ahmad Faizzan S. , Jin Yongcheng , Grassam-Rowe Alexander , Zhou Yafei , Yuan Meng , Fan Xuehui , Zhou Rui , Mu-u-min Razik , O’Shea Christopher , Ibrahim Ayman M. , Hyder Wajiha , Aguib Yasmine , Yacoub Magdi , Pavlovic Davor , Zhang Yanmin , Tan Xiaoqiu , Terrar Derek A. , Lei Ming
Published: July 2022

Cardiovascular disease is the leading cause of global mortality and morbidity. Cardiac dysrhythmias contribute significantly to this disease burden. Atrial fibrillation (AF) is the most common chronic dysrhythmia. Human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-AMs) present an exciting new model for AF but currently fail to reach maturity and so are limited in translational potential currently. We report a new approach using a combination of Gremlin 2 and retinoic acid treatment of human iPSCs for generating cardiomyocytes resembling atrial cells. More than 40% of myocytes generated by this approach showed rod-shaped morphology, expression of cardiomyocyte proteins (including RyR2 receptors, a-actinin-2, F-actin) and typically a striated appearance, all of which were broadly similar to the characteristics of adult atrial myocytes. Isolated myocytes were electrically quiescent until stimulated to fire action potentials with an atrial myocyte profile and an amplitude of approximately 100 mV, arising from a resting potential of approximately −70 mV. Single-cell RNA sequence (scRNASeq) analysis showed a high level of expression of several atrial specific transcripts including NPPA, MYL7, HOXA3, SLN, KCNJ4, KCNJ5 and KCNA5. Amplitudes of calcium transients recorded from spontaneously beating cultures were increased by the stimulation of α-adrenoceptors (activated by phenylephrine and blocked by prazosin) or β-adrenoceptors (activated by isoproterenol and blocked by CGP20712A). Thus, our new method provides an efficient approach for differentiating human atrial myocytes with mature characteristics from hiPSCs. This preparation will be very useful for studying signalling pathways in human atrial myocytes, and provides a valuable model for investigating atrial fibrillation and drug discovery.
When mechanical engineering inspired from physiology improves postural-related somatosensory processes
Authors: Sutter Chloé , Fabre Marie , Massi Francesco , Blouin Jean , Mouchnino Laurence
Published: July 2022

Being the first stimulated by the relative movement of foot skin and the underneath moving support surface, the plantar tactile receptors (i.e., mechanoreceptors) play an important role in the sensorimotor transformation giving rise to a postural reaction. In this light, a biomimetic surface, i.e., complying with the characteristics of the mechanoreceptors and the skin dermatoglyphs (i.e., pattern of the ridges) should facilitate the cortical processes in response to the somatosensory stimulation involved in the balance recovery motor control. Healthy young adults (n = 21) were standing still either on a biomimetic surface or on two control surfaces (i.e., grooved or smooth), when a sudden but low acceleration of the supporting surface along the lateral direction was triggered. A shorter and more robust evoked somatosensory response (i.e., SEP) was observed when participants were standing on the biomimetic surface. As well, a lower oscillatory response in the theta (5-7 Hz) time-frequency domain in the left posterior parietal cortex (PPC) was observed with the biomimetic surface. The greater shear forces induced by the interaction between the feet and the biomimetic surface during the platform motion was likely at the origin of the increased SEP. Besides, the decrease of theta power suggests that the balance task became less challenging. This interpretation was tested in a second experiment by adding a cognitive task, which should be less detrimental for the postural reaction when standing on a biomimetic surface. Consistent with this hypothesis, a more efficient postural reaction (i.e., shorter latency and greater amplitude) was observed when the cognitive task was performed while standing on the biomimetic surface.
Full epistatic interaction maps retrieve part of missing heritability and improve phenotypic prediction
Authors: Carré Clément , Carluer Jean Baptiste , Chaux Christian , Roche Nicolas , Mas André , Krouk Gabriel
Published: July 2022

The first Genome Wide Association Studies (GWAS) shed light on the concept of missing heritability. It constitutes a mystery with transcending consequences from plant to human genetics. This mystery lies in the fact that a large proportion of phenotypes are not explained by unique or simple genomic modifications. One has to invoke genetic interactions among different loci, also known as epistasis, to partly account for it. However, current GWAS statistical models are moderately scalable, very sensitive to False Discovery Rate (FDR) corrections and, even combined with High Performance Computing (HPC), they can take years to evaluate for a full combinatorial epistatic space for a single phenotype. Here we propose a modeling approach, named Next-Gen GWAS (NGG) that evaluates, within hours, >60 billions of single nucleotide polymorphism (SNP) combinatorial first-order interactions, on a reasonable computer power. We first benchmark NGG on state of the art GWAS model results, and applied this toArabidopsis thalianaproviding 2D epistatic maps at gene resolution. We demonstrate on several phenotypes that a large proportion of the missing heritability can i) be retrieved with this modeling approach, ii) indeed lies in epistatic interactions and iii) can be used to improve phenotype prediction.
Ageing disrupts MANF-mediated immune modulation during skeletal muscle regeneration
Authors: Sousa Neuza S. , Brás Margarida F. , Antunes Inês B. , Lindholm Päivi , Neves Joana , Sousa-Victor Pedro
Published: July 2022

Age-related decline in skeletal muscle regenerative capacity is multifactorial, yet, the contribution of immune dysfunction to regenerative failure is unknown. Here, we uncover a new mechanism of immune modulation operating during skeletal muscle regeneration that is disrupted in aged animals and relies on the regulation of macrophage function. The immune modulator MANF is induced following muscle injury in young mice, but not in aged animals, and its expression is essential for regenerative success. Regenerative impairments in the aged muscle are associated with defects in the repair-associated myeloid response similar to those found in MANF-deficient models and could be improved through MANF delivery. We propose that restoring the myeloid response through immune modulation is a promising therapeutic strategy to improve the regenerative capacity of aged muscles.
The structure of arginyltransferase 1 (ATE1)
Authors: Van Verna , Ejimogu Nna-Emeka , Bui Toan S. , Smith Aaron T.
Published: July 2022

Eukaryotic post-translational arginylation, mediated by the family of enzymes known as the arginyltransferases (ATE1s), is an important post-translational modification that can alter protein function and even dictate cellular protein half-life. Multiple major biological pathways are linked to the fidelity of this process, including neural and cardiovascular developments, cell division, and even the stress response. Despite this significance, the structural, mechanistic, and regulatory mechanisms that govern ATE1 function remain enigmatic. To that end, we have used X-ray crystallography to solve the first crystal structure of ATE1 from Saccharomyces cerevisiae ATE1 (ScATE1) to 2.85 Å resolution. The three-dimensional structure of ScATE1 reveals a bilobed protein containing a GCN5-related N-acetyltransferase (GNAT) fold, and this crystalline behavior is faithfully recapitulated in solution based on size-exclusion chromatography-coupled small angle X-ray scattering (SEC-SAXS) analyses and cryo-EM 2D class averaging. Structural superpositions and electrostatic analyses indicate this domain as the location of catalytic activity and tRNA binding, and these comparisons strongly suggest a mechanism for post-translational arginylation. Additionally, our structure reveals the spatial connectivity of the N-terminal domain, which we have previously shown to bind a regulatory [Fe-S] cluster, and the enzymatic active site, hinting at the atomic-level details of the cluster’s regulatory influence. When taken together, these insights into the first structure of ATE1 bring us closer to answering pressing questions regarding the molecular-level mechanism of eukaryotic post-translational arginylation.
A Non-invasive, Biomarker Assay for Detecting Chronic Wasting Disease Pathology in White-tailed Deer
Authors: Bradley Robert D. , Roberts Emma K. , Worsham Asha E. , Ashton Megan N. , Wright Emily A. , Saleh Ned , Hardy Daniel M.
Published: July 2022

We describe a blood test that exploits differences in the abundance of diagnostic miRNA biomarkers associated with prion infections in cervids. Using sera from 93 pen-raised white-tailed deer euthanized after unintentional exposure to Chronic Wasting Disease (CWD), quantification of candidate reference and diagnostic miRNAs revealed sensitivity of the q-RT-PCR method to interference from sample degradation, requiring exclusion of 60 specimens that exhibited excessive hemolysis or yielded poor amplification of reference or diagnostic miRNAs. Subsequent quantification of three potentially diagnostic and two control miRNAs in the 33 remaining, minimally degraded sera established diagnostic criteria congruent (100% sensitivity, 92.3% specificity, 93.9% accuracy) with results from standard CWD diagnosis by microscopic detection of immunoreactivity in obex and/or medial retropharyngeal lymph nodes (conducted by the National Veterinary Services Laboratory, NVSL, Ames, IA). Overall, the miRNA assay proved to be at least as accurate and sensitive as other CWD testing alternatives to immunohistochemical diagnosis, albeit supported by data from relatively few animals owing to the challenge of acquiring usable specimens from animals euthanized in a mass depopulation. Nevertheless, for sera acquired antemortem, this biomarker-based test may represent a useful new resource for managing spread of CWD that offers the advantages of being rapid, sensitive, non-invasive, and amenable to high throughput scaling.