bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid detection of SARS CoV-2 N501Y mutation in clinical samples
Authors: Al-Jaf Sirwan M.A. , Niranji Sherko Subhan
Published: April 2021

Severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) variants poses major threats in increasing infectivity, transmission, mortality of Coronavirus Disease 2019 (Covid-19). Additionally, SARS CoV-2 variants resist antibody neutralizations or may abolish vaccine efficacies. Researches to develop economical and fast methods will support the developing or poor countries to challenge the Covid-19 pandemic via tracking common mutations that may help to deploy the vaccination programs and control the virus. Current study has developed a novel low-cost rapid technique, exploiting real time PCR probes and conventional PCR specific primers, to identify N501Y mutation, which was independently emerged in the UK, South African and Brazilian variants. Currently, these variants tend to spread to all over the world and seem to be more infectious, transmissible and fatal. This study helps tracking the N501Y mutation for understanding its clinical and epidemiological characteristics, in those countries where sequencing facilities are lacking or expensive. Further study should focus on other common mutations in the variants of concerns of SARS CoV-2.
Rare coding variants in five DNA damage repair genes associate with timing of natural menopause
Authors: Ward Lucas D. , Parker Margaret M. , Deaton Aimee M. , Tu Ho-Chou , Flynn-Carroll Alexander O. , Hinkle Gregory , Nioi Paul
Published: April 2021

The age of menopause is associated with fertility and disease risk, and its genetic control is of great interest. We used whole-exome sequences from 119,992 women in the UK Biobank to test for associations between rare damaging variants and age at natural menopause. Rare damaging variants in three genes significantly associated with menopause:CHEK2(p = 6.2 × 10−51) andDCLRE1A(p = 1.2 × 10−12) with later menopause andTOP3A(p = 8.8 × 10−8) with earlier menopause. Two additional genes were suggestive:RAD54L(p = 2.3 × 10−6) with later menopause andHROB(p = 2.7 × 10−6) with earlier menopause. In a follow-up analysis of repeated questionnaires in women who were initially pre-menopausal,CHEK2, TOP3A, andRAD54Lgenotype associated with subsequent menopause. Consistent with previous GWAS, all five genes are involved in the DNA-damage repair pathway. Phenome-wide scans across 363,977 men and women revealed that in addition to known associations with cancers and blood cell counts, rare variants inCHEK2also associated with increased risk of uterine fibroids, polycystic ovary syndrome, and prostate hypertrophy; these associations are not shared with higher-penetrance breast cancer genes. Causal mediation analysis suggests that approximately 8% of the breast cancer risk conferred byCHEK2pathogenic variants after menopause is mediated through delayed menopause.
Using ddRAD-seq phylogeography to test for genetic effects of headwater river capture in suckermouth armored catfish (Loricariidae:Hypostomus) from the central Brazilian Shield
Authors: Bagley Justin C. , de Aquino Pedro De Podestà Uchôa , Hrbek Tomas , Hernandez-Rangel Sandra , Langeani Francisco , Colli Guarino R.
Published: April 2021

River capture is a geological process of potentially great importance in shaping the genetic diversity, distributions, and community composition of freshwater taxa. Using phylogeographic analyses of ddRAD-seq data from suckermouth armored catfish (Hypostomussp. 2) populations, we tested for predicted genetic effects of headwater river capture events in central Brazil, previously supported by geological and community ecological data. We analyzed 227 ddRAD tags (3829 SNP loci) across 42 samples. Molecular results strongly supported sixHypostomusgenetic clusters/lineages, with the deepest divergence ∼1.25 million years ago in the early Pleistocene between a clade from the Upper Paraná and Upper São Francisco river basins versus all other lineages. Consistent with the ‘Paraná Capture Hypothesis’, several lines of evidence supported mid-Pleistocene colonization and vicariant isolation ofHypostomuspopulations from an ancestral Upper Paraná population, including: (1) significant phylogeographic structure, with predicted phylogenetic patterns, (2) higher Paraná lineage diversity, (3) ancestral geographic locations reconstructed in the Paraná basin, and (4) non-random interdrainage dispersal and vicariance events, indicating river captures primarily into the Tocantins and Upper São Francisco basinsc.∼220,000–145,500 years ago. Phylogeographic inference was complicated by lack of lineage monophyly across loci and lineages distributed in multiple basins, the latter of which lent support to the non-mutually exclusive ‘Frequent Interdrainage Dispersal Hypothesis’. However, species tree and demographic modeling results suggested these were artefacts of incomplete sorting of alleles in large ancestral populations over a geologically recent timeframe of divergence. Qualitative and quantitative sensitivity analyses demonstrated that our downstream genetic results were robust to effects of varying ddRAD-seq assembly parameters, which heavily influenced the number of output loci. We predict that codistributed freshwater taxa in Central Brazil may not exhibit phylogeographic patterns similar toHypostomussp. 2 due to complex patterns of superimposed river capture events, or if smaller ancestral population sizes have allowed more complete lineage sorting in other taxa.
MS2DeepScore - a novel deep learning similarity measure for mass fragmentation spectrum comparisons
Authors: Huber Florian , van der Burg Sven , van der Hooft Justin J.J. , Ridder Lars
Published: April 2021

Mass spectrometry data is one of the key sources of information in many workflows in medicine and across the life sciences. Mass fragmentation spectra are considered characteristic signatures of the chemical compound they originate from, yet the chemical structure itself usually cannot be easily deduced from the spectrum. Often, spectral similarity measures are used as a proxy for structural similarity but this approach is strongly limited by a generally poor correlation between both metrics.

Here, we propose MS2DeepScore: a novel Siamese neural network to predict the structural similarity between two chemical structures solely based on their MS/MS fragmentation spectra. Using a cleaned dataset of >100,000 mass spectra of about 15,000 unique known compounds, MS2DeepScore learns to predict structural similarity scores for spectrum pairs with high accuracy. In addition, sampling different model varieties through Monte-Carlo Dropout is used to further improve the predictions and assess the model’s prediction uncertainty. On 3,600 spectra of 500 unseen compounds, MS2DeepScore is able to identify highly-reliable structural matches and predicts Tanimoto scores with a root mean squared error of about 0.15. The prediction uncertainty estimate can be used to select a subset of predictions with a root mean squared error of about 0.1. We demonstrate that MS2DeepScore outperforms classical spectral similarity measures in retrieving chemically related compound pairs from large mass spectral datasets, thereby illustrating its potential for spectral library matching. Finally, MS2DeepScore can also be used to create chemically meaningful mass spectral embeddings that could be used to cluster large numbers of spectra. Added to the recently introduced unsupervised Spec2Vec metric, we believe that machine learning-supported mass spectral similarity metrics have great potential for a range of metabolomics data processing pipelines.
Connecting MHC-I-binding motifs with HLA alleles via deep learning
Authors: Lee Ko-Han , Chang Yu-Chuan , Chen Ting-Fu , Juan Hsueh-Fen , Tsai Huai-Kuang , Chen Chien-Yu
Published: April 2021

The selection of peptides presented by MHC molecules is crucial for antigen discovery. Previously, several predictors have shown impressive performance on binding affinity. However, the decisive MHC residues and their relation to the selection of binding peptides are still unrevealed. Here, we connected HLA alleles with binding motifs via our deep learning-based framework, MHCfovea. MHCfovea expanded the knowledge of MHC-I-binding motifs from 150 to 13,008 alleles. After clustering N-terminal and C-terminal sub-motifs on both observed and unobserved alleles, MHCfovea calculated the hyper-motifs and the corresponding allele signatures on the important positions to disclose the relation between binding motifs and MHC-I sequences. MHCfovea delivered 32 pairs of hyper-motifs and allele signatures (HLA-A: 13, HLA-B: 12, and HLA-C: 7). The paired hyper-motifs and allele signatures disclosed the critical polymorphic residues that determine the binding preference, which are believed to be valuable for antigen discovery and vaccine design when allele specificity is concerned.
Unlocking inaccessible historical genomes preserved in formalin
Authors: Hahn Erin E. , Alexander Marina R. , Grealy Alicia , Stiller Jiri , Gardiner Donald M. , Holleley Clare E.
Published: April 2021

Background

Museum specimens represent an unparalleled record of historical genomic data. However, the wide-spread practice of formalin preservation has thus far impeded genomic analysis of a large proportion of specimens. Limited DNA sequencing from formalin-preserved specimens has yielded low genomic coverage with unpredictable success. We set out to refine sample processing methods and to identify specimen characteristics predictive of sequencing success. With a set of taxonomically diverse specimens collected between 1936 and 2015 and ranging in preservation quality, we compared the efficacy of several end-to-end whole genome sequencing workflows alongside a k-mer-based trimming-free read alignment approach to maximize mapping of endogenous sequence.

Results

We recovered complete mitochondrial genomes and up to 3X nuclear genome coverage from formalin-fixed tissues. Hot alkaline lysis coupled with phenol-chloroform extraction out- performed proteinase K digestion in recovering DNA, while library preparation method had little impact on sequencing success. The strongest predictor of DNA yield was overall specimen condition, which additively interacts with preservation conditions to accelerate DNA degradation.

Conclusions

We demonstrate a significant advance in capability beyond limited recovery of a small number of loci via PCR or target-capture sequencing. To facilitate strategic selection of suitable specimens for genomic sequencing, we present a decision-making framework that utilizes independent and non-destructive assessment criteria. Sequencing of formalin-fixed specimens will contribute to a greater understanding of temporal trends in genetic adaptation, including those associated with a changing climate. Our work enhances the value of museum collections worldwide by unlocking genomes of specimens that have been disregarded as a valid molecular resource.
Disentangling the direct and indirect effects of childhood adiposity on type 1 diabetes and immune-associated diseases: a multivariable Mendelian randomization study
Authors: Richardson Tom G , Crouch Daniel J M , Power Grace M , Berstein Fernanda Morales , Hazelwood Emma , Fang Si , Cho Yoonsu , Inshaw Jamie R J , Robertson Catherine C , Sidore Carlo , Cucca Francesco , Rich Steven S , Todd John A , Smith George Davey
Published: April 2021

Background

The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). However, robust causal evidence supporting this claim has been extremely challenging to uncover, particularly given the typical early onset of T1D.

Methods

In this study, we used genetic variation to separate the direct effect of childhood body size on T1D risk from the effects of body size at different stages in the life course using univariable and multivariable Mendelian randomization (MR). Similar MR analyses were conducted on risk of seven other chronic immune-associated diseases.

Findings

Childhood body size provided evidence of an effect on T1D (based on a sample of 5,913 cases and 8,282 controls) using a univariable model (OR=2.05 per change in body size category, 95% CI=1.20 to 3.50, P=0.008), which remained after accounting for body size at birth and during adulthood (OR=2.32, 95% CI=1.21 to 4.42, P=0.013). The direct effect of childhood body size was validated using data from a large-scale T1D meta-analysis based on n=15,573 cases and n=158,408 controls (OR=1.94, 95% CI=1.21 to 3.12, P=0.006). We also obtained evidence that childhood adiposity influences risk of asthma (OR=1.31, 95% CI=1.08 to 1.60, P=0.007), eczema (OR=1.25, 95% CI=1.03 to 1.51, P=0.024) and hypothyroidism (OR=1.42, 95% CI=1.12 to 1.80, P=0.004). However, these estimates all attenuated to the null when accounting for adult body size, suggesting that the effect of childhood adiposity on these outcomes is mediated by adiposity in later life.

Interpretation

Our findings support a causal role for higher childhood adiposity on higher risk of being diagnosed with T1D. In contrast, the effect of childhood adiposity on the other immune-associated diseases studied was explained by a long-term effect of remaining overweight for many years over the life course.
Genetic variation in activating clopidogrel: longer-term outcomes in a large community cohort
Authors: Pilling Luke C. , Türkmen Deniz , Fullalove Hannah , Atkins Janice L. , Delgado João , Kuo Chia-Ling , Kuchel George A. , Ferrucci Luigi , Bowden Jack , Masoli Jane A.H. , Melzer David
Published: April 2021

Background

The antiplatelet drug clopidogrel is commonly prescribed for stroke and myocardial infarction (MI) prevention. Clopidogrel prodrug is predominantly activated by liver enzyme CYP2C19. CYP2C19 Loss-of-function (LoF) genetic variants have been linked to excess morbidity mainly in patients hospitalized for acute ischemic events and related interventions. Little is known about the magnitude of impact of LoF variants in family practice, especially over long periods of exposure. We aimed to determine whether CYP2C19 LoF alleles increase risk of ischemic stroke and MI in primary care patients prescribed clopidogrel for up to 18 years.

Methods

Retrospective cohort analysis of 7,483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36 to 79 years at first clopidogrel prescription. We examined CYP2C19 LoF variant (*2-*8) associations with incident hospital-diagnosed ischemic stroke and MI in patients prescribed clopidogrel for at least 2 months using time-to-event models, with secondary analysis of the *17 gain of function variant.

Results

28.7% (n=2,144/7,483) of included subjects (mean age 63 years at first clopidogrel prescription) carried at least one CYP2C19 intermediate or low metabolizer LoF variant. 1.9% of LoF variant carriers had an incident ischemic stroke whilst prescribed clopidogrel (mean 2.6 years, range 2 months to 18 years), versus 1.3% without the variants (0.6% absolute excess: Hazard Ratio 1.53: 95% CI 1.04 to 2.26, p=0.031). Additionally, 26.4% of CYP2C19 LoF variant carriers had an incident MI versus 24.1% (HR 1.14: 1.04 to 1.26, p=.008). Adjustment for aspirin co-prescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischemic stroke by age 79 (the oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers: the absolute excess stroke incidence with LoF variants was 7.1% by age 79.

Conclusion

In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischemic events. Genotype-guided (or routine) prescription of antiplatelet medications unaffected by CYP2C19 variants may improve outcomes in patients for whom clopidogrel is currently indicated.
Air leaks: stapling affects porcine lungs biomechanics
Authors: Bonnet Bénédicte , Tabiai Ilyass , Rakovich George , Gosselin Frédérick P. , Villemure Isabelle
Published: April 2021

During thoracic operations, surgical staplers resect cancerous tumors and seal the spared lung. However, post-operative air leaks are undesirable clinical consequences: staple legs wound lung tissue. Subsequent to this trauma, air leaks from lung tissue into the pleural space. This affects the lung’s physiology and patients’ recovery.

The objective is to biomechanically and visually characterize porcine lung tissue with and without staples in order to gain knowledge on air leakage following pulmonary resection. Therefore, a syringe pump filled with air inflates and deflates eleven porcine lungs cyclically without exceeding 10 cmH2O of pressure. Cameras capture stereo-images of the deformed lung surface at regular intervals while a microcontroller simultaneously records the alveolar pressure and the volume of air pumped. The raw images are then used to compute tri-dimensional displacements and strains with the Digital Image Correlation method (DIC).

Air bubbles originated at staple holes of inner row from exposed porcine lung tissue due to torn pleural on costal surface. Compared during inflation, left upper or lower lobe resections have similar compliance (slope of the pressure vs volume curve), which are 9% lower than healthy lung compliance. However, lower lobes statistically burst at lower pressures than upper lobes (p-value<0.046) inex vivoconditions confirming previous clinicalin vivostudies. In parallel, the lung deformed mostly in the vicinity of staple holes and presented maximum shear strain near the observed leak location. To conclude, a novel technique DIC provided concrete evidence of the post-operative air leaks biomechanics. Further studies could investigate causal relationships between the mechanical parameters and the development of an air leak.
Appetitive learning relies on octopamine and dopamine in ants
Authors: Wissink Maarten , Nehring Volker
Published: April 2021

Associative learning relies on the detection of coincidence between a stimulus and a reward or punishment. In the insect brain, this process is thought to be carried out in the mushroom bodies under control of octopaminergic and dopaminergic neurons. It was assumed that appetitive learning is governed by octopaminergic neurons, while dopamine is required for aversive learning. This view has been recently challenged: Both neurotransmitters seem to be involved in both types of memory in bees and flies. Here, we test which neurotransmitters are required for appetitive learning in ants. We trainedLasius nigerant workers to discriminate two mixtures of linear hydrocarbons and associate one of them with a sucrose reward. We analysed the behaviour of the trained ants using machine learning and found that they preferred the rewarded odour over the other, a preference that was stable for at least 24 hours. We then treated the ants before learning with either epinastine, an octopamine receptor blocker, or with flupentixol, a dopamine receptor blocker. Ants with blocked octopamine receptors did not remember the rewarded odour. Octopamine signalling is thus necessary for the formation of appetitive memory. In contrast, ants with blocked dopamine receptors initially learned the rewarded odour but failed to retrieve this memory 24 hours later. Dopamine is thus required for long-term memory consolidation during appetitive conditioning, independent of short-term memory formation. Our results show that appetitive learning depends on both octopamine and dopamine signalling in ants.
Cell division in tissues enables macrophage infiltration
Authors: Akhmanova Maria , Gyoergy Attila , Vlasov Mikhail , Vlasov Fedor , Krueger Daniel , Akopian Andrei , Emtenani Shamsi , Ratheesh Aparna , De Renzis Stefano , Siekhaus Daria E.
Published: April 2021

Migration of cells through diverse tissues is essential for development, immune response and cancer metastasis1–3. To reach their destination, cells must overcome the resistance imposed by complex microenvironments, composed of neighboring cells and extracellular matrix (ECM)4–6. While migration through pores and tracks in ECM has been well studied4,5,7, little is known about cellular traversal into confining cell-dense tissues. Here by combining quantitative live imaging with genetic and optogenetic perturbations we identify a crucial role for cell division during cell migration into tissues. We find that normal embryonic invasion byDrosophilamacrophages between the ectoderm and mesoderm8,9absolutely requires division of an epithelial ectodermal cell at the site of entry. Dividing ectodermal cells disassemble ECM attachment formed by Integrin-mediated focal adhesions next to mesodermal cells, allowing macrophages to move their nuclei ahead and invade. Decreasing or increasing the frequency of ectodermal division correspondingly either hinders or promotes macrophage invasion. Reducing the levels of focal adhesion components in the ectoderm allows macrophage entry even in the absence of division. Our study demonstrates the critical importance of division at the entry site to enablein vivocell invasion by relieving the steric impediment caused by focal adhesions. We thus provide a new perspective on the regulation of cellular movement into tissues.
Brain structure-function coupling provides signatures for task decoding and individual fingerprinting
Authors: Griffa Alessandra , Amico Enrico , Liégeois Raphaël , Van De Ville Dimitri , Preti Maria Giulia
Published: April 2021

Brain signaturesof functional activity have shown promising results in bothdecodingbrain states, meaning distinguishing between different tasks, andfingerprinting, that is identifying individuals within a large group. Importantly, these brain signatures do not account for the underlying brain anatomy on which brain function takes place. Structure-function coupling based on graph signal processing (GSP) has recently revealed a meaningful spatial gradient from unimodal to transmodal regions, on average in healthy subjects during resting-state. Here, we explore the potential of GSP to introduce new imaging-based biomarkers to characterize tasks and individuals. We used multimodal magnetic resonance imaging of 100 unrelated healthy subjects from the Human Connectome Project both during rest and seven different tasks and adopted a support vector machine classification approach for bothdecodingandfingerprinting, with various cross-validation settings. We found that structurefunction coupling measures allow accurate classifications for both task decoding and fingerprinting. In particular, key information for fingerprinting is found in the more liberal portion of functional signals, that is the one decoupled from structure. A network mainly involving cortico-subcortical connections showed the strongest correlation with cognitive traits, assessed with partial least square analysis, corroborating its relevance for fingerprinting. By introducing a new perspective on GSP-based signal filtering and FC decomposition, these results show that brain structure-function coupling provides a new class of signatures of cognition and individual brain organization at rest and during tasks. Further, they provide insights on clarifying the role of low and high spatial frequencies of the structural connectome, leading to new understanding of where key structure-function information for characterizing individuals can be found across the structural connectome graph spectrum.

Highlights

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The relation of brain function with the underlying structural wiring is complex

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We propose new structure-informed graph signal processing (GSP) of functional data

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GSP-derived features allow accurate task decoding and individual fingerprinting

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Functional connectivity from filtered data is more unique to subject and cognition

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The role of structurally aligned and liberal graph frequencies is elucidated
Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles
Authors: Heras-Romero Yessica , Morales-Guadarrama Axayacatl , Santana-Martínez Ricardo , Ponce Isaac , Rincón-Heredia Ruth , Poot-Hernández Augusto César , Martínez-Moreno Araceli , Urrieta Esteban , Bernal-Vicente Berenice N. , Campero-Romero Aura N. , Moreno-Castilla Perla , Greig Nigel H. , Escobar Martha L. , Concha Luis , Tovar-y-Romo Luis B.
Published: April 2021

Spontaneous recovery after a stroke accounts for a major part of the neurological recovery in patients. However limited, the spontaneous recovery is mechanistically driven by axonal restorative processes for which several molecular cues have been previously described. We report the acceleration of spontaneous recovery in a preclinical model of ischemia/reperfusion in rats via a single intracerebroventricular administration of extracellular vesicles released from primary cortical astrocytes. We used MRI, confocal and multiphoton microscopy to correlate the structural remodeling of the corpus callosum and striatocortical circuits with neurological performance over 21 days. We also evaluated the functionality of the corpus callosum by repetitive recordings of compound action potentials to show that the recovery facilitated by astrocytic extracellular vesicles was both anatomical and functional. Our data provide compelling evidence that astrocytes can hasten the basal recovery that naturally occurs post-stroke through the release of cellular mediators contained in extracellular vesicles.
Fibrin Prestress Due to Platelet Aggregation and Contraction Increases Clot Stiffness
Authors: Pathare Suyog J. , Eng Wilson , Lee Sang-Joon J. , Ramasubramanian Anand K.
Published: April 2021

Efficient haemorrhagic control is attained through the formation of strong and stable blood clots at the site of injury. Although it is known that platelet-driven contraction can dramatically influence clot stiffness, the underlying mechanisms by which platelets assist fibrin networks in resisting external loads are not understood. In this study, we delineate the contribution of platelet-fibrin interactions to clot tensile mechanics using a combination of new mechanical measurements, image analysis, and structural mechanics simulation. Based on uniaxial tensile test data using custom-made microtensometer, and fluorescence microscopy of platelet aggregation and platelet-fibrin interactions, we show that integrin-mediated platelet aggregation and actomyosin-driven platelet contraction synergistically increase the elastic modulus of the clots. We demonstrate that the mechanical and geometric response of an active contraction model of platelet aggregates compacting vicinal fibrin is consistent with the experimental data. The model suggests that platelet contraction induces prestress in fibrin fibres, and increases the effective stiffness in both crosslinked and non-crosslinked clots. Our results provide evidence for fibrin compaction at discrete nodes as a major determinant of mechanical response to applied loads.
Surface residues and non-additive interactions stabilize a consensus homeodomain protein
Authors: Sternke Matt , Tripp Katherine W. , Barrick Doug
Published: April 2021

Despite the widely reported success of consensus design in producing highly stabilized proteins, little is known about the physical mechanisms underlying this stabilization. Here we explore the potential sources of stabilization by performing a systematic analysis of the 29 substitutions that we previously found to collectively stabilize a consensus homeodomain compared to an extant homeodomain. By separately introducing groups of consensus substitutions that alter or preserve charge state, occur at varying degrees of residue burial, and occur at positions of varying degrees of conservation, we determine the extent to which these three features contribute to the consensus stability enhancement. Surprisingly, we find that the largest total contribution to stability comes from consensus substitutions on the protein surface and that the largest per-substitution contributions come from substitutions that maintain charge state, suggesting that although consensus proteins are often enriched in charged residues, consensus stabilization does not result primarily from charge-charge interactions. Although consensus substitutions at strongly conserved positions also contribute disproportionately to stabilization, significant stabilization is also contributed from substitutions at weakly conserved positions. Furthermore, we find that identical consensus substitutions show larger stabilizing effects when introduced into the consensus background than when introduced into an extant homeodomain, indicating that synergistic, stabilizing interactions among the consensus residues contribute to consensus stability enhancement of the homeodomain.

Significance Statement

Proteins composed of consensus sequences from multiple sequence alignments are often more stable than extant proteins used to create them. Often about half the residues in a consensus protein differ from those of extant proteins. The contributions of these differences to stability are unknown. Here we substitute groups of residues with different properties (conservation, charge variation, solvent accessibility) to determine which substitutions lead to consensus stabilization. We find that surface and charge-conserving substitutions contribute to stability, that weakly-conserved substitutions make a significant collective contribution to stability, and that there is a significant non-additive contribution to stability in the consensus background. These results provide insights to the sequence origins of consensus stabilization and the evolutionary constraints that determine protein sequences.
Identifying Upper Airway and Evaluating Adenoid in Lateral Cephalometric Radiographs of Pediatric Patients Using Image-based Deep Learning Technique
Authors: Yao Kan , Xie Yilun , Yu Wenwen , Wei Silong , Xia Liang , Zheng Tong , Lu Xiaofeng
Published: April 2021

Purpose

Adenotonsillar hypertrophy is considered as one of the primary causes of pediatric obstructive sleep apnea. In clinical practice, pediatric patients with potential obstructive apnea should undergo assessment of upper airway obstruction and adenotonsillar size. As lack of well-trained physicians in China, large numbers of such patients could not be accurately evaluated in time. We attempted to find a better way to assess upper airway obstruction.

Methods

We developed a computational method which may allow clinicians to trace upper airway obstruction. We utilized a Detectron2 Mask R-CNN architecture that was pretrained on ImageNet-1k dataset. We then trained it on our COCO dataset using transfer learning for segmentations of upper airway and related key structures. With the instance segmentations, we utilized a tracing algorithm developed by our own to sketch the contours of key segments. At the end, our system would use the traced landmarks to calculate the targeted clinical data.

Results

We validated the effective-ness of the algorithm in two steps. First, we used a validation set (COCO dataset) to evaluate the segmentation performance of our system. Our system achieved a mean segmentation AP of 61.30, with airway segmentation AP of 55.64 and cranial base segmentation AP of 66.96. In addition, the AP50was 99.49 and AP75was 73.62. Second,we analyzed the data from our system and experts using a single rater, absolute-agreement, 2-way mixed-effects model, and got ICC value of 0.73 with 95% confident interval = 0.63-0.81.

Conclusions

In this study, we created a deep-learning based system to help clinicians evaluate upper airway in lateral cephalometric radiographs which we believe could improve clinical practice. With the evolving of technology, our system would become more integrated into medical care of OSA, freeing the clinical practitioners from repetitive tasks and enabling them to concentrate on improved patient care.
Bone innervation and vascularization regulated by osteoclasts contribute to refractive pain-related behavior in the collagen antibody-induced arthritis model
Authors: Rudjito Resti , Agalave Nilesh M , Farinotti Alex Bersellini , Baharpoor Azar , Martinez Martinez Arisai , Islas Enriqueta Muñoz , Panwar Preety , Brömme Dieter , Barbier Julie , Marchand Fabien , Mehlen Patrick , Andersen Thomas Levin , Andrade Juan Miguel Jimenez , Svensson Camilla I.
Published: April 2021

Objective

Rheumatoid arthritis is often characterized by eroded joints and chronic pain that outlasts disease activity. Whilst several reports show strong associations between bone resorption and nociception, the underlying mechanisms remain to be unraveled. Here, we used the collagen antibody-induced arthritis (CAIA) model to examine the contribution of osteoclasts in pain regulation. The antinociceptive effects of osteoclasts inhibitors and their mechanisms of actions involving bone vascularization and innervation were also explored.

Methods

BALB/c female mice were subjected to CAIA by intravenous injection of a collagen type-II antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Degree of arthritis, bone resorption, mechanical hypersensitivity, vascularization and innervation in the ankle joint were assessed. Animals were treated with osteoclast inhibitors, zoledronate and cathepsin K inhibitor (T06), and netrin-1 neutralizing antibody. Potential pronociceptive factors were examined in primary osteoclast cultures.

Results

CAIA induced local bone loss in the calcaneus with ongoing increased osteoclast activity during the inflammatory phase of the model, but not after inflammation has resolved. Mechanical hypersensitivity was reversed by zoledronate in late but not inflammatory phase CAIA. This effect was coupled to the ability of osteoclasts to modulate bone vascularization and innervation, which was inhibited by osteoclast inhibitors. CAIA-induced hypersensitivity in the late phase was also reversed by anti-netrin-1 antibody.

Conclusion

Osteoclasts induce pain-like behavior in the CAIA model independent of inflammation via effects on bone vascularization and innervation.

Key messages

What is already known about this subject?

Pain and residual signs of erosive lesions are frequently present in rheumatoid arthritis (RA) patients with good disease control

Osteoclasts can induce nociceptive signaling but the exact mechanism with respect to RA-induced pain is not clear

What does this study add?

The pronociceptive actions of osteoclasts extend beyond flares of joint inflammation and erosive activity by increasing bone innervation, bone vascularization and netrin-1 release

Osteoclast inhibitors and neutralizing netrin-1 antibodies reverse refractive pain-related behaviors in the collagen antibody-induced arthritis model

How might this impact on clinical practice or future developments?

This study provides insights to the potential of osteoclast inhibition as a therapeutic strategy for persistent pain in RA
A pilot study to define and identify future priorities intoAllocasuarina robustarecovery as part of a community program
Authors: Pearson Matthew W
Published: April 2021

TheAllocasuarina robustapilot study investigated the process involved to facilitate seed recruitment as part of a threatened species project. Several experiments occurred, each examining a specific attribute in the seed recruitment process.A. robustais a threatened species of national and local significance. The research design would help land managers and communities to conserveA. robusta. The investigation aimed to improve seed recruitment inA. robustaoccurring under natural conditions. The experiment results highlighted several experimental design flaws and identified opportunities to increase community participation as part of the recovery program.
Age-dependent genetic architecture underlines similar heritability of body size in sticklebacks
Authors: Fraimout Antoine , Li Zitong , Sillanpää Mikko J. , Merilä Juha
Published: April 2021

Heritable variation in traits under natural selection is a prerequisite for evolutionary response. While it is recognised that trait heritability may vary spatially and temporally depending under which environmental conditions traits are expressed, less is known about the possibility that genetic variance contributing to the expected selection response in a given trait may vary at different stages of ontogeny. Specifically, whether different loci underlie the expression of a trait throughout development – thus providing an additional source of variation for selection to act on – is unclear. Here we show that the heritability (h2) of body size, an important life history trait, remains constant across ontogeny in a stickleback fish. Nevertheless, both analyses of quantitative trait loci (QTL) and genetic correlations across ages show that different chromosomes/loci contribute to this heritability in different ontogenic time-points. This suggests that body size can respond to selection at different stages of ontogeny but that this response is determined by different loci at different points of development. Hence, this illustrates the notion that diverse genetic architectures may underline similar (expected) phenotypic outcomes, and that similar selection pressures may lead to genetically heterogeneous responses depending on what life stage selection is acting on.
Active Rheumatoid Arthritis in a Mouse Model is not an Independent Risk Factor for Periprosthetic Joint Infection
Authors: Trikha Rishi , Greig Danielle , Sekimura Troy , Cevallos Nicolas , Kelley Benjamin , Mamouei Zeinab , Hart Christopher , Ralston Micah , Turkmani Amr , Sassoon Adam , Stavrakis Alexandra , Bernthal Nicholas M
Published: April 2021

Introduction

Periprosthetic joint infection (PJI) represents a devastating complication of total joint arthroplasty associated with significant morbidity and mortality. Literature suggests a possible higher incidence of periprosthetic joint infection (PJI) in patients with rheumatoid arthritis (RA). There is, however, no consensus on this relative risk nor a well-defined mechanism of this purported risk. This study investigates how collagen-induced arthritis (CIA), a validated animal model of RA, impacts infectious burden in a well-established model of PJI.

Methods

Control mice were compared against CIA mice. Whole blood samples were collected to quantify systemic IgG levels via ELISA.Ex vivorespiratory burst function was measured via dihydrorhodamine assay.Ex vivo Staphylococcus aureusXen36 burden was measured directly via colony forming unit (CFU) counts and crystal violet assay to assess biofilm formation.In vivo, surgical placement of a titanium implant through the knee joint and inoculation withS. aureusXen36 was performed. Bacterial burden was then quantified by longitudinal bioluminescent imaging.

Results

Mice with CIA demonstrated significantly higher levels of systemic IgG compared with control mice (p = 0.003).Ex vivo, there was no significant difference in respiratory burst function (p=0.89) orS. aureusbacterial burden as measured by CFU counts (p=0.91) and crystal violet assay (p=0.96).In vivo, no significant difference in bacterial bioluminescence between groups was found at all postoperative time points. CFU counts of both the implant and the peri-implant tissue were not significantly different between groups (p=0.82 and 0.80, respectively).

Conclusion

This study demonstrated no significant difference inS. aureusinfectious burden between mice with CIA and control mice. These results suggest that untreated, active RA may not represent a significant intrinsic risk factor for PJI. Further mechanistic translational and clinical studies are, however, warranted to thoroughly investigate the infectious risk of RA.
Effects of straw returning with potassium fertilizer on the stem lodging resistance, grain quality and yield of spring maize (Zea mays L.)
Authors: Fan Ya-fang , Gao Ju-lin , Sun Ji-ying , Liu Jian , Su Zhi-jun , Hu Shu-ping , Wang Zhi-gang , Yu Xiao-fang
Published: April 2021

The effects of straw returning with potassium fertilizer on the stem lodging resistance, grain quality and yield of spring maize were investigated to provide a scientific basis for the rational utilization of Inner Mongolia spring maize straw and potassium fertilizer resources. This study utilized Xianyu 335 as the test material, and a split plot design was carried out in three ecological regions from eastern to western Inner Mongolia (Tumochuan Plain irrigation area, Hetao Plain irrigation area and Lingnan warm dry zone), with the straw returning method as the main plot and potassium fertilizer dosage as the subplot. The stem resistance index, grain quality and yield were systematically identified. Both application of potassium fertilizer and straw returning improved the resistance and yield indicators of spring maize. Straw returning increased the effectiveness of potassium fertilizer application on spring maize plant height, ear height, fresh weight of stems, brix of stems and stem puncture strength by 2.82%-5.22%, 3.11%-5.90%, 15.96%-19.78%, 4.35%-4.50% and 8.89%-14.82%, respectively. Straw returning increased the effectiveness of potassium fertilizer application on the spring maize grain protein content, spring maize grain crude fat content, maize yield and yield variation coefficient by 3.49%-6.50%, 2.09%-4.43%, 4.87%-12.50% and 5.07%-7.55%, respectively. Straw returning can be combined with reasonable application of potassium fertilizer to increase the effectiveness of potassium fertilizer and enhance lodging resistance. Along with increased maize yield, straw returning also improves grain quality and enhances yield stability, providing a theoretical basis for high-yield and stress-resistant cultivation of Inner Mongolia spring maize, which can be popularized and applied in the spring maize planting areas of Inner Mongolia.
Exogene: A performant workflow for detecting viral integrations from paired-end next-generation sequencing data
Authors: Stephens Zachary , O’Brien Daniel , Dehankar Mrunal , Roberts Lewis R. , Iyer Ravishankar K. , Kocher Jean-Pierre
Published: April 2021

The integration of viruses into the human genome is known to be associated with tumorigenesis in many cancers, but the accurate detection of integration breakpoints from short read sequencing data is made difficult by human-viral homologies, viral genome heterogeneity, coverage limitations, and other factors. To address this, we present Exogene, a sensitive and efficient workflow for detecting viral integrations from paired-end next generation sequencing data. Exogene’s read filtering and breakpoint detection strategies yield integration coordinates that are highly concordant with those found in long read validation sets. We demonstrate this concordance across 6 TCGA Hepatocellular carcinoma (HCC) tumor samples, identifying integrations of hepatitis B virus that are validated by long reads. Additionally, we applied Exogene to targeted capture data from 426 previously studied HCC samples, achieving 98.9% concordance with existing methods and identifying 238 high-confidence integrations that were not previously reported. Exogene is applicable to multiple types of paired-end sequence data, including genome, exome, RNA-Seq or targeted capture.
Distribution, prevalence, and causative agents of fungal keratitis: A systematic review and meta-analysis (1990 to 2020)
Authors: Ahmadikia Kazem , Gharehbolagh Sanaz Aghaei , Fallah Bahareh , Naeimi Mahsa , Malekifar Pooneh , Rahsepar Saeedeh , Getso Muhammad Ibrahim , Sharma Savitri , Mahmoudi Shahram
Published: April 2021

Fungal keratitis is a sight-threatening infection with global distribution. In this systematic review and meta-analysis we collected all the articles with data on the prevalence of fungal keratitis among various patient groups from January 1, 1990 to May 27, 2020. The 169 eligible articles were divided into 6 groups. The pooled prevalence was variable with values ranging from 0.05% among post-keratoplasty patients to 43.01% among patients with a clinical suspicion of fungal keratitis. Except for post-keratoplasty cases (yeast: 51.80%), in all patient groups moulds were more common than yeasts. Although more than 50 distinct species of fungi have been found to cause fungal keratitis,Fusariumspecies followed byAspergillusspecies were the most common causes of the disease. In general, 9.29% (95% CI 6.52, 12.38) of fungal keratitis cases were mixed with bacterial agents.
Neurodevelopment vs. the immune system: complementary contributions of maternally-inherited gene transcripts and proteins to successful egg development in fish
Authors: Żarski Daniel , Cam Aurelie Le , Frohlich Thomas , Kösters Miwako , Klopp Christophe , Nynca Joanna , Ciesielski Sławomir , Sarosiek Beata , Dryl Katarzyna , Montfort Jerome , Król Jarosław , Fontaine Pascal , Ciereszko Andrzej , Bobe Julien
Published: April 2021

Background

In Metazoans, embryonic development relies on maternally-inherited mRNAs and proteins that are critical for early developmental success and known to play major roles at later stages, beyond zygotic genome activation. However, very poor concordance between transcript and protein levels in oocytes and embryos of vertebrates suggest that maternally-inherited proteins and maternally-inherited mRNAs are playing different roles in unfertilized eggs, not considered to date comprehensively. The aim of this study was to investigate the respective contribution of maternally-inherited mRNAs and maternally-inherited proteins to egg molecular cargo and to its developmental competence using pikeperch, an ecologically and commercially relevant freshwater fish species, as a model.

Results

Our data shed new light on the importance of maternally-inherited mRNAs in nervous system development suggesting that neurogenesis is a major mRNA-dependent non-genetic inheritance factor. In contrast, our results highlight a specific role of maternally-inherited proteins in immune response in ovulated eggs suggesting that maternal proteins would rather contribute to developmental success through protection of the embryo against pathogens. Further analysis revealed susceptibility of the transcriptome to modifications during the post-vitellogenic processes (i.e., final oocyte maturation and ovulation), whereas proteomic cargo remains unaffected. This may negatively affect developmental competence of the egg and possibly influence further nervous system development of the embryo.

Conclusions

Our study provides novel insights into the understanding of type-specific roles of maternally-inherited molecules in fish. Here we show, for the first time, that transcripts and proteins have distinct, yet complementary, functions in the egg of teleost fish. Maternally-inherited mRNAs would shape embryo neurodevelopment and possibly the future behavior of the fish, while maternally-inherited proteins would rather be responsible for protecting the embryo against pathogens. Additionally, we observed that processes directly preceding ovulation may considerably affect the reproductive success by modifying expression level of genes crucial for proper embryonic development, being novel fish egg quality markers (e.g.,smarca4orh3f3a). These results are of major importance for understanding the influence of external factors on reproductive fitness in both captive and wild-type fish species.
Inactivation of SARS-CoV-2 in chlorinated swimming pool water
Authors: Brown Jonathan C , Moshe Maya , Blackwell Alex , Barclay Wendy S
Published: April 2021

SARS-CoV-2 transmission remains a global problem which exerts a significant direct cost to public health. Additionally, other aspects of physical and mental health can be affected by limited access to social and exercise venues as a result of lockdowns in the community or personal reluctance due to safety concerns. Swimming pools have reopened in the UK as of April 12th, but the effect of swimming pool water on inactivation of SARS-CoV-2 has not yet been directly demonstrated. Here we demonstrate that water which adheres to UK swimming pool guidelines is sufficient to reduce SARS-CoV-2 infectious titre by at least 3 orders of magnitude.