bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and Performance Characteristics of the Elecsys Anti-SARS-CoV-2 S assay
Authors: Taffertshofer Karin , Walter Mirko , Mackeben Peter , Kraemer Julia , Potapov Sergej , Jochum Simon
Published: July 2022

Background

Automated, high throughput assays are required to quantify the immune response after infection with or vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study on the Roche Elecsys® Anti-SARS-CoV-2 S (ACOV2S) assay provides insights on the assay design and performance.

Methods

The ACOV2S assay quantifies antibodies to the receptor-binding domain of the SARS-CoV-2 spike protein. The assigned units and the underlying standardization were compared to the international reference standard in BAU/mL. Assay specificity was assessed in samples (n=5981) collected prior to the COVID-19 pandemic and in samples from patients with non-COVID-19 respiratory infections (n=697) or other infectious diseases (n=771). Sensitivity was measured in 1313 samples from patients with mild COVID-19 and 297 samples from patients hospitalized with COVID-19. Comparison of results was performed to a comparator semi-quantitative anti-S1 assay of indirect detection format as well as a commercially available and an in-house version of a surrogate neutralization assay (ACE2-RBD).

Results

The originally assigned units for the ACOV2S assay were shown to be congruent to the units of the First International WHO Standard for anti-SARS-CoV-2 immunoglobulins. Overall specificity was 99.98% with no geographical differences noted and no loss of specificity in samples containing potentially cross-reacting antibodies. High sensitivity was observed, with 98.8% of samples reported to be reactive >14 days after infection and sustained detection of antibodies over time. For all samples, ACOV2S titers and neutralization capacities developed with comparable dynamics. Robust standardization and assay setup enable excellent reproducibility of results, independent of lot or analyzer used.

Conclusion

The results from this study confirmed that ACOV2S is a highly sensitive and specific assay and correlates well with surrogate neutralization assays. The units established for ACOV2S are also interchangeable with the units of the First International WHO Standard for anti-SARS-CoV-2 immunoglobulins. Worldwide availability of the assay and analyzers render ACOV2S a highly practical tool for population-wide assessment and monitoring of the humoral response to SARS-CoV-2 infection or vaccination.
Transcriptomic and connectomic correlates of differential spatial patterning among glioblastomas and low-grade gliomas
Authors: Romero-Garcia Rafael , Mandal Ayan S. , Bethlehem Richard AI , Crespo-Facorro Benedicto , Hart Michael G , Suckling John
Published: July 2022

Background

Unravelling the complex events driving grade-specific spatial distribution of brain tumour occurrence requires rich datasets from both healthy individuals and patients. Here, we combined open-access data from The Cancer Genome Atlas, the UKBiobank and the Allen Brain Human Atlas to disentangle how the different spatial occurrences of Glioblastoma Multiforme (GBM) and Low-Grade Gliomas (LGG) are linked to brain network features and the normative transcriptional profiles of brain regions.

Methods

From MRI of brain tumour patients we first constructed a grade-related frequency map of the regional occurrence of LGG and the more aggressive GBM. Using associated mRNA transcription data, we derived a set of differential gene expressions from GBM and LGG tissues of the same patients. By combining the resulting values with normative gene expressions frompostmortembrain tissue, we constructed a grade-related expression map indicating which brain regions express genes dysregulated in aggressive gliomas. Additionally, we derived an expression map of genes previously associated with tumour subtypes in a GWAS study (tumour-related genes).

Results

There were significant associations between grade-related frequency, grade-related expression, and tumour-related expression maps, as well as functional brain network features (specifically, nodal strength and participation coefficient) that are implicated in neurological and psychiatric disorders.

Conclusions

These findings identify brain network dynamics and transcriptomic signatures as key factors in regional vulnerability for GBM and LGG occurrence, placing primary brain tumours within a well-established framework of neurological and psychiatric cortical alterations.
Strong neutralizing antibody responses to SARS-CoV-2 variants following a single vaccine dose in subjects with previous SARS-CoV-2 infection
Authors: Ekström Nina , Haveri Anu , Solastie Anna , Virta Camilla , Österlund Pamela , Nohynek Hanna , Nieminen Tuomo , Ivaska Lauri , Tähtinen Paula A. , Lempainen Johanna , Jalkanen Pinja , Julkunen Ilkka , Palmu Arto A. , Melin Merit
Published: July 2022

Background

Previous SARS-CoV-2 infection primes the immune system and thus individuals who recovered from infection have enhanced immune responses to subsequent vaccination (hybrid immunity). However, it remains unclear how well hybrid immunity induced by severe or mild infection can cross-neutralize emerging variants. We aimed to compare the strength and breadth of antibody responses in vaccinated recovered and uninfected subjects.

Methods

We measured spike-specific IgG and neutralizing antibodies (NAbs) from vaccinated subjects including 320 with hybrid immunity and 20 without previous infection. From 29 subjects with a previous severe or mild infection, we also measured NAb responses against Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2) and Omicron (B.1.1.529/BA.1) variants following vaccination.

Results

A single vaccine dose induced 2-fold higher anti-spike IgG concentrations and 3-fold higher neutralizing potency of antibodies in previously infected compared to uninfected fully vaccinated subjects. We found similar IgG concentrations in previously infected subjects after one or two vaccine doses. NAb titers were higher in subjects with severe compared to those with mild infection. This difference remained after vaccination with sequentially decreasing titers against Alpha, Beta, Delta, and Omicron variants.

Conclusions

Hybrid immunity induced strong IgG responses, particularly after severe infection. However, the NAb titers were low against heterologous variants, especially against Omicron.
SARS-CoV-2 seroprevalence among public school staff in Metro Vancouver after the first Omicron wave in British Columbia, Canada
Authors: Watts Allison W , Mâsse Louise C , Goldfarb David M , Irvine Michael A , Hutchison Sarah M , Muttucomaroe Lauren , Poon Bethany , Barakauskas Vilte E , O’Reilly Collette , Bosman Else S , Reicherz Frederic , Coombs Daniel , Pitblado Mark , O’Brien Sheila F , Lavoie Pascal M
Published: July 2022

Objective

To determine the SARS-CoV-2 seroprevalence among school workers in the setting of full in-person schooling and the highly transmissible Omicron variants of concern.

Design

Cross-sectional study among school staff, comparing to period-, age-, sex- and postal code-weighted data from Canadian blood donors from the same community.

Setting

Three large school districts in the greater Vancouver metropolitan area, British Columbia, Canada, with serology sampling done between January 26, 2022 and April 8, 2022.

Participants

School staff actively working in the Vancouver, Richmond and Delta School Districts.

Main outcome measure

SARS-CoV-2 seroprevalence based on nucleocapsid (N)-protein testing, adjusted for the sensitivity and specificity of the assay.

Results

A majority (65.8%) of the 1845 school staff enrolled reported close contact with a COVID-19 case outside the household. Of those, about half reported close contact with a COVID-19 case at school either in a student (51.5%) or co-worker (54.9%). In a representative sample of 1620 (87.8%) school staff, the adjusted seroprevalence was 26.5% [95%CrI: 23.9 – 29.3%]. This compared to an age, sex and residency area-weighted seroprevalence of 32.4% [95%CrI: 30.6 – 34.5%] among 7164 blood donors.

Conclusion

Despite frequent COVID-19 exposures, the prevalence of SARS-CoV-2 infections among the staff of three main school districts in the Vancouver metropolitan area was no greater than a reference group of blood donors, even after the emergence of the more transmissible Omicron variant.

What is already known on this subject?

Earlier studies indicate that COVID-19 infection rates are not increased among school staff at previous stages of the pandemic compared to the community, yet controversy remains whether this will remain true after the emergence of the highly transmissible Omicron variant.

What this study adds?

Despite frequent COVID-19 exposures, this study identified no detectable increase in SARS-CoV-2 seroprevalence among school staff working in three metro Vancouver public school districts after the first Omicron wave in British Columbia, compared to a reference group of blood donors from the same age, sex and community area.
Modelling the epidemiological implications for SARS-CoV-2 of Christmas household bubbles in England
Authors: Hill Edward M.
Published: July 2022

The emergence of SARS-CoV-2 saw severe detriments to public health being inflicted by COVID-19 disease throughout 2020. In the lead up to Christmas 2020, the UK Government sought an easement of social restrictions that would permit spending time with others over the Christmas period, whilst limiting the risk of spreading SARS-CoV-2. In November 2020, plans were published to allow individuals to socialise within ‘Christmas bubbles’ with friends and family. This policy involved a planned easing of restrictions in England between 23-27 December 2020, with Christmas bubbles allowing people from up to three households to meet throughout the holiday period. We estimated the epidemiological impact of both this and alternative bubble strategies that allowed extending contacts beyond the immediate household. We used a stochastic individual-based model for a synthetic population of 100,000 households, with demographic and SARS-CoV-2 epidemiological characteristics comparable to England as of November 2020. We evaluated five Christmas bubble scenarios for the period 23-27 December 2020, assuming our populations of households did not have symptomatic infection present and were not in isolation as the eased social restrictions began. Assessment comprised incidence and cumulative infection metrics. We tested the sensitivity of the results to a situation where it was possible for households to be in isolation at the beginning of the Christmas bubble period and also when there was lower adherence to testing, contact tracing and isolation interventions. We found that visiting family and friends over the holiday period for a shorter duration and in smaller groups was less risky than spending the entire five days together. The increases in infection from greater amounts of social mixing disproportionately impacted the eldest. We provide this account as an illustration of a real-time contribution of modelling insights to a scientific advisory group, the Scientific Pandemic Influenza Group on Modelling, Operational sub-group (SPI-M-O) for the Scientific Advisory Group for Emergencies (SAGE) in the UK, during the COVID-19 pandemic. This manuscript was submitted as part of a theme issue on “Modelling COVID-19 and Preparedness for Future Pandemics”.
Tandemly repeated genes promote RNAi-mediated heterochromatin formation via an anti-silencing factor Epe1 in fission yeast
Authors: Asanuma Takahiro , Inagaki Soichi , Kakutani Tetsuji , Aburatani Hiroyuki , Murakami Yota
Published: July 2022

In most eukaryotes, constitutive heterochromatin, defined by histone H3 lysine 9 methylation (H3K9me), is enriched on repetitive DNA, such as pericentromeric repeats and transposons. Furthermore, repetitive transgenes also induce heterochromatin formation in diverse model organisms. However, the mechanisms that promote heterochromatin formation at repetitive DNA elements are still not clear. Here, using fission yeast, we show that tandemly repeated mRNA genes promote RNA interference (RNAi)-mediated heterochromatin formation in co-operation with an anti-silencing factor, Epe1. Although the presence of tandemly repeated genes itself does not cause heterochromatin formation, once complementary small RNAs are artificially supplied in trans, the RNAi machinery assembled on the repeated genes starts producing cognate small RNAs in cis to autonomously maintain heterochromatin at these sites. The establishment of this “repeat-induced RNAi” depends on the copy number of repeated genes and also requires Epe1, which is known to remove H3K9me and derepress the transcription of genes underlying heterochromatin. Analogous to repeated genes, the DNA sequence underlying constitutive heterochromatin encodes widespread transcription start sites (TSSs), from which Epe1 activates ncRNA transcription to promote RNAi-mediated heterochromatin formation. Our results suggest that, when repetitive transcription units underlie heterochromatin, Epe1 generates sufficient transcripts for the activation of RNAi without disruption of heterochromatin.
Characteristics of circadian rhythm-related genes and establishment of a prognostic scoring system (CRscore) for lung adenocarcinoma with experimental verification
Authors: Zhang Fengbin , Zhang Qi , Jiang Taie , Fan Xiaoyu , Wang Wenmiao , Liu Lehan , Liu Kun
Published: July 2022

Background

Non-small-cell lung cancer (NSCLC) is one of the most common malignant tumors worldwide. Lung adenocarcinoma (LUAD), which is the m ain subtype of NSCLC, has a poor prognosis. In recent years, circadian rhythm (CR)-related genes (CRRGs) have demonstrated associations with tumor occurrence and development, but the relationship between CRRGs and LUAD is not clear.

Methods

Based on data from The Cancer Genome Atlas and Gene Expression Omnibus databases, we explored the biological function and immune cell infiltration of LUAD in different CR clusters and quantified CR genes using principal component analysis. Then, we built a CR scoring system (CRscore) to explore the relationship between CRRGs and LUAD prognosis.

Results

Patients were divided into three clusters (A, B, and C). Biological characteristics, such as survival, immune cell infiltration, and gene enrichment, were significantly different among the three clusters. We then established the usefulness of the CR score, which could effectively predict the prognosis of LUAD. Specifically, patients with a high CR score had a better prognosis and were more sensitive to chemotherapy than patients with a low CR score.

Conclusion

CRRGs can be used to assess the prognosis of patients with LUAD. Quantification of CR using the CRscore tool in patients with LUAD could help to guide personalized cancer immunotherapy strategies in the future. Thus, the CRscore may be a powerful prognostic tool for LUAD.
Modification Mechanism of Phenol-formaldehyde Resin with Crude Bio-oil by Model Compound Method
Authors: Yu Yuxiang , Qiu Xiaoqian , Li Chao , Chang Jianmin , Bao Defu
Published: July 2022

To clarify the modification mechanism of bio-oil for phenol-formaldehyde resin with crude bio-oil (BPF), the bio-oil compounds were simplified by model compound method according to the component distribution. The phenol-formaldehyde resin with bio-oil model compounds (BMPF) were prepared and their basic performance, bonding strength and aging characteristics were determined. The changes on the microstructure and chemical bonds of BMPF were also analyzed by scanning electron microscope, Fourier transform infrared spectroscopy, and nuclear magnetic resonance analysis. Results showed that the components of bio-oil had different influence on the performance and microstructure of BMPF, especially phenols. Structural analysis indicated that the phenols and ketones of bio-oil had positive effects on the synthesis of BMPF, while the aldehydes and acids had negative effects. But all components of bio-oil could improve the aging resistance of BMPF inordinately. These results could provide a basis for the modification of BPF.
Autoimmunity in Satoyoshi Disease: a Systematic Review
Authors: Montanaro Vinícius Viana Abreu , Solís-García del Pozo Julián , Falcão Hora Thiago , León Beatriz Helena , de Cabo Carlos , Solera Javier
Published: July 2022

Background

Satoyoshi syndrome (SS) is a rare multisystem disease. Although its cause is unknown, an autoimmune etiology has been postulated. In this paper we carried out a systematic review of all published cases of SS to evaluate the available evidence to support that autoimmune hypothesis.

Methods

We carried out a systematic review of the published cases of SS following the recommendations of the PRISMA statement for systematic reviews. We searched for SS cases in PubMed, the Web of Knowledge (WOS) and Scopus up to January 2022, using keywords “Satoyoshi syndrome” or “Komuragaeri disease”. Data on symptoms, associated autoimmune diseases, presence of autoantibodies and response to treatment were collected.

Results

77 patients from 57 articles published between 1967 and 2021 were included. 59 patients were women. The mean age at diagnosis was 21.2 years. All cases had painful muscular spasms and alopecia. Other frequent manifestations included: diarrhea, malabsorption, growth retardation, amenorrhea and bone deformity. SS was associated with other autoimmune diseases: myasthenia gravis (2 patients), autoimmune thyroiditis (one patient), idiopathic thrombocytopenic purpura (one patient), atopic dermatitis (one patient), bronchial asthma (one patient) and lupus erythematosus (one patient). Autoantibody determinations were performed in 39 patients, of which 27 had positive results. The most frequently detected autoantibodies were antinuclear antibodies (21 patients). Other less frequently found auto-antibodies were: anti-acetylcholine receptor antibodies (7 patients), anti-DNA antibodies (5 patients), antithyroid antibodies (3 patients), anti-GAD (2 patients) and anti-gliadin antibodies (2 patients). Pharmacological treatment was reported in 50 patients. Most of them improved with corticosteroids (33 patients), immunosuppressants (9 patients) and immunoglobulins (10 patients), or a combination of these medications.

Conclusions

SS is associated with other autoimmune diseases and a variety of autoantibodies. Improvement after corticosteroid or other immunosupressant treatment was observed in 90% of cases. These data support an autoimmune etiology for SS. More studies are necessary, including the systematic determination of autoantibodies in all patients with SS to help us advance in our understanding of this disease.
CEP peptide and cytokinin pathways converge on CEPD glutaredoxins to inhibit root growth
Authors: Taleski Michael , Chapman Kelly , Novák Ondřej , Schmülling Thomas , Frank Manuel , Djordjevic Michael A
Published: July 2022

C-TERMINALLY ENCODED PEPTIDE (CEP) and cytokinin hormones act over short and long distances to control plant responses to environmental cues. CEP and cytokinin pathway mutants share phenotypes, however, it is not known if these pathways intersect. We show that CEP and cytokinin signalling converge on CEP DOWNSTREAM (CEPD) glutaredoxins to inhibit primary root growth. CEP inhibition of root growth was impaired in mutants defective in trans-zeatin (tZ)-type cytokinin biosynthesis, transport, perception, and output. Concordantly, mutants affected in CEP RECEPTOR 1 showed reduced root growth inhibition in response to tZ, and altered levels of tZ-type cytokinins. Grafting and organ-specific hormone treatments showed that tZ-mediated root growth inhibition required CEPD activity in roots. By contrast, root growth inhibition by CEP depended on shoot CEPD function. The results demonstrate that CEP and cytokinin pathways intersect, and utilise signalling circuits in separate organs involving common glutaredoxin genes to coordinate root growth.
Childhood cancer mutagenesis caused by a domesticated DNA transposase
Authors: Keller Ross , Yamada Makiko , Cameron Daniel , Suzuki Hiromichi , Sanghrajka Reeti , Vaynshteyn Jake , Gerwin Jeffrey , Maura Francesco , Hooper William , Shah Minita , Robine Nicolas , Demarest Philip , Bayin N. Sumru , Jubierre Luz , Reed Casie , Taylor Michael D. , Joyner Alexandra L. , Raju G. Praveen , Kentsis Alex
Published: July 2022

Genomic rearrangements are a hallmark of most solid tumors, including medulloblastoma, one of the most common brain tumors in children. Childhood cancers involve dysregulated cell development, but their mutational causes remain largely unknown. One of the most common forms of medulloblastoma is caused by ectopic activation of Sonic Hedgehog (SHH) signaling in cerebellar granule cell progenitors, associated with genetic deletions, amplifications, and other oncogenic chromosomal rearrangements. Here, we show thatPiggyBac Transposable Element Derived 5 (Pgbd5)promotes tumor development in multiple developmentally-accurate mouse models of SHH medulloblastoma. Most mice withPgbd5deficiency do not develop tumors, whilePgbd5-deficient mice maintain largely normal cerebellar development. Mouse medulloblastomas expressingPgbd5exhibit significantly increased numbers of somatic structural DNA rearrangements, with PGBD5-specific transposon sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. Therefore, this study identifies PGBD5 as a primary medulloblastoma mutator and provides a genetic mechanism responsible for the generation of somatic oncogenic DNA rearrangements in childhood cancer.

One-Sentence Summary

Induction of somatic oncogenic mutations by the DNA transposase PGBD5 in cerebellar progenitor cells promotes medulloblastoma development.
Licensing Microgels Prolong the Immunomodulatory Phenotype of Mesenchymal Stromal Cells
Authors: Patrick Matthew , Annamalai Ramkumar T.
Published: July 2022

Mesenchymal stromal cells (MSC) are sensors of inflammation, and they exert immunomodulatory properties through the secretion of cytokines and exosomes and direct cell-cell interactions. MSC are routinely used in clinical trials and effectively resolve inflammatory conditions. Nevertheless, inconsistent clinical outcomes necessitate the need for more robust therapeutic phenotypes. The immunomodulatory properties of MSC can be enhanced and protracted by priming (aka licensing) them with IFNγ and TNFα. Yet these enhanced properties rapidly diminish, and prolonged stimulation could tolerize their response. Hence a balanced approach is needed to enhance the therapeutic potential of the MSC for consistent clinical performance. Here, we investigated the concentration-dependent effects of IFNγ and TNFα and developed gelatin-based microgels to sustain a licensed MSC phenotype. We show that IFNγ treatment is more beneficial than TNFα in promoting an immunomodulatory MSC phenotype. We also show that the microgels possess integrin-binding sites to support MSC attachment and a net positive charge to sequester the licensing cytokines electrostatically. Microgels are enzymatically degradable, and the rate is dependent on the enzyme concentration and matrix density. Our studies show that one milligram of microgels by dry mass can sequester up to 641 ± 81 ng of IFNγ. Upon enzymatic degradation, microgels exhibited a sustained release of IFNγ that linearly correlated with their degradation rate. The MSC cultured on the IFNγ sequestered microgels displayed efficient licensing potential comparable to or exceeding the effects of bolus IFNγ treatment. When cultured with proinflammatory M1-like macrophages, the MSC-seeded on licensing microgel showed an enhanced immunomodulatory potential compared to untreated MSC and MSC treated with bolus IFNγ treatment. Specifically, the MSC seeded on licensing microgels significantly upregulated Arg1, Mrc1, and Igf1, and downregulated Tnfa in M1-like macrophages compared to other treatment conditions. These licensing microgels are a potent immunomodulatory approach that shows substantial promise in elevating the efficacy of current MSC therapies and may find utility in treating chronic inflammatory conditions.
dach-1, a cytochrome P450 gene, regulates synaptic and developmental plasticity during the diapause ofCaenorhabditis elegans
Authors: Son Sangwon , Choi Myung-Kyu , Lim Daisy S. , Shim Jaegal , Lee Junho
Published: July 2022

Animals exhibit phenotypic plasticity through the interaction of genes with the environment, and little is known about the genetic factors that change synaptic function at different developmental stages. Here, we investigated the genetic determinants of how developmental stages alter synaptic transmission using the free-living nematodeCaenorhabditis elegans. C. elegansenters the stress-resistant dauer larval stage under harsh conditions. Although dauer is known to have reduced permeability and increased resistance to most known exogenous chemicals, we discovered that dauer is hypersensitive to a cholinesterase inhibitor, aldicarb. To investigate genes regulating dauer-specific acetylcholine transduction, we first screened for aldicarb-resistant mutations in dauer and then performed a secondary screen to rule out aldicarb-resistant mutations that also affect adults. We isolated two different mutations of a single gene calledcyp-34A4ordach-1encoding a cytochrome P450. In the non-dauer stages,dach-1is mainly expressed in the intestine, but its expression is robustly increased in the epidermis of dauers. By tissue-specific rescue experiments, we found thatdach-1modulates aldicarb sensitivity in a cell non-autonomous manner. In addition,dach-1plays pleiotropic functions in dauers by regulating quiescence and surviving heat shock and hyperosmolar stress. Our study reveals novel functions of the cytochrome P450 in synaptic and physiological changes during developmental plasticity.
Ordered deployment of distinct ciliary beating machines in growing axonemes of vertebrate multiciliated cells
Authors: Lee Chanjae , Ma Yun , Tu Fan , Wallingford John B.
Published: July 2022

The beating of motile cilia requires to coordinated action of diverse machineries that include not only the axonemal dynein arms, but also the central apparatus, the radial spokes, and the microtubule inner proteins. These machines exhibit complex radial and proximodistal patterns in mature axonemes, but little is known about the interplay between them during motile ciliogenesis. Here, we describe and quantify the relative rates of axonemal deployment for these diverse cilia beating machineries during the final stages of differentiation of Xenopus epidermal multiciliated cells.
Post-vaccination Omicron infections induce broader immunity across antigenic space than prototype mRNA COVID-19 booster vaccination or primary infection
Authors: Wang Wei , Lusvarghi Sabrina , Subramanian Rahul , Epsi Nusrat J. , Wang Richard , Goguet Emilie , Fries Anthony C , Echegaray Fernando , Vassell Russell , Coggins Si’Ana , Richard Stephanie A. , Lindholm David A. , Mende Katrin , Ewers Evan , Larson Derek , Colombo Rhonda E. , Colombo Christopher , Joseph Janet O. , Rozman Julia , Smith Alfred , Lalani Tahaniyat , Berjohn Catherine , Maves Ryan , Jones Milissa , Mody Rupal , Huprikar Nikhil , Livezey Jeffrey , Saunders David , Hollis-Perry Monique , Wang Gregory , Ganesan Anuradha , Simons Mark P. , Broder Christopher C. , Tribble David , Laing Eric D. , Agan Brian , Burgess Timothy H. , Mitre Edward , Pollett Simon D. , Katzelnick Leah C. , Weiss Carol D.
Published: July 2022

The rapid emergence of new SARS-CoV-2 variants challenges vaccination strategies. Here, we measured antigenic diversity among variants and interpreted neutralizing antibody responses following single and multiple exposures in longitudinal infection and vaccine cohorts. Antigenic cartography using primary infection antisera showed that BA.2, BA.4/BA.5, and BA.2.12.1 are distinct from BA.1 and closer to the Beta cluster. Three doses of an mRNA COVID-19 vaccine increased breadth to BA.1 more than to BA.4/BA.5 or BA.2.12.1. Omicron BA.1 post-vaccination infection elicited antibody landscapes characterized by broader immunity across antigenic space than three doses alone, although with less breadth than expected to BA.2.12.1 and BA.4/BA.5. Those with Omicron BA.1 infection after two or three vaccinations had similar neutralizing titer magnitude and antigenic breadth. Accounting for antigenic differences among variants of concern when interpreting neutralizing antibody titers aids understanding of complex patterns in humoral immunity and informs selection of future COVID-19 vaccine strains.
SpliceWiz: easy, optimized, and accurate alternative splicing analysis in R
Authors: Wong Alex CH , Wong Justin J-L , Rasko John EJ , Schmitz Ulf
Published: July 2022

Despite an abundance of publicly available RNA sequencing datasets, a lack of integrated user-friendly tools hinder exploration of alternative splicing. SpliceWiz is an innovative, ultra-fast graphical R application that accurately quantifies splicing events using isoform-specific alignments. It is designed to accommodate hundreds of samples typically seen in clinical datasets. Novel event filters remove low-confidence measurements from analysis, enhancing accuracy over existing methods. Group-averaged strand-specific sequencing coverage plots enable clear visualization of group differences in alternative splicing, using a new file format with demonstrable performance improvements over the current BigWig standard. ompBAM, a C++ library upon which SpliceWiz is built, automates multi-threaded alignment file processing for R package developers. SpliceWiz is a powerful platform for diverse users to explore alternative splicing in large datasets.
Learning efficient representations of environmental priors in working memory
Authors: Eissa Tahra L , Kilpatrick Zachary P
Published: July 2022

Experience shapes our expectations and helps us learn the structure of the environment. Inference models render such learning as a gradual refinement of the observer’s estimate of the environmental prior. For instance, when retaining an estimate of an object’s features in working memory, learned priors may bias the estimate in the direction of common feature values. Humans display such biases when retaining color estimates on short time intervals. We propose that these systematic biases emerge from modulation of synaptic connectivity in a neural circuit based on the experienced stimulus history, shaping the persistent and collective neural activity that encodes the stimulus estimate. Resulting neural activity attractors are aligned to common stimulus values. Using recently published human response data from a delayed-estimation task in which stimuli (colors) were drawn from a heterogeneous distribution that did not necessarily correspond with reported population biases, we confirm that most subjects’ response distributions are better described by experience-dependent learning models than by models with no learned biases. This work suggests that systematic limitations in working memory reflect efficient representations of inferred environmental structure, providing new insights into how humans integrate environmental knowledge into their cognitive strategies.
Microplastic pollution in aquatic environments may facilitate misfeeding by fish
Authors: Yagi Mitsuharu , Ono Yurika , Kawaguchi Toshiya
Published: July 2022

Numerous recent studies have documented ingestion of microplastics (MPs) by many aquatic animals, yet an explanation for misfeeding by fish remains unexplained. Here we tested the hypothesis that biofilm (biofouling) on MP surfaces due to exposure in the aquatic environment facilitates misfeeding in fish. Spherical polystyrene (PS) was cultured for 0 to 22 weeks in a freshwater environment to grow biofilm on the MP. Goldfish were employed in a simple feeding experiment with and without provision of genuine food at ecologically relevant MP concentrations. The absorbance (ABS), which is a proxy for biofilm formation increased exponentially within three weeks of initiation and reached a plateau after approximately five weeks. Although fish did not swallow the MPs, “capture” occurred when food pellets were in the vicinity and significantly increased in probability with exposure time. Duration of capture also increased significantly with increasing exposure. These results suggest that the drift of MPs in aquatic environments may facilitate fish misidentification of MPs as edible prey.
Phage genome cleavage enables resuscitation from Cas13-induced bacterial dormancy
Authors: Williams Madison C , Reker Alexandra E , Margolis Shally R , Liao Jingqiu , Wiedmann Martin , Rojas Enrique R. , Meeske Alexander J
Published: July 2022

CRISPR-Cas systems provide their prokaryotic hosts with sequence-specific immunity to foreign genetic elements, including bacteriophages and plasmids. While most interfere with phage infection though cleavage of viral DNA, type VI CRISPR systems use the RNA-guided nuclease Cas13 to recognize mRNA targets. Upon engaging with target RNA, Cas13 cleaves both phage and host transcripts nonspecifically, leading to a state of cell dormancy that is incompatible with phage propagation. However, whether and how infected cells recover from dormancy is not clear. Here we show that type VI CRISPR systems frequently co-occur with DNA-cleaving restriction modification (RM) systems. Using genetics and microscopy, we show that Cas13 and RM systems synergize in anti-phage defense in the natural type VI CRISPR host Listeria seeligeri. Cleavage of the phage genome by RM removes the source of phage transcripts, enabling cells to recover from Cas13-induced cellular dormancy. We find that Cas13 and RM systems operating simultaneously eliminate phage DNA and neutralize infection more effectively than either defense alone. Thus, cells harboring both defense systems exhibit robust anti-phage immunity and survive infection. Our work therefore reveals that type VI CRISPR immunity is cell-autonomous and non-abortive, if paired with RM or similar DNA-targeting defenses. The ability of an abortive response to be resolved by the actions of another anti-phage defense has implications for the roles of diverse host-directed immune systems in bacteria.
Internal selective attention is delayed by competition between endogenous and exogenous factors
Authors: Ester Edward F. , Nouri Asal
Published: July 2022

External selective attention is mediated by competition between endogenous (goal-driven) and exogenous (stimulus-driven) factors, with the balance of competition determining which stimuli are selected. Occasionally, exogenous factors “win” this competition and drive the selection of task-irrelevant stimuli. Endogenous and exogenous selection mechanisms may also compete to control the selection of internal representations (e.g., those stored in working memory), but how this competition manifests and whether it is resolved in the same way as external attention is unknown. Here, we leveraged the high temporal resolution of human EEG to determine how competition between endogenous and exogenous factors influences the selection of internal representations. Unlike external attention, competition between endogenous and exogenous factors did not prompt the selection of task-irrelevant working memory content. Instead, it simply delayed the endogenous selection of task-relevant working memory content by several hundred milliseconds. Thus, competition between endogenous and exogenous factors influences internal selective attention, but in a different way than external selective attention.
Effects of Face Repetition on Ventral Visual Stream Connectivity using Dynamic Causal Modelling of fMRI data
Authors: Lee Sung-Mu , Tibon Roni , Zeidman Peter , Yadav Pranay S. , Henson Richard
Published: July 2022

Stimulus repetition normally causes reduced neural activity in brain regions that process that stimulus. Some theories claim that this “repetition suppression” reflects local mechanisms such as neuronal fatigue or sharpening within a region, whereas other theories claim that it results from changed connectivity between regions, following changes in synchrony or top-down predictions. In this study, we applied dynamic causal modelling (DCM) on a public fMRI dataset involving repeated presentations of faces and scrambled faces to test whether repetition affected local (self-connections) and/or between-region connectivity in left and right early visual cortex (EVC), occipital face area (OFA) and fusiform face area (FFA). Face “perception” (faces versus scrambled faces) modulated nearly all connections, within and between regions, including direct connections from EVC to FFA, supporting a non-hierarchical view of face processing. Face “recognition” (familiar versus unfamiliar faces) modulated connections between EVC and OFA/FFA, particularly in the left hemisphere. Most importantly, immediate and delayed repetition of stimuli were also best captured by modulations of connections between EVC and OFA/FFA, but not self-connections of OFA/FFA, consistent with synchronization or predictive coding theories.
Knockout of AMD-associated gene POLDIP2 reduces mitochondrial superoxide in human retinal pigment epithelial cells
Authors: Nguyen Tu , Urrutia-Cabrera Daniel , Wang Luozixian , Lees Jarmon G. , Wang Jiang-Hui , Hung Sandy S.C. , Hewitt Alex W. , Edwards Thomas L , Lim Shiang Y. , Luu Chi , Guymer Robyn , Wong Raymond C.B.
Published: July 2022

Genetic and epidemiologic studies have significantly advanced our understanding of the genetic factors contributing to age-related macular degeneration (AMD). In particular, recent expression quantitative trait loci (eQTL) studies have highlighted POLDIP2 as a significant gene that confers risk of developing AMD. However, the role of POLDIP2 in retinal cells such as retinal pigment epithelium (RPE) and how it contributes to AMD pathology are unknown. Here we report the generation of a stable human RPE cell line with POLDIP2 knockout using CRISPR/Cas, providing an in vitro model to investigate the functions of POLDIP2. We conducted functional studies on the POLDIP2 knockout cell line and showed that they retained normal levels of cell proliferation, cell viability, phagocytosis and autophagy. Also, we performed RNA sequencing to profile the transcriptome of POLDIP2 knockout cells. Our results highlighted significant changes in genes involved in immune response, complement activation, oxidative damage and vascular development. We showed that loss of POLDIP2 causes a reduction in mitochondrial superoxide levels, which is consistent with the upregulation of the mitochondrial superoxide dismutase SOD2. In conclusion, this study demonstrates a novel link between POLDIP2 and SOD2, which supports a potential role of POLDIP2 in regulating oxidative stress in AMD pathology.
Large excess capacity of glycolytic enzymes in Saccharomyces cerevisiae under glucose-limited conditions
Authors: Grigaitis Pranas , Teusink Bas
Published: July 2022

In Nature, microbes live in very nutrient-dynamic environments. Rapid scavenging and consumption of newly introduced nutrients therefore offer a way to outcompete competitors. This may explain the observation that many microorganisms, including the budding yeast Saccharomyces cerevisiae, appear to keep “excess” glycolytic proteins at low growth rates, i.e. the maximal capacity of glycolytic enzymes (largely) exceeds the actual flux through the enzymes. However, such a strategy requires investment into preparatory protein expression that may come at the cost of current fitness. Moreover, at low nutrient levels, enzymes cannot operate at high saturation, and overcapacity is poorly defined without taking enzyme kinetics into account.

Here we use computational modeling to suggest that in yeast the overcapacity of the glycolytic enzymes at low specific growth rates is a genuine excess, rather than the optimal enzyme demand dictated by enzyme kinetics. We found that the observed expression of the glycolytic enzymes did match the predicted optimal expression when S. cerevisiae exhibits mixed respiro-fermentative growth, while the expression of tricarboxylic acid cycle enzymes always follows the demand. Moreover, we compared the predicted metabolite concentrations with the experimental measurements and found the best agreement in glucose-excess conditions. We argue that the excess capacity of glycolytic proteins in glucose-scarce conditions is an adaptation of S. cerevisiae to fluctuations of nutrient availability in the environment.
Mobile stamens enhance pollen dispersal by scaring floral visitors away
Authors: Li Deng-Fei , Han Wen-Long , Renner Susanne S. , Huang Shuang-Quan
Published: July 2022

Animal-pollinated plants have to get pollen to a conspecific stigma while protecting it from getting eaten. We provide experimental evidence that touch-sensitive stamens function in (i) enhancing pollen export and (ii) reducing pollen loss to thieves. Stamens of Berberis and Mahonia are inserted between paired nectar glands and when touched by an insect’s tongue rapidly snap forward so that their valvate anthers press pollen on the insect’s tongue or face. We immobilized the stamens in otherwise unmodified flowers and studied pollen transfer in the field and under enclosed conditions. On flowers with immobilized stamens, the commonest bee visitor stayed up to 3.6x longer, yet removed 1.3x fewer pollen grains and deposited 2.1x fewer grains on stigmas per visit. Self-pollen from a single stamen hitting the stigma amounted to 6% of the grains received from single bee visits. Bees discarded pollen passively placed on their bodies, likely because of its berberine content; nectar has no berberine. Syrphid flies fed on both nectar and pollen, taking more when stamens were immobilized. Pollen-tracking experiments in two species showed that mobile-stamen-flowers donate pollen to many more recipients. These results demonstrate another mechanism by which plants simultaneously meter out their pollen and reduce pollen theft.

Highlights

Stamens that snap forward when triggered by a flower visitor may serve to meter out pollen, scare away pollen thieves, or place pollen more accurately.

We tested these hypotheses by experimentally immobilizing all six stamens in numerous flowers of Berberis and Mahonia species in the field and under enclosed conditions.

In flowers with immobilized stamens, the commonest bee species stayed up to 3.6x longer, yet removed 1.3x fewer pollen grains and deposited 2.1x fewer grains on stigmas per visit. Mobile stamens exported their pollen to significantly more neighboring flowers.

Graphic abstract

Behaviour and pollen transfer after flower visitors received a beating on the tongue or in the face by the forward-snapping stamens of Berberis. Stamens only snap forward if their filament basis is touched by an insect tongue.
Solanum lycopersicum CLASS-II KNOXgenes regulate fruit anatomy via gibberellin-dependent and independent pathways
Authors: Shtern Amit , Keren-Keiserman Alexandra , Mauxion Jean-Philippe , Furumizu Chihiro , Alvarez John Paul , Amsellem Ziva , Gil Naama , Motenko Etel , Alkalai-Tuvia Sharon , Fallik Elazar , Gonzalez Nathalie , Goldshmidt Alexander
Published: July 2022

The pericarp is the predominant tissue determining the structural characteristics of most fruits. However, the molecular and genetic mechanisms controlling pericarp development remain only partially understood. Previous studies have identified that CLASS-II KNOX genes regulate fruit size, shape, and maturation inArabidopsis thalianaandSolanum lycopersicum. Here we characterized the roles of theSolanum lycopersicumCLASS-II KNOX (TKN-II) genes in pericarp development via a detailed histological, anatomical, and karyotype analysis of theTKN-IIknockdown (35S:amiR-TKN-II) fruits. We identify that35S:amiR-TKN-IIpericarps contain more cells around their equatorial perimeter and fewer cell layers than the control. In addition, the cell sizes but not the ploidy levels of these pericarps were dramatically reduced.

Further, we demonstrate that fruit shape and pericarp layer number phenotypes of the35S:amiR-TKN-IIfruits can be overridden by theproceramutant, known to induce a constitutive response to the plant hormone gibberellin. However, neither theproceramutation nor exogenous gibberellin application can fully rescue the reduced pericarp width and cell size phenotype of35S:amiR-TKN-IIpericarps. Our findings establish that TKN-II genes regulate tomato fruit anatomy, acting via gibberellin to control fruit shape but utilizing a gibberellin-independent pathway to control the size of pericarp cells.

Highlight

TomatoCLASS-II KNOXgenes regulate fruit and pericarp anatomy via GA-dependent and independent pathways.
Trans-species microRNA loci in the parasitic plant Cuscuta campestris have a U6-like snRNA promoter
Authors: Hudzik Collin , Maguire Sean , Guan Shengxi , Held Jeremy , Axtell Michael J.
Published: July 2022

Small regulatory RNAs can move between organisms during pathogenic interactions and regulate gene expression in the recipient. If and how such “trans-species” small RNAs are distinguished from normal small RNAs is not known. The parasitic plant Cuscuta campestris produces a number of microRNAs that specifically accumulate at the interface between parasite and host, several of which have been demonstrated to have trans-species activity. We find that induction of C. campestris interface-induced microRNAs was similar regardless of host species, and can be replicated in haustoria stimulated to develop in the complete absence of a host. We also find that the loci encoding C. campestris interface-induced microRNAs are distinguished by a common 10 base-pair cis-regulatory element. This element is identical to a previously described upstream sequence element used by all plant small nuclear RNA loci. The sequence context of this element strongly suggests U6-like transcription by RNA polymerase III. The element promotes accumulation of interface-induced miRNAs in a heterologous system. This common promoter element distinguishes C. campestris interface-induced microRNA loci from other plant small RNAs; other plant small RNA loci are transcribed by polymerases II or IV, and lack any common promoter motifs. Our data suggest that C. campestris interface-induced miRNAs are produced in a manner distinct from canonical miRNAs. All confirmed C. campestris microRNAs with confirmed trans-species activity are interface-induced and possess these features. We speculate that this distinct production may allow these miRNAs to be exported to hosts.
Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor
Authors: Li Jie , Wu Jiayi , Bai Xiao-chen , Choi Eunhee
Published: July 2022

The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the Γ-shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a T-shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the T-shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation.