bluuebunny/crossref_metadata_2025 huggingface dataset:
Nucks1 gene polymorphism rs823114 is associated with the positive symptoms and neurocognitive function of patients with schizophrenia in parts of southern China
Authors: Wen Xia , Xu Xusan , Luo Xudong , Yin Jinwen , Liang Chunmei , Zhu Jinyuan , Nong Xueyan , Zhu Xiudeng , Ning Fan , Gu Shanshan , Xiong Susu , Fu Jiawu , Zhu Dongjian , Dai Zhun , Lv Dong , Lin Zhixiong , Lin Juda , Li You , Ma Guoda , Wang Yajun
Published: May 2021

Nuclear casein kinase and cyclin-dependent kinase substrate 1 (nucks1) are considered a potential susceptibility gene for certain neurological diseases, such as Parkinson’s disease (PD). In our study, we genotyped three single nucleotide polymorphisms (SNPs) (rs4951261, rs823114 and rs951366) of the nucks1 gene in 774 schizophrenic patients and 819 healthy controls using the improved multiplex ligation detection reaction (imLDR) technique. Furthermore, we also studied the relationship between the above SNPs and the clinical psychiatric symptoms and neurocognitive function of the patients. Genotype distributions and allele frequencies of these SNPs showed no significant differences and were found between patients and healthy controls. However, in an analysis of the positive symptom score of rs823114 among male patients, we found that the score of the A/A genotype was lower than that of the G/A+G/G genotypes (P = 0.001, P(corr) = 0.003]. Additionally, we also found that among the female patients, G allele carriers with rs823114 had lower semantic fluency scores than subjects with the A/A genotype (P = 0.010, P(corr) = 0.030]. Our data show for the first time that rs823114 polymorphism of nucks1 may affect positive symptoms and neurocognitive function in patients with schizophrenia in parts of southern China.
Origami and materials science
Authors: Liu H. , Plucinsky P. , Feng F. , James R. D.
Published: May 2021

Origami, the ancient art of folding thin sheets, has attracted increasing attention for its practical value in diverse fields: architectural design, therapeutics, deployable space structures, medical stent design, antenna design and robotics. In this survey article, we highlight its suggestive value for the design of materials. At continuum level, the rules for constructing origami have direct analogues in the analysis of the microstructure of materials. At atomistic level, the structure of crystals, nanostructures, viruses and quasi-crystals all link to simplified methods of constructing origami. Underlying these linkages are basic physical scaling laws, the role of isometries, and the simplifying role of group theory. Non-discrete isometry groups suggest an unexpected framework for the design of novel materials.

This article is part of the theme issue ‘Topics in mathematical design of complex materials’.
Nutations in growing plant shoots as a morphoelastic flutter instability
Authors: Agostinelli D. , Noselli G. , DeSimone A.
Published: May 2021

Growing plant shoots exhibit spontaneous oscillations that Darwin observed, and termed ‘circumnutations’. Recently, they have received renewed attention for the design and optimal actuation of bioinspired robotic devices. We discuss a possible interpretation of these spontaneous oscillations as a Hopf-type bifurcation in a growing morphoelastic rod. Using a three-dimensional model and numerical simulations, we analyse the salient features of this flutter-like phenomenon (e.g. the characteristic period of the oscillations) and their dependence on the model details (in particular, the impact of choosing different growth models) finding that, overall, these features are robust with respect to changes in the details of the growth model adopted.

This article is part of the theme issue ‘Topics in mathematical design of complex materials’.
Genome analysis reveals that the correct name of type strain Adlercreutzia caecicola DSM 22242T is Parvibacter caecicola Clavel et al. 2013
Authors: Stoll Dominic A. , Danylec Nicolas , Grimmler Christina , Kulling Sabine E. , Huch Melanie
Published: May 2021

The strain

Adlercreutzia caecicola

DSM 22242T (=CCUG 57646T=NR06T) was taxonomically described in 2013 and named as

Parvibacter caecicola

Clavel et al. 2013. In 2018, the name of the strain DSM 22242T was changed to

Adlercreutzia caecicola

(Clavel et al. 2013) Nouioui et al. 2018 due to taxonomic investigations of the closely related genera Adlercreutzia, Asaccharobacter and

Enterorhabdus

within the phylum

Actinobacteria

. However, the first whole draft genome of strain DSM 22242T was published by our group in 2019. Therefore, the genome was not available within the study of Nouioui et al. (2018). The results of the polyphasic approach within this study, including phenotypic and biochemical analyses and genome-based taxonomic investigations [genome-wide average nucleotide identity (gANI), alignment fraction (AF), average amino acid identity (AAI), percentage of orthologous conserved proteins (POCP) and genome blast distance phylogeny (GBDP) tree], indicated that the proposed change of the name

Parvibacter caecicola

to

Adlercreutzia caecicola

was not correct. Therefore, it is proposed that the correct name of

Adlercreutzia caecicola

(Clavel et al. 2013) Nouioui et al. 2018 strain DSM 22242T is

Parvibacter caecicola

Clavel et al. 2013.
Attitudes Toward The COVID-19 Vaccine Among North Carolina Participants In The COVID-19 Community Research Partnership
Authors: Enwezor Chukwunyelu H , Peacock James E. , Edelstein Sharon L , Hinkelman Amy N , Seals Austin L , Wierzba Thomas F , Munawar Iqra , Maguire Patrick D , Lagarde William H , Runyon Michael S , Gibbs Michael A , Gallaher Thomas R , Sanders John W. , Herrington David M.
Published: May 2021

Willingness to receive the newly developed Coronavirus Disease-2019 (COVID-19) vaccines is highly variable. To assess the receptiveness of a select sample of North Carolinians to COVID-19 vaccination, a brief survey was conducted among participants in the COVID-19 Community Research Partnership (CCRP) affiliated with five medical centers in North Carolina. A total of 20,232 CCRP participants completed a multiple choice, mini survey electronically between December 17, 2020 and January 13, 2021. Of the 20,232 survey respondents, 15,422 (76.2%) were receptive to vaccination. Vaccine receptiveness increased incrementally with age with those >70 years being the most willing to be vaccinated compared to all other age groups. Respondents with no previous COVID-19 diagnosis were more likely to accept the vaccine compared to those that have a previous COVID-19 diagnosis (76.6% vs 60.9%). Comparative analysis of gender, race/ethnicity, and residence locale revealed that women, African Americans, and suburban participants were less willing to get a COVID-19 vaccine. There was no difference in vaccine intent based on healthcare worker status. Of those unwilling to get the vaccine, 82% indicated that the reason was uncertainty about the safety and efficacy of the vaccine.
COVID-19 Fatality Rate Classification using Synthetic Minority Oversampling Technique (SMOTE) for Imbalance Class
Authors: Oladunni Timothy , Stephan Justin , Coulibaly Lala Aicha
Published: May 2021

SARS-Cov-2 is not to be introduced anymore. The global pandemic that originated more than a year ago in Wuhan, China has claimed thousands of lives. Since the arrival of this plague, face mask has become part of our dressing code. The focus of this study is to design, develop and evaluate a COVID-19 fatality rate classifier at the county level. The proposed model predicts fatality rate as low, moderate, or high. This will help government and decision makers to improve mitigation strategy and provide measures to reduce the spread of the disease. Tourists and travelers will also find the work useful in planning of trips. Dataset used in the experiment contained imbalanced fatality levels. Therefore, class imbalance was offset using SMOTE. Evaluation of the proposed model was based on precision, F1 score, accuracy, and ROC curve. Five learning algorithms were trained and evaluated. Experimental results showed the Bagging model has the best performance.
A facile immunopeptidomics workflow for capturing the HLA-I ligandome with PEAKS XPro
Authors: Hoffman Kyle S. , Shan Baozhen , Krieger Jonathan R.
Published: May 2021

Identifying antigens displayed specifically on tumour cell surfaces by human leukocyte antigen (HLA) proteins is important for the development of immunotherapies and cancer vaccines. The difficulty in capturing an HLA ligandome stems from the fact that many HLA ligands are derived from splicing events or contain mutations, hindering their identification in a standard database search. To address this challenge, we developed an immunopeptidomics workflow with PEAKS XPro that uses de novo sequencing to uncover such peptides and identifies mutations for neoantigen discovery. We demonstrate the utility of this workflow by re-analyzing HLA-I ligandome datasets and reveal a vast diversity in peptide sequences among clones derived from a colorectal cancer tumour. Over 8000 peptides predicted to bind HLA-I molecules were identified by de novo sequencing only (not found in the UniProt database) and make up over 50% of identified peptides from each sample. Lastly, tumour-specific mutations and consensus sequence motif characteristics are defined. This workflow is widely applicable to any immunopeptidomic mass spectrometry dataset and does not require custom database generation for neoantigen discovery.
Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations
Authors: Schwarz Niklas , Seiffert Simone , Pendziwiat Manuela , Rademacher Annika , Brünger Tobias , Hedrich Ulrike B.S. , Augustijn Paul B , Baier Hartmut , Bayat Allan , Bisulli Francesca , Buono Russell J , Bruria Ben Zeev , Doyle Michael G , Guerrini Renzo , Heimer Gali , Iacomino Michele , Kearney Hugh , Klein Karl Martin , Kousiappa Ioanna , Kunz Wolfram S. , Lerche Holger , Licchetta Laura , Lohmann Ebba , Minardi Raffaella , McDonald Marie , Montgomery Sarah , Mulahasanovic Lejla , Oegema Renske , Ortal Barel , Papacostas Savvas S. , Ragona Francesca , Granata Tiziana , Reif Philipp S. , Rosenow Felix , Rothschild Annick , Scudieri Paolo , Striano Pasquale , Tinuper Paolo , Tanteles George A. , Vetro Annalisa , Zahnert Felix , Zara Federico , Lal Dennis , May Patrick , Muhle Hiltrud , Helbig Ingo , Weber Yvonne
Published: May 2021

Background

KCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain.

Methods

Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes.

Results

We identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid.

Conclusion

These findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.
T-cell and antibody immunity after COVID-19 mRNA vaccines in healthy and immunocompromised subjects-An exploratory study
Authors: Sindhi Rakesh , Ashokkumar Chethan , Spishock Brianna , Saunders Maggie , Mabasa Angelo , Sethi Pradeep , Reddy Ashok , Nibhanupudy Bobby
Published: May 2021

Background

In recent studies, up to half of immunocompromised (IC) subject populations fail to develop antibodies after COVID-19 vaccination.

Purpose and Methods

Here, we explore whether T-cells which respond to the spike (S) antigenic sequence and its less conserved S1, and the conserved S2 component are present in serial samples before and after each dose of mRNA1273 or BNT162b2 vaccines in 20 healthy immunocompetent subjects. Single samples from 7 vaccinated IC subjects were also tested. Simultaneously, we measured IgG antibodies to the receptor binding domain (RBD) of S1, and anti-S IgG, and frequencies of monocytic CD14+HLA-DR-(M-MDSC) and polymorphonuclear CD14-CD15+CD11b+ (PMN-MDSC) myeloid-derived suppressor cells.

Results

In healthy subjects, S1-, S2-, and S-reactive CD4 and CD8 T-cell frequencies showed a numeric but not statistically significant decrease after the first vaccine dose and were accompanied by increased MDSC frequencies (p<0.05). After the second dose, S2-and S-reactive CD4 and CD8 cells and MDSC approached pre-vaccination levels. In healthy subjects, a) S1-reactive CD8 frequencies were significantly higher after the second dose compared with pre-vaccination levels (p=0.015), b) anti-RBD and anti-S IgG were present in all after the second dose. Among seven IC subjects, anti-RBD and anti-S IgG were absent in 4 and 3 subjects, respectively. S1-reactive CD8 cells were identified in 2 of 4 anti-RBD negative subjects. S-reactive CD4 or CD8 cells were identified in all three anti-S negative subjects.

Conclusions

In healthy immunocompetent subjects, mRNA vaccines induce antibodies to the spike antigenic sequences and augment CD8 cells reactive to the S1 spike sequence, which is more specific for the SARS-CoV-2 virus. In this exploratory cohort of vaccinated immunocompromised subjects, S1-reactive CD8 cells can be detected in some who are negative for RBD antibody, and S-reactive T-cells are present in all who are negative for spike antibody.
Persistent clotting protein pathology in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin
Authors: Pretorius Etheresia , Vlok Mare , Venter Chantelle , Bezuidenhout Johannes A. , Laubscher Gert Jacobus , Steenkamp Janami , Kell Douglas B.
Published: May 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by acute clinical pathologies, including various coagulopathies that may be accompanied by hypercoagulation and platelet hyperactivation. Recently, a new COVID-19 phenotype has been noted in patients after they have ostensibly recovered from acute COVID-19 symptoms. This new syndrome is commonly termed Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Here we refer to it as Long COVID/PASC. Lingering symptoms persist for as much as 6 months (or longer) after acute infection, where COVID-19 survivors complain of recurring fatigue or muscle weakness, being out of breath, sleep difficulties, and anxiety or depression. Given that blood clots can block microcapillaries and thereby inhibit oxygen exchange, we here investigate if the lingering symptoms that individuals with Long COVID/PASC manifest might be due to the presence of persistent circulating plasma clots that are resistant to fibrinolysis. We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms. We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits. We also show that these anomalous deposits in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits. Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might therefore benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.
BODY MASS INDEX TRAJECTORY BEFORE DEATH IN COMMUNITY-DWELLING OLDER ADULTS. POPULATION-BASED COHORT STUDY
Authors: Pai Hari V , Gulliford Martin C
Published: May 2021

Background and objective

Both low and high body mass index (BMI) have been associated with greater mortality in older adults. This study evaluated the trajectory of BMI in the final years of life.

Design

Population-based cohort study.

Setting

Community-dwelling adults in the English Longitudinal Study of Ageing between 1998 and 2012.

Measurements

Body mass index, years before death and all-cause mortality. Analyses were adjusted for age, gender, educational level, housing tenure and social class.

Results

Data were analysed for 16,924 participants with 31,857 BMI records; mean age at study start, 61.6 (SD 10.9) years; mean BMI, 27.5 (4.7) Kg/m2. There were 3,686 participants (4,794 BMI records) who died and 13,238 participants (27,063 BMI records) who were alive at last follow-up. Mean BMI increased with age to 60-69 years but then declined, but the age-related decline was more rapid in decedents. At ages 80-89 years, mean BMI in decedents was 26.1 (4.7) compared with 27.1 (4.4) Kg/m2 in survivors. After adjusting for age and covariates, mean BMI declined in the five years before death. From 9 to 5 years before death or end of study, adjusted mean BMI was 0.51 (95% confidence interval 0.24 to 0.78) Kg/m2 lower for decedents than survivors; and from four to zero years before death, 1.55 (1.26 to 1.84) Kg/m2 lower in decedents.

Conclusions

In community-dwelling older adults, mean body mass index enters an accelerating decline during five years before death. Reverse causation may account for the association of lower BMI with mortality.
Perceptions of and obstacles to SARS-CoV-2 vaccination among adults in Lebanon: a cross-sectional online survey
Authors: Abou-Arraj Nadeem E. , Maddah Diana , Buhamdan Vanessa , Abbas Roua , Jawad Nadine , Karaki Fatima , Alami Nael H. , Geldsetzer Pascal
Published: May 2021

The COVID-19 pandemic is an additional burden on Lebanon’s stressed population, fragmented healthcare system, and political, economic, and refugee crises. Understanding the population’s intentions to vaccinate, and perceptions of and obstacles to SARS-CoV-2 vaccination, can inform Lebanon’s vaccination efforts. We performed a cross-sectional study from 29 Jan 2021 to 11 Mar 2021 using an online questionnaire in Arabic via convenience “snowball” sampling to assess the perceptions of adults residing in Lebanon. 1,185 adults participated in the survey. % [95% CI: 43.2%-49.0%] of survey participants intended to take the SARS-CoV-2 vaccine when available to them, 19.0% [16.8%-21.4%] indicated that they would not, and 34.0% [31.3%-36.8%] were unsure. The most common reasons for hesitancy were concerns about safety, limited testing, side effects, and efficacy. Vaccine hesitancy appears to be high in Lebanon. Disseminating clear, consistent, evidence-based safety and efficacy information on vaccines may help reduce vaccine hesitancy, especially among the large proportion of adults who appear to be unsure about (rather than opposed to) vaccination.
Multi-omics analysis reveals the impact of microbiota on host metabolism in hepatic steatosis
Authors: Zeybel Mujdat , Arif Muhammad , Li Xiangyu , Altay Ozlem , Shi Mengnan , Akyildiz Murat , Saglam Burcin , Gonenli Mehmet Gokhan , Yigit Buket , Ulukan Burge , Ural Dilek , Shoaie Saeed , Turkez Hasan , Nielsen Jens , Zhang Cheng , Uhlén Mathias , Borén Jan , Mardinoglu Adil
Published: May 2021

Non-alcoholic fatty liver disease (NAFLD) is a complex disease involving alterations in multiple biological processes regulated by the interactions between obesity, genetic background and environmental factors including the microbiome. To decipher hepatic steatosis (HS) pathogenesis by excluding critical confounding factors including genetic variants, obesity and diabetes, we characterized 56 heterogeneous NAFLD patients by generating multi-omics data including oral and gut metagenomics as well as plasma metabolomics and inflammatory proteomics data. We explored the dysbiosis in the oral and gut microbiome and revealed host-microbiome interactions based on global metabolic and inflammatory processes. We integrated this multi-omics data using the biological network and identified HS’s key features using multi-omics data. We finally predicted HS using these key features and validated our findings in a validation dataset, where we characterized 22 subjects with varying degree of HS.

Significance statement

The oral and gut microbiota alterations have been linked to NAFLD. There is a lack of data on multi-omics characteristics of hepatic steatosis by exclusion of major confounding factors of obesity and metabolic syndrome. We observed that the oral and gut microbiota remodelling starts at early stages of the NAFLD spectrum, independent of obesity and metabolic syndrome. Our analysis suggested that the bacterial diversity is correlated with multi-omics signatures in NAFLD and our predictive model created based on multi-omics variables can successfully predict hepatic steatosis. The components of the multi-omics signatures may serve as biomarkers and can be pharmaceutically targeted. Future clinical trials with microbiota manipulation could consider intervention at early stages of NAFLD.
Effectiveness of COVID-19 vaccines against the B.1.617.2 variant
Authors: Bernal Jamie Lopez , Andrews Nick , Gower Charlotte , Gallagher Eileen , Simmons Ruth , Thelwall Simon , Stowe Julia , Tessier Elise , Groves Natalie , Dabrera Gavin , Myers Richard , Campbell Colin , Amirthalingam Gayatri , Edmunds Matt , Zambon Maria , Brown Kevin , Hopkins Susan , Chand Meera , Ramsay Mary
Published: May 2021

Background

The B.1.617.2 COVID-19 variant has contributed to the surge in cases in India and has now been detected across the globe, including a notable increase in cases in the UK. We estimate the effectiveness of the BNT162b2 and ChAdOx1 COVID-19 vaccines against this variant.

Methods

A test negative case control design was used to estimate the effectiveness of vaccination against symptomatic disease with both variants over the period that B.1.617.2 began circulating with cases identified based on sequencing and S-gene target status. Data on all symptomatic sequenced cases of COVID-19 in England was used to estimate the proportion of cases with B.1.617.2 compared to the predominant strain (B.1.1.7) by vaccination status.

Results

Effectiveness was notably lower after 1 dose of vaccine with B.1.617.2 cases 33.5% (95%CI: 20.6 to 44.3) compared to B.1.1.7 cases 51.1% (95%CI: 47.3 to 54.7) with similar results for both vaccines. With BNT162b2 2 dose effectiveness reduced from 93.4% (95%CI: 90.4 to 95.5) with B.1.1.7 to 87.9% (95%CI: 78.2 to 93.2) with B.1.617.2. With ChAdOx1 2 dose effectiveness reduced from 66.1% (95% CI: 54.0 to 75.0) with B.1.1.7 to 59.8% (95%CI: 28.9 to 77.3) with B.1.617.2. Sequenced cases detected after 1 or 2 doses of vaccination had a higher odds of infection with B.1.617.2 compared to unvaccinated cases (OR 1.40; 95%CI: 1.13-1.75).

Conclusions

After 2 doses of either vaccine there were only modest differences in vaccine effectiveness with the B.1.617.2 variant. Absolute differences in vaccine effectiveness were more marked with dose 1. This would support maximising vaccine uptake with two doses among vulnerable groups.
Computing Minimal Boolean Models of Gene Regulatory Networks
Authors: Karlebach Guy , Robinson Peter N
Published: May 2021

Models of Gene Regulatory Networks (GRNs) capture the dynamics of the regulatory processes that occur within the cell as a means to understand the variability observed in gene expression between different conditions. Arguably the simplest mathematical construct used for modeling is the Boolean network, which dictates a set of logical rules for transition between states described as Boolean vectors. Due to the complexity of gene regulation and the limitations of experimental technologies, in most cases knowledge about regulatory interactions and Boolean states is partial. In addition, the logical rules themselves are not known a-priori. Our goal in this work is to create an algorithm that finds the network that fits the data optimally, and identify the network states that correspond to the noise-free data. We present a novel methodology for integrating experimental data and performing a search for the optimal consistent structure via optimization of a linear objective function under a set of linear constraints. In addition, we extend our methodology into a heuristic that alleviates the computational complexity of the problem for datasets that are generated by single-cell RNA-Sequencing(scRNA-Seq). We demonstrate the effectiveness of these tools using a public scRNA-Seq dataset and the GRN that is associated with it. Our methodology will enable researchers to obtain a better understanding of the dynamics of gene regulatory networks and their biological role.
Differential ADAR editing landscapes in major depressive disorder and suicide
Authors: Plonski Noel-Marie , Meindl Richard , Piontkivska Helen
Published: May 2021

Neuropsychiatric disorders, including depression and suicide, are becoming an increasing public health concern. Rising rates of both depression and suicide, exacerbated by the current COVID19 pandemic, have only hastened our need for objective and reliable diagnostic biomarkers. These can aide clinicians treating depressive disorders in both diagnosing and developing treatment plans. While differential gene expression analysis has highlighted the serotonin signaling cascade among other critical neurotransmitter pathways to underly the pathology of depression and suicide, the biological mechanisms remain elusive. Here we propose a novel approach to better understand molecular underpinnings of neuropsychiatric disorders by examining patterns of differential RNA editing by adenosine deaminases acting on RNA (ADARs). We take advantage of publicly available RNA-seq datasets to map ADAR editing landscapes in a global gene-centric view. We use a unique combination of Guttman scaling and random forest classification modeling to create, describe and compare ADAR editing profiles focusing on both spatial and biological sex differences. We use a subset of experimentally confirmed ADAR editing sites located in known protein coding regions, the excitome, to map ADAR editing profiles in Major Depressive Disorder (MDD) and suicide. Using Guttman scaling, we were able to describe significant changes in editing profiles across brain regions in males and females with respect to cause of death (COD) and MDD diagnosis. The spatial distribution of editing sites may provide insight into biological mechanisms under-pinning clinical symptoms associated with MDD and suicidal behavior. Additionally, we use random forest modeling including these differential profiles among other markers of global editing patterns in order to highlight potential biomarkers that offer insights into molecular changes underlying synaptic plasticity. Together, these models identify potential prognostic, diagnostic and therapeutic biomarkers for MDD diagnosis and/or suicide.
DIRECT DETECTION OF LISTERIA MONOCYTOGENES BY RECOMBINASE POLYMERASE AMPLIFICATION
Authors: Tran Hau Thi , Tran Diem Hong , Pham Trang Nguyen Minh , Phung Huong Thi Thu
Published: May 2021

Listeria monocytogenes is one of the most common types of food poisoning bacteria which can cause serious foodborne diseases or even lethality. Generally, L. monocytogenes can be detected using traditional microbiology or molecular biology techniques, notably PCR. However, the application of these methods at the field is restricted due to the strict requirement of equipment and skilled personnel. In this study, recombinase polymerase amplification (RPA), an isothermal PCR assay was developed to rapidly detect L. monocytogenes in the crude samples. The results showed that the RPA reaction, without requiring complex thermal cycles, was well-performed in the optimal conditions of 39°C within only 25 minutes. The limit of detection was identified as 310 fg of L. monocytogenes genomic DNA, which was 1000-fold more sensitive than the conventional PCR. In addition, RPA also succeeded to directly detect L. monocytogenes cells at a concentration as low as 2.5 × 101 Colony Forming Unit (CFU)/ml in pure cultures and 2.5 × 102 CFU/ml in crude samples without sample extraction or processing. Therefore, RPA established in this study could be an alternative standard method to confirm the presence of L. monocytogenes in food. Accordingly, this rapid and sensitive method could be further applied to clinical testing for the diagnosis of L. monocytogenes infection, especially in areas with limited settings.
TRIM25 and ZAP target the Ebola virus ribonucleoprotein complex to mediate interferon-induced restriction
Authors: Galão Rui Pedro , Wilson Harry , Schierhorn Kristina L , Debeljak Franka , Bodmer Bianca S , Goldhill Daniel , Hoenen Thomas , Wilson Sam J , Swanson Chad M , Neil Stuart J D
Published: May 2021

Ebola virus (EBOV) causes highly pathogenic disease in primates. Through screening a library of human interferon-stimulated genes (ISGs), we identified TRIM25 as a potent inhibitor of EBOV transcription-and-replication-competent virus-like particle (trVLP) propagation. TRIM25 overexpression inhibited the accumulation of viral genomic and messenger RNAs independently of the RNA sensor RIG-I or secondary proinflammatory gene expression. Deletion of TRIM25 strongly attenuated the sensitivity of trVLPs to inhibition by type-I interferon. The antiviral activity of TRIM25 required ZAP and the effect of type-I interferon was modulated by the CpG dinucleotide content of the viral genome. We find that TRIM25 interacts with the EBOV vRNP, resulting in its autoubiquitination and ubiquitination of the viral nucleoprotein (NP). TRIM25 is recruited to incoming vRNPs shortly after cell entry, and leads to dissociation of NP from the vRNA. We propose that TRIM25 targets the EBOV vRNP, exposing CpG-rich viral RNA species to restriction by ZAP.

Highlights

TRIM25 and ZAP play a major role on type I IFN-mediated inhibition of EBOV trVLP replication

TRIM25 interacts with the EBOV NP and is recruited to vRNPs in the cytoplasm after viral entry

TRIM25 ubiquitinates NP and displaces it from the viral genome, facilitating ZAP interaction

ZAP targets CpGs in the EBOV genome to inhibit EBOV trVLP replication
RNase E endonuclease activity and its inhibition by pseudoridine
Authors: Islam Md. Saiful , Bandyra Katarzyna J. , Chao Yanjie , Vogel Jörg , Luisi Ben F.
Published: May 2021

The conserved endoribonuclease RNase E dominates the dynamic landscape of RNA metabolism and underpins control mediated by small regulatory RNAs in diverse bacterial species. We explored the enzyme’s hydrolytic mechanism, allosteric activation, and interplay with partner proteins in the multi-component RNA degradosome assembly. RNase E cleaves single-stranded RNA with preference to attack the phosphate located at the 5□ nucleotide preceding uracil, and we corroborate key interactions that select that base. Unexpectedly, RNase E activity is impeded strongly when the recognised uracil is isomerised to 5-ribosyluracil (pseudouridine), from which we infer the detailed geometry of the hydrolytic attack process. Kinetics analyses support models for recognition of secondary structure in substrates by RNase E and for allosteric auto-regulation. The catalytic power of the enzyme is boosted when it is assembled into the multi-enzyme RNA degradosome, most likely as a consequence of substrate channeling. Our results rationalize the origins of substrate preferences of RNase E and illuminate its catalytic mechanism, supporting the roles of allosteric domain closure and cooperation with other components of the RNA degradosome complex.
Visuomotor association orthogonalizes visual cortical population codes
Authors: Failor Samuel W. , Carandini Matteo , Harris Kenneth D.
Published: May 2021

Training in behavioral tasks can alter visual cortical stimulus coding, but the precise form of this plasticity is unclear. We measured orientation tuning in 4,000-neuron populations of mouse V1 before and after training on a visuomotor task. Changes to single-cell tuning curves were apparently complex, including appearance of asymmetric and multi-peaked tuning curves. Nevertheless, these changes reflected a simple mathematical transformation of population activity, suppressing responses to motor-associated stimuli specifically in cells responding at intermediate levels. The strength of the transformation varied across trials, suggesting a dynamic circuit mechanism rather than static synaptic plasticity. This transformation resulted in sparsening and orthogonalization of population codes for motor-associated stimuli. Training did not improve the performance of an optimal stimulus decoder, which was already perfect even for naïve codes, but the resulting orthogonalization improved the performance of a suboptimal decoder model with inductive bias as might be found in downstream readout circuits.
Hidden multivalency in phosphatase recruitment by a disordered AKAP scaffold
Authors: Watson Matthew , Almeida Teresa B. , Ray Arundhati , Hanack Christina , Elston Rory , Btesh Joan , McNaughton Peter A. , Stott Katherine
Published: May 2021

Disordered scaffold proteins provide multivalent landing pads that, via a series of embedded Short Linear Motifs (SLiMs), bring together the components of a complex to orchestrate precise spatial and temporal regulation of cellular processes. One such protein is AKAP5, which contains SLiMs that anchor PKA and Calcineurin, and recruit substrate (the TRPV1 receptor). Calcineurin is anchored to AKAP5 by a well-characterised PxIxIT SLiM. Here we show, using a combination of biochemical and biophysical approaches, that the Calcineurin PxIxIT-binding groove also recognises several hitherto unknown lower-affinity SLiMs in addition to the PxIxIT motif. We demonstrate that the assembly is in reality a complex system with conserved SLiMs spanning a wide affinity range. The capture is analogous to that seen for many DNA-binding proteins that have a weak non-specific affinity for DNA outside the canonical binding site, but different in that it involves (i) two proteins, and (ii) hydrophobic rather than electrostatic interactions. It is also compatible with the requirement for both stable anchoring of the enzyme and responsive downstream signalling. We conclude that the AKAP5 C-terminus is enriched in lower-affinity/mini-SLiMs that, together with the canonical SLiM, maintain a structurally disordered but tightly regulated signalosome.
Profiling the baseline performance and limits of machine learning models for adaptive immune receptor repertoire classification
Authors: Kanduri Chakravarthi , Pavlović Milena , Scheffer Lonneke , Motwani Keshav , Chernigovskaya Maria , Greiff Victor , Sandve Geir K.
Published: May 2021

Background

Machine learning (ML) methodology development for classification of immune states in adaptive immune receptor repertoires (AIRR) has seen a recent surge of interest. However, so far, there does not exist a systematic evaluation of scenarios where classical ML methods (such as penalized logistic regression) already perform adequately for AIRR classification. This hinders investigative reorientation to those scenarios where further method development of more sophisticated ML approaches may be required.

Results

To identify those scenarios where a baseline method is able to perform well for AIRR classification, we generated a collection of synthetic benchmark datasets encompassing a wide range of dataset architecture-associated and immune state-associated sequence pattern (signal) complexity. We trained ≈1300 ML models with varying assumptions regarding immune signal on≈850 datasets with a total of ≈210’000 repertoires containing ≈42 billion TCRβ CDR3 amino acid sequences, thereby surpassing the sample sizes of current state-of-the-art AIRR ML setups by two orders of magnitude. We found that L1-penalized logistic regression achieved high prediction accuracy even when the immune signal occurs only in 1 out of 50’000 AIR sequences.

Conclusions

We provide a reference benchmark to guide new AIRR ML classification methodology by: (i) identifying those scenarios characterised by immune signal and dataset complexity, where baseline methods already achieve high prediction accuracy and (ii) facilitating realistic expectations of the performance of AIRR ML models given training dataset properties and assumptions. Our study serves as a template for defining specialized AIRR benchmark datasets for comprehensive benchmarking of AIRR ML methods.
Microbial community structure in rice, crops, and pastures rotation systems with different intensification levels in the temperate region of Uruguay
Authors: Martínez Sebastián
Published: May 2021

Rice is an important crop in Uruguay associated mostly with livestock production in a rice and pasture rotation system since the 1920s. However, in recent years there has been interest in intensifying the production in some of these systems to satisfy market demands and increase income. Intensification occurs by augmenting the rice frequency in the rotation, including new crops like sorghum and soybean, or shortening the pasture phase. A long-term experiment was established in 2012 in the main rice producing area of Uruguay with the objective to study the impact of intensification in rice rotations. After the first cycle of rotation soils from seven rotation phases were sampled and microbial communities were studied by means of high-throughput sequencing of Illumina NovaSeq 6000. Archaeal/bacterial and fungal community composition were studied (16S rRNA and 18S gene regions) detecting 3662 and 807 bacterial and fungal Operational Taxonomic Units (OTUs), respectively.Actinobacteria,FirmicutesandProteobacteriawere the most common bacterial phyla. Among them, onlyProteobacteriadiffered significantly between rotations. Although most fungal OTUs were unidentified,Ascomycota,BasidiomycotaandMucoromycotawere the most abundant fungal classes within identified taxa. Bacterial communities differed between rotations forming three groups according to the percentage of rice in the system. Fungal communities clustered in four groups, although not well differentiated, and mostly associated with the antecessor crop. Only P and C:N varied between rotations among soil physicochemical variables after six years, and individual bacterial OTUs appeared weakly influenced by P, pH, Mg and fungal OTUs by P. The results suggest that after six years, bacteria/archaeal communities were influenced by the time with rice in the rotation, and fungal communities were more influenced by the antecessor crop. More studies are needed to associate fungal communities with certain rotational or environmental variables. Some taxa were associated with a particular rotation, and some bacterial taxa were identified as biomarkers. Fungal indicator taxa were not identified at the species level for any rotation.
P53 is a direct regulator of the immune co-stimulatory molecule CD80
Authors: Alibo Eziwoma , Mollaoglu Gurkan , Dhainaut Maxime , Zhao Royce , Rose Samuel , Baccarini Alessia , Parsons Ramon , Brown Brian D.
Published: May 2021

Increasing evidence indicates oncogenes and tumor suppressors not only influence cell fitness but can also control the immunophenotype of cells. Here, we examined how 34 commonly mutated genes in colorectal cancer (CRC) may influence the expression of 8 key immunomodulatory proteins. To do this, we employed a functional genomics approach utilizing Pro-Code/CRISPR libraries for high-dimensional analysis. We introduced a library of 102 Pro-Code/gRNA combinations, targeting each of the 34 genes, in CT26 cells, a CRC cell model, and measured the expression of each of the immunomodulatory proteins by CyTOF mass cytometry. Notably, cells carrying a Pro-Code/CRISPR targeting the Trp53 lost expression of the immune co-stimulatory molecule CD80. Validation confirmed that Trp53 knockout resulted in the loss of CD80 and that activation of P53, through DNA damage or stabilization, resulted in CD80 upregulation. P53 ChIP-seq identified the CD80 promoter as a direct target of P53. CD80 regulation by P53 was identified in other cells, including normal epithelial cells and macrophages. Functionally, CD80 reduction caused by P53 loss led to a reduced capacity for CRC to prime antigen-specific T cells. These studies establish CD80, a canonical co-stimulatory molecule, as a direct target of the tumor suppressor and DNA damage response gene, P53.
Splice sites obey the power-law during splicing in leukemia cells
Authors: Grinev Vasily , Siomava Natalia , Vallar Laurent , Nazarov Petr
Published: May 2021

Alternative splicing is an essential characteristic of living cells that usually infers a various exon-exon junction governed by different splice sites. The traditional classification based on the mode of use designates splice site to one of the two groups, constitutive or alternative. Here, we considered another criterion and reorganized splice sites into “unisplice” and “multisplice” groups according to the number of undertaken splicing events. This approach provided us with a new insight in the organization and functionality of leukemia cells. We determined features associated with uni- and multisplice sites and found that combinatorics of these sites follows strict rules of the power-law in the t(8;21)-positive leukemia cells. We also found that system splicing characteristics of the transcriptome of leukemia cells remained persistent after drastic changes in the transcript composition caused by knockdown of the RUNX1-RUNX1T1 oncogene. In this work, we show for the first time that leukemia cells possess a sub-set of unisplice sites with a hidden multisplice potential. These findings reveal a new side in organization and functioning of the leukemic cells and open up new perspectives in the study of the t(8;21)-positive leukemia.
Coordination of KIF3A and KIF13A regulates leading edge localization of MT1-MMP to promote cancer cell invasion
Authors: Gifford Valentina , Woskowicz Anna , Ito Noriko , Balint Stefan , Dustin Michael L. , Itoh Yoshifumi
Published: May 2021

MT1-MMP plays a crucial role in promoting the cellular invasion of cancer cells by degrading the extracellular matrix to create a path for migration. During this process, its localization at the leading edge of migrating cells is critical, and it is achieved by targeted transport of MT1-MMP-containing vesicles along microtubules by kinesin superfamily proteins (KIFs). Here we identified three KIFs involved in MT1-MMP vesicle transport: KIF3A, KIF13A, and KIF9. Knockdown of KIF3A and KIF13A effectively inhibited MT1-MMP-dependent collagen degradation and invasion, while knockdown of KIF9 increased collagen degradation and invasion. Our data suggest that KIF9 competes with KIF3A/KIF13A to bring MT1-MMP vesicles to different locations in the plasma membrane. Live-cell imaging analyses have indicated that KIF3A and KIF13A coordinate to transport the same MT1-MMP-containing vesicles. Taken together, we have identified a unique interplay between three KIFs to regulate leading edge localization of MT1-MMP and MT1-MMP-dependent cancer cell invasion.
G-Protein coupled Purinergic P2Y12 receptor interacts and internalizes TauRD-mediated by membrane-associated actin cytoskeleton remodelling in microglia
Authors: Chidambaram Hariharakrishnan , Das Rashmi , Chinnathambi Subashchandrabose
Published: May 2021

In Alzheimer’s disease, the microtubule-associated protein, Tau misfolds to form aggregates and filaments in the intra- and extracellular region of neuronal cells. Microglial cells are the resident brain macrophage cells that are involved in constant surveillance and are activated by the extracellular deposits. Purinergic receptors are involved in chemotactic migration of microglial cells towards the site of inflammation. In our recent study, we found that microglial P2Y12 receptor has been involved in phagocytosis of full-length Tau species such as monomers, oligomers and aggregates by actin-driven chemotaxis. In this study, we have showed the interaction of repeat-domain of Tau (TauRD) with microglial P2Y12 receptor and analysed the corresponding residues for interaction by variousin-silicoapproaches. In cellular studies, TauRDwas found to interact with microglial P2Y12R and induces its cellular expression as confirmed by coimmunoprecipitation and western blot analysis respectively. Similarly, immunofluorescence microscopic studies emphasized that TauRDwere phagocytosed by microglial P2Y12Rviathe membrane-associated actin remodelling as filopodia extension. Furthermore, the P2Yl2R-mediated TauRDinternalization has activated the microglia with an increase in the Iba1 level and TauRDbecome accumulated at peri-nuclear region as localized with Iba1. Altogether, microglial P2Y12R interacts with TauRDand mediates directed migration and activation for its internalization.
Crystal structure of the Thr316Ala mutant of a yeast JAMM deubiquitinase: implication of active-site loop dynamics in catalysis
Authors: Shrestha Rashmi , Das Chittaranjan
Published: May 2021

AMSH, an endosome-associated deubiquitinase (DUB) with a high specificity for Lys63-linked polyubiquitin chains, plays an important role in endosomal–lysosomal sorting and down-regulation of cell-surface receptors. AMSH belongs to the JAMM family of DUBs that contain two insertion segments, Ins-1 and Ins-2, in the catalytic domain relative to the JAMM core found in the archaebacterial AfJAMM. Structural analyses of the AMSH homologs human AMSH-LP and fission yeast Sst2 reveal a flap-like structure formed by Ins-2 near the active site that appears to open and close during its catalytic cycle. A conserved phenylalanine residue of the flap interacts with a conserved aspartate residue of the Ins-1 β-turn to form a closed `lid' over the active site in the substrate-bound state. Analyses of these two residues (Phe403 and Asp315) in Sst2 showed that their interaction plays an important role in controlling the flexibility of Ins-2. The Lys63-linked diubiquitin substrate-bound form of Sst2 showed that the conserved phenylalanine also interacts with Thr316 of Ins-1, which is substituted by tyrosine in other AMSH orthologs. Although Thr316 makes no direct interaction with the substrate, its mutation to alanine resulted in a significant loss of activity. In order to understand the contribution of Thr316 to catalysis, the crystal structure of this mutant was determined. In spite of the effect of the mutation on catalytic activity, the structure of the Sst2 Thr316Ala mutant did not reveal significant changes in either the overall structure or the active-site arrangement relative to the wild type. The Phe403–Thr316 van der Waals interaction is impaired by the Thr316Ala mutation, abrogating the adoption of the closed active-site conformation required for catalysis. Since van der Waals interactions with phenylalanine are conserved across substrate-bound forms of AMSH-LP and Sst2, these interactions may be critical for loop immobilization and the positioning of the isopeptide bond of Lys63-linked polyubiquitin-chain substrates.