bluuebunny/crossref_metadata_2025 huggingface dataset:
Mouth-rinses and SARS-CoV-2 viral load in saliva: A living systematic review
Authors: Hernández-Vásquez Akram , Barrenechea-Pulache Antonio , Comandé Daniel , Azañedo Diego
Published: March 2021

Objective

To conduct a living systematic review of the clinical evidence regarding the effect of different mouth-rinses on the viral load of SARS-CoV-2 in the saliva of infected patients. The viral load in aerosols, the duration of the reduction in viral load, viral clearance, SARS-CoV-2 cellular infectivity, and salivary cytokine profiles were also evaluated.

Materials and methods

This study was reported using the PRISMA guidelines. An electronic search was conducted in seven databases and in preprint repositories. We included human clinical trials that evaluated the effect of mouth-rinses with antiseptic substances on the viral load of SARS-CoV-2 in the saliva of children or adults that tested positive for SARS-CoV-2 using reverse transcriptase polymerase chain reaction (RT-PCR). Risk of bias was assessed using the ROBINS-I tool. PROSPERO registration number CRD42021240561.

Results

Four studies matching eligibility criteria were selected for evaluation (n=32 participants). Study participants underwent oral rinses with hydrogen peroxide (H2O2) at 1 %, povidone–iodine (PI) at 0.5% or 1%, chlorhexidine gluconate (CHX) at 0.2% or 0.12% or cetylpyridinium chloride (CPC) at 0.075%. Only one study included a control group with sterile water. Three of the studies identified a significant reduction in viral load up to 3, 4, and 6 hours after the use of mouthwashes with PI, CHX, and CPC or PI vs. sterile water, respectively, while one study did not identify a significant reduction in viral load after the use of H2O2 rinses.

Conclusions

According to the present systematic review, the effect of the use of mouth-rinses on SARS-CoV-2 viral load in the saliva of COVID-19 patients remains uncertain. This is mainly due to the limited number of patients included and a high risk of bias present in the studies analyzed. Evidence from well-designed randomized clinical trials is required for further and more objective evaluation of this effect.
Case Study: Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient
Authors: Klein Jonathan , Brito Anderson F. , Trubin Paul , Lu Peiwen , Wong Patrick , Alpert Tara , Peña-Hernández Mario A. , Haynes Winston , Kamath Kathy , Liu Feimei , Vogels Chantal B. F. , Fauver Joseph R. , Lucas Carolina , Oh Jieun , Mao Tianyang , Silva Julio , Wyllie Anne L. , Muenker M. Catherine , Casanovas-Massana Arnau , Moore Adam J. , Petrone Mary E. , Kalinich Chaney C. ,   Yale IMPACT Research Team, Cruz Charles Dela , Farhadian Shelli , Ring Aaron , Shon John , Ko Albert I. , Grubaugh Nathan D. , Israelow Benjamin , Iwasaki Akiko , Azar Marwan M.
Published: March 2021

Prior to the emergence of antigenically distinct SARS-CoV-2 variants, reinfections were reported infrequently - presumably due to the generation of durable and protective immune responses. However, case reports also suggested that rare, repeated infections may occur as soon as 48 days following initial disease onset. The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection - confirmed by whole virus genome sequencing - 7 months after primary infection. To elucidate the immunological mechanisms responsible for SARS-CoV-2 reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses. The patient’s immune system was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we also identified the development of neutralizing antibodies and the formation of humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation in this patient. In summary, our study suggests that a low neutralizing antibody presence alone is not sufficient to confer resistance against reinfection. Thus, patients with solid organ transplantation, or patients who are otherwise immunosuppressed, who recover from infection with SARS-CoV-2 may not develop sufficient protective immunity and are at risk of reinfection.
Focal amplification of FAL1, an oncogenic enhancer lncRNA mapping to chromosome 1q is associated with dysregulated BMI1/p21 axis and an adverse event in intracranial ependymomas
Authors: Malgulwar Prit Benny , Pathak Pankaj , Sharma Vikas , Jha Pankaj , Nambirajan Aruna , Rajeshwari Madhu , Singh Manmohan , Suri Vaishali , Sarkar Chitra , Sharma Mehar Chand
Published: March 2021

Gain of chromosome 1q locus is a common cytogenetic feature associated with intracranial ependymomas; however, candidate non-coding RNAs on this locus have not been identified. Recent studies have reported somatic copy number alterations for long non coding RNA (lncRNA) FAL1/FALEC residing on chromosome 1q to stabilize BMI1, an epigenetic repressor and PRC1 component, leading with to downregulation of p21/CDKN1A tumor suppressor gene. We aimed to study the role of FAL1 in ependymomas, its association with 1q gain, BMI1/p21 regulatory axis and clinicopathological parameters. Using SNP array analysis (GSE32101), 31% (discovery cohort) and 63.8% (in-house cohort) showed amplification/gain of FAL1 locus with higher prevalence in intracranial tumors. Copy number gain of FAL1 locus was significantly associated with increased FAL1 (p=0.003) and BMI1 (p=0.007) levels, and reduced p21 (p=0.001) expressions. Interestingly, gain of FAL1 locus and FAL1 transcripts did not show any association with 1q gain or RELA fusions. Subcellular localization reported FAL1 to be expressed in nuclear compartment in ependymomas. Chromatin immunoprecipitation-qPCR demonstrated in-vivo binding of BMI1 at p21 promoter locus with BMI1 target genes to be enriched in cell architecture related pathways. A 3-tier survival analysis between FAL1 gain and increased expression levels of FAL1 and BMI1 correlated with poor outcome in our cohort. Ours is the first study demonstrating gain of FAL1 locus and its interplay with the BMI1/p21 axis in intracranial ependymomas. Further studies into this epigenetic regulatory mechanism will unravel novel driver mutations in intracranial ependymomas

Highlights

Somatic variations in enhancer long non-coding RNA has been recently attributed for various clinical malignancies including cancers. Gain of 1q locus is a common cytogenetic variation observed in intracranial ependymomas. Our study has demonstrated, focal amplification of enhancer lncRNA mapping to Chromosome 1q, FAL1/FALEC, to be involved in oncogenicity/ progression of ependymomas. Moreover, our data suggests a positive association with BMI1 (a PRC1 component) with FAL1 levels, indicating downregulation of BMI1 target gene involved in cell cycle, p21. Furthermore, a 3-tier prognosis analysis (between FAL1 gain, FAL1 and BMI1 expressions) suggests a negative survival outcome. Our study highlights the importance of somatic variation in non-coding genome with ependymoma survival.
Public Opinion about the UK Government during COVID-19 and Implications for Public Health: A Topic Modelling Analysis of Open-Ended Survey Response Data
Authors: Wright Liam , Burton Alexandra , McKinlay Alison , Steptoe Andrew , Fancourt Daisy
Published: March 2021

Confidence in the central UK Government has declined since the beginning of the COVID-19 pandemic, and while this may be linked to specific government actions to curb the spread of the virus, understanding is still incomplete. Examining public opinion is important, as research suggests that low confidence in government increases the extent of non-compliance with infection-dampening rules (for instance, social distancing); however, the detailed reasons for this association are still unclear. To understand public opinion on the central UK government during COVID-19, we used structural topic modelling, a text mining technique, to extract themes from over 4000 free-text survey responses, collected between 14 October and 26 November 2020. We identified eleven topics, among which were topics related to perceived government corruption and cronyism, complaints about inconsistency in rules and messaging, lack of clear planning, and lack of openness and transparency. Participants reported that elements of the government’s approach had made it difficult to comply with guidelines (e.g., changing rules) or were having impacts on mental wellbeing (e.g., inability to plan for the future). Results suggested that consistent, transparent communication and messaging from the government is critical to improving compliance with measures to contain the virus, as well as protecting mental health during health emergencies.
Understanding and Addressing Vaccine Hesitancy in the Context of COVID-19: Development of a Digital intervention
Authors: Knight Holly , Jia Ru , Ayling Kieran , Bradbury Katherine , Baker Katherine , Chalder Trudie , Morling Joanne R , Durrant Lindy , Avery Tony , Ball Jonathan , Barker Caroline , Bennett Robert , McKeever Tricia , Vedhara Kavita
Published: March 2021

Background

Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) was identified in late 2019, spreading to over 200 countries and resulting in almost two million deaths worldwide. The emergence of safe and effective vaccines provides a route out of the pandemic, with vaccination uptake of 75-90% needed to achieve population protection. Vaccine hesitancy is problematic for vaccine rollout; global reports suggest only 73% of the population may agree to being vaccinated. As a result, there is an urgent need to develop equitable and accessible interventions to address vaccine hesitancy at the population level.

Method

We report the development of a scalable digital intervention seeking to address COVID-19 vaccine hesitancy and enhance uptake of COVID-19 vaccines. Guided by motivational interviewing (MI) principles, the intervention includes a series of therapeutic dialogues addressing 10 key concerns of vaccine hesitant individuals. Development of the intervention occurred linearly across four stages. During stage 1, we identified common reasons for COVID-19 vaccine hesitancy through analysis of existing survey data, a rapid systematic literature review, and public engagement workshops. Stage 2 comprised qualitative interviews with medical, immunological, and public health experts. Rapid content and thematic analysis of the data provided evidence-based responses to common vaccine concerns. Stage 3 involved the development of therapeutic dialogues through workshops with psychological and digital behaviour change experts. Dialogues were developed to address concerns using MI principles, including embracing resistance and supporting self-efficacy.

Finally, stage 4 involved digitisation of the dialogues and pilot testing with members of the public.

Discussion

The digital intervention provides an evidence-based approach to addressing vaccine hesitancy through MI principles. The dialogues are user-selected, allowing exploration of relevant issues associated with hesitancy in a non-judgmental context. The text-based content and digital format allow for rapid modification to changing information and scalability for wider dissemination.
The gut microbiome and rotavirus vaccine immunogenicity in rural Zimbabwean infants
Authors: Robertson Ruairi C. , Church James A. , Edens Thaddeus J. , Mutasa Kuda , Geum Hyun Min , Baharmand Iman , Gill Sandeep K. , Ntozini Robert , Chasekwa Bernard , Carr Lynnea , Majo Florence D. , Kirkpatrick Beth D. , Lee Benjamin , Moulton Lawrence H. , Humphrey Jean H. , Prendergast Andrew J. , Manges Amee R. ,   SHINE Trial Team
Published: March 2021

Background

Oral rotavirus vaccine (RVV) immunogenicity is considerably lower in low-versus high-income populations; however, the mechanisms underlying this remain unclear. Previous evidence suggests that the gut microbiota may contribute to differences in oral vaccine efficacy.

Methods

We performed whole metagenome shotgun sequencing on stool samples and measured anti-rotavirus immunoglobulin A in plasma samples from a subset of infants enrolled in a cluster randomized 2×2 factorial trial of improved water, sanitation and hygiene and infant feeding in rural Zimbabwe (SHINE trial: NCT01824940). We examined taxonomic and functional microbiome composition using random forest models, differential abundance testing and regression analyses to explored associations with RVV immunogenicity.

Results

Among 158 infants with stool samples and anti-rotavirus IgA titres, 34 were RVV seroconverters. The median age at stool collection was 43 days. The infant microbiome was dominated by Bifidobacterium longum. The gut microbiome differed significantly between early (≤42 days) and later samples (>42 days) however, we observed no meaningful differences in alpha diversity, beta diversity, species composition or functional metagenomic composition by RVV seroconversion status. Bacteroides thetaiotaomicron was the only species associated with anti-rotavirus IgA titre. Random forest models poorly classified seroconversion status by both composition and functional microbiome variables.

Conclusions

RVV immunogenicity is low in this rural Zimbabwean setting, however it is not explained by the composition or function of the early-life gut microbiome. Further research is warranted to examine the mechanisms of poor oral RVV efficacy in low-income countries.
DNA methylation signatures and the contribution of age-associated methylomic drift to carcinogenesis in early-onset colorectal cancer
Authors: Joo Jihoon E. , Clendenning Mark , Wong Ee Ming , Rosty Christophe , Mahmood Khalid , Georgeson Peter , Winship Ingrid M. , Preston Susan G. , Win Aung Ko , Dugué Pierre-Antoine , Jayasekara Harindra , English Dallas , Macrae Finlay A. , Hopper John L. , Jenkins Mark A. , Milne Roger L. , Giles Graham G. , Southey Melissa C. , Buchanan Daniel D.
Published: March 2021

Background

The role of DNA methylation (DNAm) in the carcinogenesis of colorectal cancer (CRC) diagnosed <50years of age (early-onset CRC or EOCRC) is currently unknown. We investigated aberrant DNAm changes and the contribution of ageing-associated methylomic drift, and age acceleration to EOCRC carcinogenesis.

Methods

Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: 1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and 2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2.

Results

Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups (p=3.7×10−16) and young people without CRC (p=5.8×10−6).

Conclusion

EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. We found accelerated ageing in normal mucosa from people with EOCRC, as evidenced by a faster stem-cell division rate, potentially contributing to EOCRC carcinogenesis.
QTNet: Predicting Drug-Induced QT prolongation with Deep Neural Networks
Authors: Jethani Neil , Zhang Hao , Chinitz Larry , Aphinyanaphongs Yindalon , Ranganath Rajesh , Jankelson Lior
Published: March 2021

Background

Drug-induced QTc prolongation (diQTP) is frequent and associated with a risk of sudden cardiac death. Identifying patients at risk of diQTP can enhance monitoring and treatment plans.

Objective

To develop a machine learning architecture for prediction of extreme diQTP (QTc >500ms OR ΔQTc >60ms) at the onset of treatment with a QTc prolonging drug.

Methods

We included 4,628 adult patients who received a baseline ECG within 6 months prior to treatment onset with a QTc prolonging drug and a follow-up ECG after the fifth dose. We collected known clinical QTc prolongation risk factors (CF). We developed a novel neural network architecture (QTNet) to predict diQTP from both the CF and baseline ECG data (ECGD), composed of both the ECG waveform and measurements (i.e. QTc),by fusing a state-of-the-art convolution neural network to process raw ECG waveforms with the CF using amulti-layer perceptron. We fit a logistic regression model using the CF, replicating RISQ-PATH as Baseline. We further compared the performance of QTNet (CF+ECGD) to neural network models trained using three variable subsets: a) baseline QTc (QTC-NN), b) CF-NN, and c) ECGD-NN.

Results

diQTP was present in 1030 patients (22.3%), of which baseline QTc was normal (QTc<450ms:Male/<470ms:Female) in 405 patients (39.3%). QTNet achieved the best performance (Figure 1)(AUROC, 0.802 [95% CI, 0.782-0.820]), outperforming predictions based on the Baseline (AUROC, 0.738 [95%CI, 0.716-0.757]), QTC-NN (AUROC, 0.735 [95% CI, 0.710-0.757]), CF-NN (AUROC, 0.778 [95% CI, 0.757-0.799]), and ECGD-NN (AUROC, 0.774 [95% CI, 0.750-0.794]).

Conclusion

We developed QTNet, the first deep learning model for predicting extreme diQTP, outperforming models trained on known clinical risk factors.
Acute and longer-term psychological distress associated with testing positive for COVID-19: longitudinal evidence from a population-based study of US adults
Authors: Daly Michael , Robinson Eric
Published: March 2021

Background

The novel coronavirus (SARS-CoV-2) has produced a considerable public health burden but the impact that contracting the disease has on mental health is unclear. In this observational population-based cohort study, we examined longitudinal changes in psychological distress associated with testing positive for COVID-19.

Methods

Participants (N = 8,002; Observations = 139,035) were drawn from 23 waves of the Understanding America Study, a nationally representative survey of American adults followed-up every two weeks from April 1 2020 to February 15 2021. Psychological distress was assessed using the standardized total score on the Patient Health Questionnaire-4 (PHQ-4).

Results

Over the course of the study 576 participants reported testing positive for COVID-19. Using regression analysis including individual and time fixed effects we found that psychological distress increased by 0.29 standard deviations (p<.001) during the two-week period when participants first tested positive for COVID-19. Distress levels remained significantly elevated (d= 0.16, p <.01) for a further two weeks, before returning to baseline levels. Coronavirus symptom severity explained changes in distress attributable to COVID-19, whereby distress was more pronounced among those whose symptoms were more severe and were slower to subside.

Conclusions

This study indicates that testing positive for COVID-19 is associated with an initial increase in psychological distress that diminishes quickly as symptoms subside. While COVID-19 may not produce lasting psychological distress among the majority of the general population it remains possible that a minority may suffer longer-term mental health consequences.
Molecular beacons allow specific RT-LAMP detection of B.1.1.7 variant SARS-CoV-2
Authors: Sherrill-Mix Scott , Duyne Gregory D. Van , Bushman Frederic D.
Published: March 2021

Over the course of the COVID-19 pandemic, several SARS-CoV-2 genetic variants of concern have appeared and spread throughout the world. Detection and identification of these variants is important to understanding and controlling their rapid spread. Current detection methods for a particularly concerning variant, B.1.1.7, require expensive qPCR machines and depend on the absence of a signal rather than a positive indicator of variant presence. Here we report an assay using a pair of molecular beacons paired with reverse transcription loop mediated amplification to allow isothermal amplification from saliva to specifically detect B.1.1.7 and other variants which contain a characteristic deletion in the gene encoding the viral spike protein. This assay is specific, affordable and allows multiplexing with other SARS-CoV-2 LAMP primer sets.
The Ophthalmic Surgical Backlog caused by the COVID-19 Pandemic: A population-based and microsimulation modelling study
Authors: Felfeli Tina , Ximenes Raphael , Naimark David MJ , Hooper Philip L , Campbell Robert J , El-Defrawy Sherif R , Sander Beate
Published: March 2021

Background

Jurisdictions worldwide ramped down ophthalmic surgeries to mitigate the effects of coronavirus disease 2019 (COVID-19), creating a global surgical backlog. We sought to predict the long-term impact of COVID-19 on ophthalmology surgical care delivery.

Methods

This is a population-based and a microsimulation modelling study. Provincial administrative data from January 2019 to May 2021 was used to estimate the backlog size and wait-times following the COVID-19 pandemic. For the post-pandemic recovery phase, we estimated the resources required to clear the backlog of patients accumulated on the waitlist during the pandemic.

Results

A total of 56,923 patients were on the waitlist in the province of Ontario awaiting non-emergency ophthalmic surgery as of March 15, 2020. The number of non-emergency surgeries performed in the province decreased by 45-98% from March to May 2020, and 48-80% from April to May 2021 compared to the same months in 2019. By 2 years and 3 years, the overall estimated number of patients awaiting surgery grew by 129% and 150%, respectively. The estimated mean wait-time for patients for all subspecialty surgeries increased to 282 (SD 91) in March 2023 compared to 94 days (SD 97) in 2019. The provincial monthly additional resources required to clear the backlog by March 2023 was estimated to be a 34% escalation from the pre-pandemic volumes (4,626 additional surgeries).

Interpretation

The magnitude of the ophthalmic surgical backlog from COVID-19 has important implications for the recovery phase. The estimates from this microsimulation modelling can be adapted to other jurisdictions to assist with recovery planning for vision saving surgeries.
Characterisation of FADD interactome reveals novel insights into FADD recruitment and signalling at the Death Inducing Signalling Complex (DISC)
Authors: Fox Joanna L , Dickens Laura S , Jukes-Jones Rebekah , Miles Gareth J , Langlais Claudia , Cain Kelvin , MacFarlane Marion
Published: March 2021

Fas-associated death domain protein (FADD) plays a vital role in the extrinsic apoptotic pathway, where it forms an essential component of the death-inducing signaling complex (DISC). However, the precise early molecular events that facilitate recruitment of FADD to the DISC remain poorly defined. Using affinity purification and mass spectrometry we investigated the FADD interactome in untreated cells and following death receptor stimulation to identify novel FADD-interacting proteins. As expected, in death receptor-stimulated samples our analysis identified key components of the DISC such as Caspase-8. In addition, we identified novel binding partners including Transferrin Receptor 1 (TfR1) and Myosin Light Chain Kinase 2 (MYLK2) that are able to modulate FADD recruitment to the DISC and consequently downstream apoptotic signaling. TfR1 is pre-associated with FADD and recruited into the DISC; moreover, our data reveal that TfR1 is also pre-associated with the death receptors, TRAIL-R1 and TRAIL-R2, thereby functioning as a key regulator of DISC formation. In the case of MYLK2, specific binding of FADD to MYLK2 in non-apoptotic cells sequesters FADD from other DISC components ensuring aberrant apoptosis is not initiated. Furthermore, MYLK2 enzymatic activity is required to for it to translocate, in complex with FADD, to sites of DISC-mediated death receptor oligimerization. Taken together, our study highlights the important role that additional novel FADD binding partners play in the regulation of death receptor-mediated apoptotic cell death, in part by modulating FADD recruitment to the DISC.
SINEultaneous profiling of epigenetic heterogeneity and transcriptome in single cells
Authors: Hunt Kooper V , Burnard Sean M , Roper Ellise A , Bond Danielle R , Dun Matthew D , Verrills Nicole M , Enjeti Anoop K , Lee Heather J
Published: March 2021

Global changes in DNA methylation are observed in developmental and disease contexts, and singlecell analyses are highlighting the heterogeneous regulation of these processes. However, technical challenges associated with single-cell analysis of DNA methylation limit these studies. We present single-cell transposable element methylation sequencing (scTEM-seq) for cost-effective estimation of global DNA methylation levels. By targeting high-copy LINE-1 and SINE Alu elements, we achieve amplicon bisulphite sequencing with thousands of loci covered in each library. Parallel transcriptome analysis is also performed to link global DNA methylation heterogeneity with gene expression. We apply scTEM-seq to KG1a acute myeloid leukaemia (AML) cells, and primary AML cells. Decitabine treatment of KG1a cells induces global DNA methylation heterogeneity associated with altered expression of immune process genes. We also compare global levels of DNA methylation to expression of transposable elements and find a predominance of negative correlations in both the KG1a and patient cells. Finally, we observe co-ordinated upregulation of many transposable elements in a sub-set of decitabine treated cells. By linking global DNA methylation heterogeneity with transcription, scTEM-seq will refine our understanding of epigenetic regulation in cancer and beyond.
Cockayne Syndrome B protein selectively interacts and resolves intermolecular DNA G-quadruplex structures
Authors: Liano Denise , Antonio Marco Di
Published: March 2021

Guanine-rich DNA can fold into secondary structures known as G-quadruplexes (G4s). G4s can form from a single DNA-strand (intramolecular) or from multiple DNA-strands (intermolecular), but studies on their biological functions have been often limited to intramolecular G4s, owing to the low probability of intermolecular G4s to form within genomic DNA. Herein, we report that the endogenous protein Cockayne Syndrome B (CSB) binds with picomolar affinity to intermolecular G4s, whilst displaying negligible binding towards intramolecular structures. We also observed that CSB can selectively resolve intermolecular G4s in an ATP independent fashion. Our study demonstrates that intermolecular G4s formed within ribosomal DNA are natural substrates for CSB, strongly suggesting that these structures might be formed in the nucleolus of living cells. Given that CSB loss of function elicits premature ageing phenotypes, our findings indicate that the interaction between CSB and ribosomal DNA intermolecular G4s is essential to maintain cellular homeostasis.
Conserved hormonal and molecular mechanisms underlying behavioural maturation in open- and cavity-nesting honey bees
Authors: Unnikrishnan Sruthi , Shah Aridni , Bais Deepika , Suryanarayanan Ashwin , Brockmann Axel
Published: March 2021

Division of labour in honey bees is based on a process of behavioural development where the worker bee successively performs different tasks at different ages. Workers start with tasks related to brood care and nest maintenance and move on to become foragers. This process of worker behavioural maturation is well studied inApis mellifera. Juvenile hormone is one of the major drivers of this behavioural maturation, which is also accompanied by changes in brain physiology and anatomy including changes in neuronal gene expression and connections of neurons. Recent studies have identified whole networks of genes associated with specific tasks like nursing, guarding and foraging. Based on this detailed knowledge inA. mellifera, we ask whether major characteristics of the behavioural maturation process and the underlying hormonal and molecular changes are similar or different in two other honey bee species, the phylogenetically ancestral open-nestingA. floreaand the more derived cavity-nestingA. cerana. Our behavioural studies show that workers ofA. floreaexhibit a slower pace of behavioural maturation and on average start foraging at a later age. However, the basic hormonal and molecular changes associated with onset of foraging are similar between both species. Based on our findings, we propose that evolution of accelerated behavioural maturation in cavity-nesting species is likely attributed to changes in the temporal dynamics of juvenile hormone titres.
Structural basis for HCMV Pentamer recognition by antibodies and neuropilin 2
Authors: Wrapp Daniel , Ye Xiaohua , Ku Zhiqiang , Su Hang , Jones Harrison G. , Wang Nianshuang , Mishra Akaash K. , Freed Daniel C. , Li Fengsheng , Tang Aimin , Li Leike , Jaijyan Dabbu Kumar , Zhu Hua , Wang Dai , Fu Tong-Ming , Zhang Ningyan , An Zhiqiang , McLellan Jason S.
Published: March 2021

Human cytomegalovirus (HCMV) encodes for multiple surface glycoproteins and glycoprotein complexes1, 2. One of these complexes, the HCMV Pentamer (gH, gL, UL128, UL130 and UL131), mediates tropism to both epithelial and endothelial cells by interacting with the cell surface receptor neuropilin 2 (NRP2)3, 4. Despite the critical nature of this interaction, the molecular determinants that govern NRP2 recognition remain unclear. Here we describe the cryo-EM structure of NRP2 bound to the HCMV Pentamer. The high-affinity interaction between these proteins is calcium-dependent and differs from the canonical C-terminal arginine (CendR) binding that NRP2 typically utilizes5, 6. The interaction is primarily mediated by NRP2 domains a2 and b2, which interact with UL128 and UL131. We also determine the structures of four human-derived neutralizing antibodies in complex with the HCMV Pentamer to define susceptible epitopes. The two most potent antibodies recognize a novel epitope yet do not compete with NRP2 binding. Collectively, these findings provide a structural basis for HCMV tropism and antibody-mediated neutralization, and serve as a guide for the development of HCMV treatments and vaccines.
Performance of generalist hemiparasiticEuphrasiaacross a phylogenetically diverse host spectrum
Authors: Brown Max R. , Moore Paloma G.P. , Twyford Alex D.
Published: March 2021

Generalist hemiparasites may attach to many different host species and experience complex parasite-host interactions. How these parasite-host interactions impact on the fitness of hemiparasitic plants remain largely unknown.

We used experimentally tractable eyebrights(Euphrasia,Orobanchaceae) to understand parasite-host interactions affecting the performance of a generalist hemiparasitic plant. Common garden experiments were carried out measuringEuphrasiaperformance across 45 diverse hosts and in different parasite-host combinations.

We showed that variation in hemiparasite performance could be attributed mainly to host species and host phylogenetic relationships (λ = 0.82; 0.17-1.00 Cl). When this variation in performance is broken down temporally, annual host species cause earlier flowering, and lead to poorer performance late in the season. WhileEuphrasiaspecies typically perform similarly on a given host species, some eyebrights show more specialised parasite-host interactions.

Our results show that generalist hemiparasites only benefit from attaching to a limited, but phylogenetically divergent, subset of hosts. The conserved responses of divergentEuphrasiaspecies suggest hemiparasite performance is affected by common host attributes. However, evidence for more complex parasite-host interactions show that a generalist hemiparasite can potentially respond to individual host selection pressures and may adapt to local host communities.
Modelling The Effect of MUC1 on Influenza Virus Infection Kinetics and Macrophage Dynamics
Authors: Li Ke , Cao Pengxing , McCaw James M.
Published: March 2021

MUC1 belongs to the family of cell surface (cs-) mucins. Experimental evidence indicates that its presence reducesin vivoinfluenza viral infection severity. However, the mechanisms by which MUC1 influences viral dynamics and the host immune response are not yet well understood, limiting our ability to predict the efficacy of potential treatments that target MUC1. To address this limitation, we utilize availablein vivokinetic data for both virus and macrophage populations in wildtype and MUC1 knockout mice. We apply two mathematical models of within-host influenza dynamics to this data. The models differ in how they categorise the mechanisms of viral control. Both models provide evidence that MUC1 reduces the susceptibility of epithelial cells to influenza virus and regulates macrophage recruitment. Furthermore, we predict and compare some key infection-related quantities between the two mice groups. We find that MUC1 significantly reduces the basic reproduction number of viral replication as well as the number of cumulative macrophages but has little impact on the cumulative viral load. Our analyses suggest that the viral replication rate in the early stages of infection influences the kinetics of the host immune response, with consequences for infection outcomes, such as severity. We also show that MUC1 plays a strong anti-inflammatory role in the regulation of the host immune response. This study improves our understanding of the dynamic role of MUC1 against influenza infection and may support the development of novel antiviral treatments and immunomodulators that target MUC1.
Integrated population genomic analysis and numerical simulation to estimate larval dispersal of Acanthaster cf. solaris between Ogasawara and other Japanese regions
Authors: Horoiwa Mizuki , Nakamura Takashi , Yuasa Hideaki , Kajitani Rei , Ameda Yosuke , Sasaki Tetsuro , Taninaka Hiroki , Kikuchi Taisei , Yamakita Takehisa , Toyoda Atsushi , Itoh Takehiko , Yasuda Nina
Published: March 2021

The estimation of larval dispersal of marine species occurring on an ecological timescale is significant for conservation. In 2018, a semi-population outbreak of crown of thorns starfish, Acanthaster cf. solaris was observed on a relatively isolated oceanic island, Ogasawara. The aim of this study was to assess whether this population outbreak was caused by large-scale larval recruitment (termed secondary outbreak) from the Kuroshio region. We estimated larval dispersal of the coral predator A. cf. solaris between the Kuroshio and Ogasawara regions using both population genomic analysis and oceanographic dispersal simulation. Population genomic analysis revealed overall genetically homogenized patterns among Ogasawara and other Japanese populations, suggesting that the origin of the populations in the two regions is the same. In contrast, a simulation of 26-year oceanographic dispersal indicated that larvae are mostly self-seeded in Ogasawara populations and have difficulty reaching Ogasawara from the Kuroshio region within one generation. However, a connectivity matrix produced by the larval dispersal simulation assuming a Markov chain indicated gradual larval dispersal migration from the Kuroshio region to Ogasawara in a stepping-stone manner over multiple years. These results suggest that, while large-scale larval dispersal from an outbreak of the Kuroshio population spreading to the Ogasawara population within one generation is unlikely. This study also highlighted the importance of using both genomic and oceanographic methods to estimate larval dispersal, which provides significant insight into larval dispersal that occurs on ecological and evolutionary timescales.
A pipelining mechanism supporting previewing during visual exploration and reading
Authors: Jensen Ole , Pan Yali , Frisson Steven , Wang Lin
Published: March 2021

Humans have a remarkable ability to efficiently explore visual scenes and text by means of eye-movements. Humans typically make eye-movements (saccades) every ~250ms. Since the saccadic motor planning and execution takes 100ms this leaves only ~150ms to recognize the fixated object (or word), while simultaneously previewing candidates for the next saccade goal. We propose apipelining mechanismthat efficiently can coordinate visual exploration and reading. The mechanism is timed by alpha oscillations that coordinate the saccades, visual recognition and previewing in the cortical hierarchy. Consequently, the neuronal mechanism supporting visual processing and saccades must be studied in unison to uncover the brain mechanism supporting visual exploration and reading.

Highlights

Humans have a remarkable ability to efficiently acquire information from visual scenes and pages of text by means of saccadic exploration.

Visual exploration is surprisingly efficient given the temporal and spatial constraints imposed by the visual system. As such, both information from current fixations as well as upcoming locations must be processed within a 150 ms time window.

New data recording in humans and non-human primates points to a link between the timing of saccades and alpha oscillations.

We present a framework in which visual exploration and reading are supported by similar neuronal mechanisms.

We propose a novel mechanism in which visual exploration and reading is supported by a pipelining mechanism organized by alpha oscillations.

According to the pipelining mechanism, fixated and previewed objects/words are represented at different phases of an alpha cycle.
Genomic surveillance and phylodynamic analyses reveal emergence of novel mutation and co-mutation patterns within SARS-CoV2 variants prevalent in India
Authors: Biswas Nupur , Mallick Priyanka , Maity Sujay Krishna , Bhowmik Debaleena , Mitra Arpita Ghosh , Saha Soumen , Roy Aviral , Chakrabarti Partha , Paul Sandip , Chakrabarti Saikat
Published: March 2021

Emergence of distinct viral clades has been observed in SARS-CoV2 variants across the world and India. Identification of the genomic diversity and the phylodynamic profiles of the prevalent strains of the country are critical to understand the evolution and spread of the variants. We performed whole-genome sequencing of 54 SARS-CoV2 strains collected from COVID-19 patients in Kolkata, West Bengal during August to October 2020. Phylogeographic and phylodynamic analyses were performed using these 54 and other sequences from India and abroad available in GISAID database. Spatio-temporal evolutionary dynamics of the pathogen across various regions and states of India over three different time periods in the year 2020 were analyzed. We estimated the clade dynamics of the Indian strains and compared the clade specific mutations and the co-mutation patterns across states and union territories of India over the time course. We observed that GR, GH and G (GISAID) or 20B and 20A (Nextstrain) clades were the prevalent clades in India during middle and later half of the year 2020. However, frequent mutations and co-mutations observed within the major clades across time periods do not show much overlap, indicating emergence of newer mutations in the viral population prevailing in the country. Further, we explored the possible association of specific mutations and co-mutations with the infection outcomes manifested within the Indian patients.
Drying of virus-containing aerosol particles: Modelling effects of droplet origin and composition
Authors: Jarvis Michael C.
Published: March 2021

Background and Purpose

Virus-containing aerosol droplets emitted by breathing, speech or coughing dry rapidly to equilibrium with ambient relative humidity (RH), increasing in solute concentration with effects on virus survival and decreasing in diameter with effects on sedimentation and respiratory uptake. The aim of this paper is to model the effect of ionic and macromolecular solutes on droplet drying and solute concentration.

Methods

Deliquescence-efflorescence concepts and Kohler theory were used to simulate the evolution of solute concentrations and water activity in respiratory droplets, starting from efflorescence data on mixed NaCl/KCl aerosols and osmotic pressure data on respiratory macromolecules.

Results

In NaCl/KCl solutions supersaturated total salt concentrations were shown to reach 10-15M at the efflorescence RH of 40-55%, depending on the K:Na ratio. Dependence on K:Na ratio implies that the evaporation curves differ between aerosols derived from saliva and from airway surfaces. The direct effect of liquid droplet size through the Kelvin term was shown to be smaller and largely restricted to breath emissions. Modelling the effect of proteins and glycoproteins showed that salts determine drying equilibria down to the efflorescence RH, and macromolecules at lower RH.

Conclusion

Differences in drying behaviour are predicted between breathing, speech and coughing emissions and between droplet size fractions within these. High salt concentrations may inactivate some viruses.
Molecular Dynamics Study on the Effects of Charged Amino Acid Distribution Under low pH Condition to the Unfolding of Hen Egg White Lysozyme and Formation of Beta Strands
Authors: Zein Husnul Fuad , Alam Ibra , Asanithi Piyapong , Sutthibutpong Thana
Published: March 2021

Aggregation of unfolded or misfolded proteins into amyloid fibrils can cause various diseases in humans. However, the fibrils synthesized in vitro can be developed toward useful biomaterials under some physicochemical conditions. In this study, atomistic molecular dynamics simulations were performed to address the mechanism of beta-sheet formation of the unfolded hen egg white lysozyme (HEWL) under a high temperature and low pH. Simulations of the protonated HEWL at pH 2 and the non-protonated HEWL at pH 7 were performed at the highly elevated temperature of 450 K to accelerate the unfolding, followed by the 333 K temperature in some previous in vitro studies. The simulations showed that HEWL unfolded faster and refolded into structures with higher beta-strand contents at pH 2. The mechanism of beta-strand formation at the earlier stage of amyloidosis was addressed in terms of the radial distribution of amino acids, affected by the high protonation level at a low pH.
Phylogenomic discordance suggests polytomies along the backbone of the large genusSolanum
Authors: Gagnon Edeline , Hilgenhof Rebecca , Orejuela Andrés , McDonnell Angela , Sablok Gaurav , Aubriot Xavier , Giacomin Leandro , Gouvêa Yuri , Bragionis Thamyris , Stehmann João Renato , Bohs Lynn , Dodsworth Steven , Martine Christopher , Poczai Péter , Knapp Sandra , Särkinen Tiina
Published: March 2021

Premise of the study

Evolutionary studies require solid phylogenetic frameworks, but increased volumes of phylogenomic data have revealed incongruent topologies among gene trees in many organisms both between and within genomes. Some of these incongruences indicate polytomies that may remain impossible to resolve. Here we investigate the degree of gene-tree discordance inSolanum,one of the largest flowering plant genera that includes the cultivated potato, tomato, and eggplant, as well as 24 minor crop plants.

Methods

A densely sampled species-level phylogeny ofSolanumis built using unpublished and publicly available Sanger sequences comprising 60% of all accepted species (742 spp.) and nine regions (ITS,waxy, and seven plastid markers). The robustness of this topology is tested by examining a full plastome dataset with 140 species and a nuclear target-capture dataset with 39 species ofSolanum(Angiosperms353 probe set).

Key results

While the taxonomic framework ofSolanumremained stable, gene tree conflicts and discordance between phylogenetic trees generated from the target-capture and plastome datasets were observed. The latter correspond to regions with short internodal branches, and network analysis and polytomy tests suggest the backbone is composed of three polytomies found at different evolutionary depths. The strongest area of discordance, near the crown node ofSolanum,could potentially represent a hard polytomy.

Conclusions

We argue that incomplete lineage sorting due to rapid diversification is the most likely cause for these polytomies, and that embracing the uncertainty that underlies them is crucial to understand the evolution of large and rapidly radiating lineages.
Experimental characterization ofin silicored-shift predicted iLOVL470T/Q489Kand iLOVV392K/F410V/A426Smutants
Authors: Wehler Pierre , Armbruster Daniel , Günter Andreas , Schleicher Erik , Di Ventura Barbara , Öztürk Mehmet Ali
Published: March 2021

iLOV is a flavin mononucleotide-binding fluorescent protein used forin vivocellular imaging similar to the green fluorescent protein. To expand the range of applications of iLOV, spectrally tuned red-shifted variants are desirable to have reduced phototoxicity and better tissue penetration. In this report, we experimentally tested two iLOV mutants, iLOVL470T/Q489Kand iLOVV392K/F410V/A426S, which were previously computationally proposed by Khrenova et al. (DOI: 10.1021/acs.jpcb.7b07533) to have red-shifted excitation and emission spectra. We found that mutants bearing the V392K mutation lost the ability to bind FMN. While iLOVL470T/Q489Kis about 20% brighter compared to WT iLOVin vitro, it exhibits a blue shift in contrast to QM/MM predictions. Additionally, both mutants are expressed at low levels and have undetectable fluorescence in living cells, which prevents their utilization in imaging applications. Our results suggest that rational fluorescent protein design efforts can benefit fromin silicoprotein stability and ligand affinity calculations.