bluuebunny/crossref_metadata_2025 huggingface dataset:
The economic value of quarantine is higher at lower case prevalence, with quarantine justified at lower risk of infection
Authors: Petrie James , Masel Joanna
Published: September 2021

Some infectious diseases, such as COVID-19 or the influenza pandemic of 1918, are so harmful that they justify broad-scale social distancing. Targeted quarantine can reduce the amount of indiscriminate social distancing needed to control transmission. Finding the optimal balance between targeted versus broad-scale policies can be operationalized by minimizing the total amount of social isolation needed to achieve a target reproductive number. Optimality is achieved by quarantining on the basis of a risk threshold that depends strongly on current disease prevalence, suggesting that very different disease control policies should be used at different times or places. Aggressive quarantine is warranted given low disease prevalence, while populations with a higher base rate of infection should rely more on social distancing by all. The total value of a quarantine policy rises as case counts fall, is relatively insensitive to vaccination unless the vaccinated are exempt from distancing policies, and is substantially increased by the availability of modestly more information about individual risk of infectiousness.
‘The grand strategy of an observatory’: George Airy's vision for the division of astronomical labour among observatories during the nineteenth century
Authors: Belteki Daniel
Published: September 2021

The downfall of the Parramatta Observatory during the 1840s led the British Government to reconsider the funding it provided to observatories. George Biddell Airy—the Astronomer Royal at the Royal Observatory, Greenwich—recommended the establishment of a central Colonial Board of Visitors (based in London) to oversee the management of observatories within the British Empire. The recommendation ultimately never materialized, but it showcased the support of the astronomical community and the British Government for centralizing the management of the vast network of observatories. This centralized vision continued to influence the founding of new observatories and the organization of their work. The article examines Airy's vision of a centralized organization of division of labour among observatories through his involvement in the discussions about the Colonial Board of Visitors. It also examines how he continued supporting the same vision through articles about the work of observatories, and through written advice about establishing observatories. The article demonstrates how he envisioned the grand strategy of an observatory to encompass public utility while also fitting it within the general policy of observatories in relation to the division of astronomical labour.
Recent insights into mechanisms preventing ectopic centromere formation
Authors: Dong Qianhua , Yang Jinpu , Gao Jinxin , Li Fei
Published: September 2021

The centromere is a specialized chromosomal structure essential for chromosome segregation. Centromere dysfunction leads to chromosome segregation errors and genome instability. In most eukaryotes, centromere identity is specified epigenetically by CENP-A, a centromere-specific histone H3 variant. CENP-A replaces histone H3 in centromeres, and nucleates the assembly of the kinetochore complex. Mislocalization of CENP-A to non-centromeric regions causes ectopic assembly of CENP-A chromatin, which has a devastating impact on chromosome segregation and has been linked to a variety of human cancers. How non-centromeric regions are protected from CENP-A misincorporation in normal cells is largely unexplored. Here, we review the most recent advances on the mechanisms underlying the prevention of ectopic centromere formation, and discuss the implications in human disease.
Hydroacoustic and hydrodynamic investigation of bio-inspired leading-edge tubercles on marine-ducted thrusters
Authors: Stark Callum , Shi Weichao
Published: September 2021

Underwater radiated noise (URN) has a negative impact on the marine acoustic environment where it can disrupt marine creature's basic living functions such as navigation and communication. To control the ambient ocean noise levels due to human activities, international governing bodies such as the International Maritime Organization (IMO) have issued non-mandatory guidelines to address this issue. Under such framework, the hydroacoustic performance of marine vehicles has become a critical factor to be evaluated and controlled throughout the vehicles' service life in order to mitigate the URN level and the role humankind plays in the ocean. This study aims to apply leading-edge (LE) tubercles of the humpback whales’ pectoral fins to a benchmark ducted propeller to investigate its potential in noise mitigation. This was conducted using CFD, where the high-fidelity improved delayed detached eddy simulations (IDDES) in combination with the porous Ffowcs-Williams Hawkings (FW-H) acoustic analogy was used to solve the hydrodynamic flow field and propagate the generated noise to the far-field. It has been found that the LE tubercles have shown promising noise mitigation capabilities in the far-field, where the OASPL atJ= 0.1 was reduced to a maximum of 3.4 dB with a maximum of 11 dB reduction in certain frequency ranges at other operating conditions. Based on detailed flow analysis researching the fundamental vortex dynamics, this noise reduction is shown to be due to the disruption of the coherent turbulent wake structure in the propeller slipstream causing the acceleration in the dissipation of turbulence and vorticity-induced noise.
A novel matrix technique for multi-order pantograph differential equations of fractional order
Authors: Izadi Mohammad , Srivastava H. M.
Published: September 2021

The main purpose of this article is to investigate a novel set of (orthogonal) basis functions for treating a class of multi-order fractional pantograph differential equations (MOFPDEs) computationally. These polynomials, denoted bySn(x)and calledspecial polynomials, were first discovered in a study of a certain family of isotropic turbulence fields. They are expressible in terms of the generalized Laguerre polynomials and are related to the Bessel and Srivastava–Singhal polynomials. Unlike the Laguerre polynomials, all coefficients of the special polynomials are positive. We further introduce the fractional order of the special polynomials and use them along with some suitable collocation points in a special matrix technique to treat fractional-order MOFPDEs. Moreover, the convergence analysis of these polynomials is established. Through five example applications, the utility and efficiency of the present matrix approach are demonstrated and comparisons with some existing numerical schemes have been performed in this class.
The critical period: neurochemical and synaptic mechanisms shared by the visual cortex and the brain stem respiratory system
Authors: Wong-Riley Margaret T. T.
Published: September 2021

The landmark studies of Wiesel and Hubel in the 1960's initiated a surge of investigations into the critical period of visual cortical development, when abnormal visual experience can alter cortical structures and functions. Most studies focused on the visual cortex, with relatively little attention to subcortical structures. The goal of the present review is to elucidate neurochemical and synaptic mechanisms common to the critical periods of the visual cortex and the brain stem respiratory system in thenormalrat. In both regions, the critical period is a time of (i) heightened inhibition; (ii)reducedexpression of brain-derived neurotrophic factor (BDNF); and (iii)synaptic imbalance, with heightened inhibition and suppressed excitation. The last two mechanisms are contrary to the conventional premise. Synaptic imbalance renders developing neurons more vulnerable to external stressors. However, the critical period isnecessaryto enable each system to strengthen its circuitry, adapt to its environment, and transition from immaturity to maturity, when a state of relative synaptic balance is attained. Failure to achieve such a balance leads to neurological disorders.
Adlercreutzia rubneri sp. nov., a resveratrol-metabolizing bacterium isolated from human faeces and emended description of the genus Adlercreutzia
Authors: Stoll Dominic A. , Danylec Nicolas , Soukup Sebastian T. , Hetzer Birgit , Kulling Sabine E. , Huch Melanie
Published: September 2021

The novel, anaerobic, Gram-positive, rod-shaped bacterial strain, ResAG-91T, was isolated from a faecal sample of a male human volunteer. Analysis of the 16S rRNA gene sequence revealed that strain ResAG-91T showed high similarity to the type strains of

Adlercreutzia equolifaciens

subsp.

equolifaciens

and

Adlercreutzia equolifaciens

subsp.

celatus

. Analysis of the whole draft genome sequences, i.e. digital DNA–DNA hybridization (dDDH) and average nucleotide identity (ANI), of strain ResAG-91T and the type strains of

Adlercreutzia

species revealed that strain ResAG-91T represents a novel species of the genus

Adlercreutzia

. The genome size of strain ResAG-91T is 2.8 Mbp and the G+C content is 63.3 mol%. The major respiratory quinone of strain ResAG-91T was MMK-5 (methylmenaquinone). Major cellular fatty acids were C15 : 0 anteiso, C14 : 0 iso and C14 : 0 2-OH. Galactose and ribose were detected as major whole cell sugars. Furthermore, the peptidoglycan type of strain ResAG-91T was A1γ with meso-diaminopimelic acid. The polar lipids were phosphatidylglycerol, diphosphatidylglycerol, one unidentified lipid, three unidentified phospholipids and five unidentified glycolipids. Strain ResAG-91T was able to metabolize the stilbene resveratrol into dihydroresveratrol. On the basis of this polyphasic approach, including phenotypical, molecular (16S rRNA gene and whole genome sequencing) and biochemical (fatty acids, quinones, polar lipids, peptidoglycan, whole cell sugars, Rapid ID32A and API20A) analyses, we propose the novel species Adlercreutzia rubneri sp. nov. with the type and only strain ResAG-91T (=DSM 111416T=JCM 34176T=LMG 31897T).
Characterization of a novel reassortment Tibet orbivirus isolated from Culicoides spp. in Yunnan, PR China
Authors: Ren Nanjie , Wang Xiaoyu , Liang Mengying , Tian Shen , Ochieng Christabel , Zhao Lu , Huang Doudou , Xia Qianfeng , Yuan Zhiming , Xia Han
Published: September 2021

Orbiviruses are arboviruses with 10 double-stranded linear RNA segments, and some have been identified as pathogens of dramatic epizootics in both wild and domestic ruminants. Tibet orbivirus (TIBOV) is a new orbivirus isolated from hematophagous insects in recent decades, and, currently, most of the strains have been isolated from insects in PR China, except for two from Japan. In this study, we isolated a novel reassortment TIBOV strain, YN15-283-01, from Culicoides spp. To identify and understand more characteristics of YN15-283-01, electrophoresis profiles of the viral genome, electron microscopic observations, plaque assays, growth curves in various cell lines, and bioinformatic analysis were conducted. The results indicated that YN15-283-01 replicated efficiently in mosquito cells, rodent cells and several primate cells. Furthermore, the maximum likelihood phylogenetic trees and simplot analysis of the 10 segments indicated that YN15-283-01 is a natural reassortment isolate that had emerged mainly from XZ0906 and SX-2017a.
The dilution effect limits plasmid horizontal transmission in multispecies bacterial communities
Authors: Kottara Anastasia , Carrilero Laura , Harrison Ellie , Hall James P. J. , Brockhurst Michael A.
Published: September 2021

By transferring ecologically important traits between species, plasmids drive genomic divergence and evolutionary innovation in their bacterial hosts. Bacterial communities are often diverse and contain multiple coexisting plasmids, but the dynamics of plasmids in multi-species communities are poorly understood. Here, we show, using experimental multi-species communities containing two plasmids, that bacterial diversity limits the horizontal transmission of plasmids due to the ‘dilution effect’; this is an epidemiological phenomenon whereby living alongside less proficient host species reduces the expected infection risk for a focal host species. In addition, plasmid horizontal transmission was also affected by plasmid diversity, such that the rate of plasmid conjugation was reduced from co-infected host cells carrying both plasmids. In diverse microbial communities, plasmid spread may be limited by the dilution effect and plasmid–plasmid interactions, reducing the rate of horizontal transmission.
Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2-infected cells
Authors: Venet Manon , Sa Ribeiro Margarida , Décembre Elodie , Bellomo Alicia , Joshi Garima , Villard Marine , Cluet David , Perret Magali , Pescamona Rémi , Paidassi Helena , Walzer Thierry , Allatif Omran , Belot Alexandre , Assant Sophie , Ricci Emiliano , Dreux Marlène
Published: September 2021

Type I and III interferons (IFN-I/λ) are key antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that plasmacytoid dendritic cells (pDCs) are the predominant IFN-I/λ source following their sensing of SARS-CoV-2-infected cells. Mechanistically, this short-range sensing by pDCs requires sustained integrin-mediated cell adhesion with infected cells. In turn, pDCs restrict viral spread by an IFN-I/λ response directed toward SARS-CoV-2-infected cells. This specialized function enables pDCs to efficiently turn-off viral replication, likelyviaa local response at the contact site with infected cells. By exploring the pDC response in SARS-CoV-2 patients, we further demonstrate that pDC responsiveness inversely correlates with the severity of the disease. The pDC response is particularly impaired in severe COVID-19 patients. Overall, we propose that pDC activation is essential to control SARS-CoV-2-infection. Failure to unfold this response could be key to understand severe cases of COVID-19.
Analytic approaches to clinical validation of results from preclinical models of glioblastoma: a systematic review
Authors: Fitt Beth , Loy Grace , Christopher Edward , Brennan Paul M. , Poon Michael T.C.
Published: September 2021

Introduction

Analytic approaches to clinical validation of results from preclinical models are important in assessment of their relevance to human disease. This systematic review examined consistency in reporting of glioblastoma cohorts from The Cancer Genome Atlas (TCGA) or Chinese Glioma Genome Atlas (CGGA) and assessed whether studies included patient characteristics in their survival analyses.

Methods

We searched Embase and Medline on 02Feb21 for studies using preclinical models of glioblastoma published after Jan2008 that used data from TCGA or CGGA to validate the association between at least one molecular marker and overall survival in adult patients with glioblastoma. Main data items included cohort characteristics, statistical significance of the survival analysis, and model covariates.

Results

There were 58 eligible studies from 1,751 non-duplicate records investigating 126 individual molecular markers. In 14 studies published between 2017 and 2020 using TCGA RNA microarray data that should have the same cohort, the median number of patients was 464.5 (interquartile range 220.5-525). Of the 15 molecular markers that underwent more than one univariable or multivariable survival analyses, five had discrepancies between studies. Covariates used in the 17 studies that used multivariable survival analyses were age (76.5%), pre-operative functional status (35.3%), sex (29.4%) MGMT promoter methylation (29.4%), radiotherapy (23.5%), chemotherapy (17.6%), IDH mutation (17.6%) and extent of resection (5.9%).

Conclusion

Preclinical glioblastoma studies that used TCGA for validation did not provide sufficient information about their cohort selection and there were inconsistent results. Transparency in reporting and the use of analytic approaches that adjust for clinical variables can improve the reproducibility between studies.
Epidemiological, clinical Characteristics and mortality of patients Infected with SARS-CoV-2 Admitted of Kinshasa University Hospital, Democratic Republic of the Congo from March 24, 2020 to January 30, 2021: Two waves, two faces?
Authors: Mandina Madone , Makulo Jean-Robert , Wumba Roger , Bepouka Ben , Odio Jerome , Nkodila Aliocha , Longokolo Murielle , Mayasi Nadine , Mangala Donatien , Kamwiziku Guyguy , Longo Auguy Luzayadio , Mpia Guillaume , Kokusa Yamin , Keke Hervé , Mbula Marcel , Situakibanza Hippolyte , Sumaili Ernest , Kayembe Jean-Marie
Published: September 2021

Background

The objective of our retrospective study was to establish a comparison between the first and the second waves of demographic and clinical characteristics as well as mortality and its determinants.

Methods

A total of 411 COVID-19 patients were enrolled in Kinshasa University Hospital and categorized into two groups according to the pandemic pattern, demographics, and disease severity. The clinical characteristics were compared according to the two waves. To describe survival from the first day of hospitalization until death, we used Kaplan Meier’s method. We used the Log Rank test to compare the survival curves between the two waves. The Cox regression was used to identify independent predictors of mortality.

Results

During the study period, 411 patients with confirmed COVID-19 were admitted to the hospital. The average age of patients in the 2nd wave was higher than in the first wave (52.4 ±17.5 vs 58.1 ±15.7, p=0.026). The mean saturation was lower in the first wave than in the second. The death rate of patients in the first wave was higher than in the second wave (p=0.009). Survival was reduced in the first wave compared to the second wave. In the first wave, age over 60 years, respiratory distress, law oxygen saturation (≤89%) and severe stage of COVID-19 emerged as factors associated with death, while in the second wave it was mainly respiratory distress, law oxygen saturation (≤ 89%) and severe stage. The predictors of mortality present in both the first and second waves were respiratory distress and severe COVID-19 stage.

Conclusion

Mortality decreased in the second wave. Age no longer emerged as a factor in mortality in the second wave. Health system strengthening and outreach to those at high risk of mortality should continue to maintain and improve gains.
Susceptibility to postmortem (co)-pathologies in antemortem atrophy-based subtypes of Alzheimer’s disease
Authors: Mohanty Rosaleena , Ferreira Daniel , Frerich Simon , Muehlboeck J-Sebastian , Grothe Michel , Westman Eric ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2021

Objectives

To investigate whether antemortem atrophy-based subtypes of Alzheimer’s disease (AD) may be differentially susceptible to individual or concomitance of AD and non-AD (co)-pathologies, assessed neuropathologically at postmortem.

Methods

We selected 31 individuals from the AD neuroimaging initiative with: an antemortem magnetic resonance imaging scan evaluating brain atrophy available within two years before death; an antemortem diagnosis of AD dementia or prodromal AD; and postmortem neuropathological confirmation of AD. Antemortem atrophy-based subtypes was modeled as a continuous phenomenon in terms of two recently proposed dimensions: typicality (ranging from limbic-predominant AD to hippocampal-sparing AD subtypes) and severity (ranging from typical AD to minimal atrophy AD subtypes). Postmortem neuropathological evaluation included global and regional outcomes: AD hallmark pathologies of amyloid-beta and tau; non-AD co-pathologies of alpha-synuclein Lewy body and TDP-43; and the overall concomitance across these four (co)-pathologies. Partial correlation and linear regression models were used to assess the association between antemortem atrophy-based subtypes and postmortem neuropathological outcomes.

Results

We observed significant global and regional associations between antemortem typicality and postmortem (co)-pathologies including tau, alpha-synuclein Lewy bodies and TDP-43. Antemortem typicality demonstrated stronger regional associations with concomitance of multiple postmortem (co)-pathologies in comparison to antemortem severity. Our findings suggest the following susceptibilities of atrophy-based subtypes: limbic-predominant AD towards higher burden of tau and TDP-43 pathologies while hippocampal-sparing AD towards lower burdens; limbic-predominant AD and typical AD towards higher burden of alpha-synuclein Lewy body pathology while hippocampal-sparing AD and minimal-atrophy AD towards lower burdens.

Discussion

Through a direct antemortem-to-postmortem validation, our study highlights the importance of understanding heterogeneity in AD in relation to concomitance of AD and non-AD pathologies. Our findings provide a deeper understanding of both global and regional vulnerabilities of the biological subtypes of AD brain towards (co)-pathologies. Relative involvement of both AD hallmark and non-AD (co)-pathologies will enhance prevailing knowledge of biological heterogeneity in AD and could thus, contribute towards tracking disease progression and designing clinical trials in the future.
Home alone: A population neuroscience investigation of brain morphology substrates
Authors: Noonan MaryAnn , Zajner Chris , Bzdok Danilo
Published: September 2021

As a social species, ready exchange with peers is a pivotal asset - our “social capital”. Yet, single-person households have come to pervade metropolitan cities worldwide, with unknown consequences in the long run. Here, we systematically explore the morphological manifestations associated with singular living in ∼40,000 UK Biobank participants. The uncovered population-level signature spotlights the highly associative default mode network, in addition to findings such as in the amygdala central, cortical and corticoamygdaloid nuclei groups, as well as the hippocampal fimbria and dentate gyrus. Sex-stratified analyses revealed male-specific neural substrates, including somatomotor, saliency and visual systems, while female-specific neural substrates centred on the dorsomedial prefrontal cortex. In line with our demographic profiling results, the discovered neural imprint of living alone is potentially linked to alcohol and tobacco consumption, anxiety, sleep quality as well as daily TV watching. The secular trend for solitary living will require new answers from public-health decision makers.
A New Perspective on Individual Reliability beyond Group Effects for Event-related Potentials: A Multisensory Investigation and Computational Modeling
Authors: Hu Zhenxing , Zhang Zhiguo , Liang Zhen , Zhang Li , Li Linling , Huang Gan
Published: September 2021

The dominant approach in investigating the individual reliability for event-related potentials (ERPs) is to extract peak-related features at electrodes showing the strongest group effects. Such a peak-based approach implicitly assumes ERP components showing a stronger group effect are also more reliable, but this assumption has not been substantially validated and few studies have investigated the reliability of ERPs beyond peaks. In this study, we performed a rigorous evaluation of the test-retest reliability of ERPs collected in a multisensory and cognitive experiment from 82 healthy adolescents, each having two sessions. By comparing group effects and individual reliability, we found that a stronger group-level response in ERPs did not guarantee a higher reliability. Further, by simulating ERPs with a computational model, we found that the consistency between group-level ERP responses and individual reliability was modulated by inter-subject latency jitter and inter-trial variability. The current findings suggest that the conventional peak-based approach may underestimate the individual reliability in ERPs. Hence, a comprehensive evaluation of the reliability of ERP measurements should be considered in individual-level neurophysiological trait evaluation and psychiatric disorder diagnosis.
Deep conservation of histone variants in Thermococcales archaea
Authors: Stevens Kathryn M , Hocher Antoine , Warnecke Tobias
Published: September 2021

Histones are ubiquitous in eukaryotes where they assemble into nucleosomes, binding and wrapping DNA to form chromatin. One process to modify chromatin and regulate DNA accessibility is the replacement of histones in the nucleosome with paralogous variants. Histones are also present in archaea but whether and how histone variants contribute to the generation of different physiologically relevant chromatin states in these organisms remains largely unknown. Conservation of paralogs with distinct properties can provide prima facie evidence for defined functional roles. We recently revealed deep conservation of histone paralogs with different properties in the Methanobacteriales, but little is known experimentally about these histones. In contrast, the two histones of the model archaeon Thermococcus kodakarensis, HTkA and HTkB, have been examined in some depth, both in vitro and in vivo. HTkA and HTkB exhibit distinct DNA-binding behaviours and elicit unique transcriptional responses when deleted. Here, we consider the evolution of HTkA/B and their orthologs across the order Thermococcales. We find histones with signature HTkA- and HTkB-like properties to be present in almost all Thermococcales genomes. Phylogenetic analysis indicates the presence of one HTkA- and one HTkB-like histone in the ancestor of Thermococcales and long-term maintenance of these two paralogs throughout Thermococcales diversification. Our results support the notion that archaea and eukaryotes have convergently evolved histone variants that carry out distinct adaptive functions. Intriguingly, we also detect more highly diverged histone-fold proteins, related to those found in some bacteria, in several Thermococcales genomes. The functions of these bacteria-type histones remain entirely unknown, but structural modelling suggests that they can form heterodimers with HTkA/B-like histones.
Human electromagnetic and haemodynamic networks systematically converge in unimodal cortex and diverge in transmodal cortex
Authors: Shafiei Golia , Baillet Sylvain , Misic Bratislav
Published: September 2021

Whole-brain neural communication is typically estimated from statistical associations among electromagnetic or haemodynamic time-series. The relationship between functional network architectures recovered from these two types of neural activity remains unknown. Here we map electromagnetic networks (measured using magnetoencephalography; MEG) to haemodynamic networks (measured using functional magnetic resonance imaging; fMRI). We find that the relationship between the two modalities is regionally heterogeneous and systematically follows the cortical hierarchy, with close correspondence in unimodal cortex and poor correspondence in transmodal cortex. Comparison with the BigBrain histological atlas reveals that electromagnetic-haemodynamic coupling is driven by laminar differentiation and neuron density, suggesting that the mapping between the two modalities can be explained by cytoarchitectural variation. Importantly, haemodynamic connectivity cannot be explained by electromagnetic activity in a single frequency band, but rather arises from the mixing of multiple neurophysiological rhythms. Correspondence between the two is largely driven by MEG functional connectivity at the beta (15-29 Hz) frequency band. Collectively, these findings demonstrate highly organized but only partly overlapping patterns of connectivity in MEG and fMRI functional networks, opening fundamentally new avenues for studying the relationship between cortical microarchitecture and multi-modal connectivity patterns.
In vitro discovery and optimization of a human monoclonal antibody that neutralizes neurotoxicity and lethality of cobra snake venom
Authors: Ledsgaard Line , Laustsen Andreas H. , Pus Urska , Wade Jack , Villar Pedro , Boddum Kim , Slavny Peter , Masters Edward W. , Arias Ana S. , Oscoz Saioa , Griffiths Daniel T. , Luther Alice M. , Lindholm Majken , Leah Rachael A. , Møller Marie Sofie , Ali Hanif , McCafferty John , Lomonte Bruno , Gutiérrez José M. , Karatt-Vellatt Aneesh
Published: September 2021

The monocled cobra (Naja kaouthia) is one of the most feared snakes in Southeast Asia. It is a highly dangerous species with a potent venom deriving its toxicity predominantly from abundant long-chain α-neurotoxins. The only specific treatment for snakebite envenoming is antivenom, which is based on animal-derived polyclonal antibodies. Despite the lifesaving importance of these medicines over the past 120 years, and their ongoing role in combating snakebite disease, major limitations in safety, supply consistency, and efficacy creates a need for a new generation of improved treatments based on modern biotechnological techniques. Here, we describe the initial discovery and subsequent optimization of a recombinant human monoclonal immunoglobin G (IgG) antibody against α-cobratoxin using phage display technology. Affinity maturation of the parental antibody by light chain-shuffling resulted in an 8-fold increase in affinity, translating to a significant increase in in vitro neutralization potency and in vivo efficacy. While the parental antibody prolonged survival of mice challenged with purified α-cobratoxin, the optimized antibody prevented lethality when incubated with N. kaouthia whole venom prior to intravenous injection. This study is the first to demonstrate neutralization of whole snake venom by a single recombinant monoclonal antibody. Importantly, this suggests that for venoms whose toxicity relies on a single predominant toxin group, such as that of N. kaouthia, as little as one monoclonal antibody may be sufficient to prevent lethality, thus providing a tantalizing prospect of bringing recombinant antivenoms based on human monoclonal or oligoclonal antibodies to the clinic.

One Sentence Summary

A recombinant human monoclonal immunoglobulin G antibody, discovered and optimized using in vitro methods, was demonstrated to neutralize the lethal effect of whole venom from the monocled cobra in mice via abrogation of α-neurotoxin-mediated neurotoxicity.
How do I bite thee? Let me count the ways: Exploring the Implications of Individual Biting Habits of Aedes aegypti for Dengue Transmission
Authors: Christofferson Rebecca C. , Wearing Helen J. , Turner Erik A. , Walsh Christine S. , Salje Henrik , Kiem Cécile Tran , Cauchemez Simon
Published: September 2021

In models of mosquito-borne transmission, the mosquito biting rate is an influential parameter, and understanding the heterogeneity of the process of biting is important, as biting is usually assumed to be relatively homogeneous across individuals, with time-between-bites described by an exponentially distributed process. However, these assumptions have not been addressed through laboratory experimentation. We experimentally investigated the daily biting habits of Ae. aegypti at three temperatures (24°C, 28°C, and 32°C) and determined that there was individual heterogeneity in biting habits (number of bites, timing of bites, etc.). We further explored the consequences of biting heterogeneity using an individual-based model designed to examine whether a particular biting profile determines whether a mosquito is more or less likely to 1) become exposed given a single index case of dengue (DENV) and 2) transmit to a susceptible human individual. Our experimental results indicate that there is heterogeneity among individuals and among temperature treatments. We further show that this results in altered probabilities of transmission of DENV to and from individual mosquitoes based on biting profiles. While current model representation of biting may work under some conditions, it might not uniformly be the best fit for this process. Our data also confirm that biting is a non-monotonic process with temperatures around 28°C being optimum.

Author Summary

Mosquito biting is a necessary and critical part of arbovirus transmission. The mosquito must bite once to acquire a virus and again to transmit, and these two bites must be separated by sufficient time for the virus to get to the salivary glands of the mosquito. Thus, both the number and timing of bites is important. We experimentally investigated how these bite characteristics might be different among individuals and further explored how temperature affected the overall heterogeneity of biting in Aedes aegypti mosquitoes, which carry many arboviruses like dengue virus (DENV). We found that the biting profiles – including number and timing thereof – did vary within temperature groups among individuals and compared outcomes associated with each individual in an individual based model of household DENV transmission. Our results further confirmed that temperatures around 28°C are optimal for mosquito biting (and transmission), that correlations between biting characteristics and transmission were not uniform across temperature, which represents another layer of heterogeneity, and that – at least at 28°C – the null assumption of an exponential or an exponential like (geometric) distribution of biting in mathematical models of transmission is not the best and offer an alternative.
Freeze-thaw Cycles Enable a Prebiotically Plausible and Continuous Pathway from Nucleotide Activation to Nonenzymatic RNA Copying
Authors: Zhang Stephanie J. , Duzdevich Daniel , Carr Christopher E. , Szostak Jack W.
Published: September 2021

Nonenzymatic template-directed RNA copying using chemically activated nucleotides is thought to have played a key role in the emergence of genetic information on the early Earth. A longstanding question concerns the number and nature of different environments that might have been necessary to enable all of the steps from nucleotide synthesis to RNA replication. Here we explore three sequential steps from this overall pathway: nucleotide activation, synthesis of imidazolium-bridged dinucleotides, and template-directed primer extension. We find that all three steps can take place in one reaction mixture, under conditions of multiple freeze-thaw cycles. Recent experiments have demonstrated a potentially prebiotic methyl isocyanide-based nucleotide activation chemistry. Unfortunately, the original version of this approach is incompatible with nonenzymatic RNA copying because the high required concentration of the imidazole activating group prevents the accumulation of the essential imidazolium-bridged dinucleotide needed for primer extension. Here we report that ice eutectic phase conditions facilitate not only the methyl isocyanide-based activation of ribonucleotide 5′-monophosphates with stoichiometric 2-aminoimidazole, but also the subsequent conversion of these activated mononucleotides into imidazolium-bridged dinucleotides. Furthermore, this one pot approach is compatible with template-directed primer extension in the same reaction mixture. Our results suggest that the simple and common environmental fluctuation of freeze-thaw cycles could have played an important role in prebiotic nucleotide activation and nonenzymatic RNA copying.

Significance Statement

The replication of RNA without the aid of evolved enzymes may have enabled the inheritance of useful molecular functions during the origin of life. Several key steps on the path to RNA replication have been studied in isolation, including chemical nucleotide activation, synthesis of a key reactive intermediate, and nonenzymatic RNA copying. Here we report a prebiotically plausible scenario under which these reactions can happen together under mutually compatible conditions. Thus, this pathway could potentially have operated in nature without the complicating requirement for exchange of materials between distinct environments.
Sex biases in cancer and autoimmune disease incidence are strongly positively correlated with mitochondrial gene expression across human tissues
Authors: Crawford David R. , Sinha Sanju , Nair Nishanth Ulhas , Ryan Bríd M. , Barnholtz-Sloan Jill S. , Mount Stephen M. , Erez Ayelet , Aldape Ken , Castle Philip E. , Rajagopal Padma S. , Day Chi-Ping , Schäffer Alejandro A. , Ruppin Eytan
Published: September 2021

Cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 167 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-matched cancer-AID incidence rate sex bias data pairs, we find that, indeed, the sex biases observed in the incidence of AIDs and cancers that occur in the same tissue are positively correlated across human tissues. The common key factor whose levels across human tissues are most strongly associated with these incidence rate sex biases is the sex bias in the expression of the 37 genes encoded in the mitochondrial genome.
Empirical estimates of the mutation rate for an alphabaculovirus
Authors: Boezen Dieke , Ali Ghulam , Wang Manli , Wang Xi , van der Werf Wopke , Vlak Just M. , Zwart Mark P.
Published: September 2021

Mutation rates are of key importance for understanding evolutionary processes and predicting their outcomes. Empirical estimates of mutation rate are available for a number of RNA viruses, but few are available for DNA viruses, which tend to have larger genomes. Whilst some viruses have very high mutation rates, lower mutation rates are expected for viruses with large genomes to ensure genome integrity. Alphabaculoviruses are insect viruses with large genomes and often have high levels of polymorphism, suggesting high mutation rates despite evidence of proofreading activity by the replication machinery. Here, we report an empirical estimate of the mutation rate per base per strand copying (s/n/r) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV). To avoid biases due to selection, we analyzed mutations that occurred in a stable, non-functional genomic insert after five serial passages in Spodoptera exigua larvae. Population bottlenecks, viral mode of replication and thresholds for mutation detection likely affect mutation rate estimates, and we therefore used population genetic models that account for these processes to infer the mutation rate. We estimated a mutation rate of 1×10−7 s/n/r. This estimate was not sensitive to different model assumptions or including whole genome data. The rates at which different classes of mutations accumulate provide good evidence for neutrality of mutations occurring within the inserted region. We therefore present a robust approach for mutation rate estimation for viruses with stable genomes, and strong evidence of a much lower alphabaculovirus mutation rate than supposed based on the high levels of polymorphism observed.

Author Summary

Virus populations can evolve rapidly, driven by the large number of mutations that occur during virus replication. It is challenging to measure mutation rates because selection will affect which mutations are observed: beneficial mutations are overrepresented in virus populations, while deleterious mutations are selected against and therefore underrepresented. Few mutation rates have been estimated for viruses with large DNA genomes, and there are no estimates for any insect virus. Here, we estimate the mutation rate for an alphabaculovirus, a virus that infects caterpillars and has a large, 134 kilobase pair DNA genome. To ensure that selection did not bias our estimate of mutation rate, we studied which mutations occurred in a large artificial region inserted into the virus genome, where mutations did not affect viral fitness. We deep sequenced evolved virus populations, and compared the distribution of observed mutants to predictions from a simulation model to estimate mutation rate. We found evidence for a relatively low mutation rate, of one mutation in every 10 million bases replicated. This estimate is in line with expectations for a virus with self-correcting replication machinery and a large genome.
Lifespan analysis of dystrophic mdx fast-twitch muscle morphology and its impact on contractile function
Authors: Kiriaev Leonit , Kueh Sindy , Morley John W. , North Kathryn N. , Houweling Peter J. , Head Stewart I.
Published: September 2021

Duchenne muscular dystrophy is caused by the absence of the protein dystrophin from skeletal muscle and is characterized by progressive cycles of necrosis/regeneration. Using the dystrophin deficient mdx mouse model we studied the morphological and contractile chronology of dystrophic skeletal muscle pathology in fast twitch EDL muscles from animals 4-22 months of age containing 100% regenerated muscle fibers. Catastrophically, the older age groups lost ∼80% of their maximum force after one eccentric contraction of 20% strain, with the greatest loss ∼93% recorded in senescent 22 month old mdx mice. In old age groups there was minimal force recovery ∼24% after 120 minutes, correlated with a dramatic increase in the number and complexity of branched fibers. This data supports our two-stage model where a “tipping point” is reached when branched fibers rupture irrevocably on eccentric contraction. These findings have important implications for pre-clinical drug studies and genetic rescue strategies.
Sapogenin based self-assembly structures activating a non-apoptotic cell death via multiple pathways
Authors: Üner Göklem , Bedir Erdal , Serçinoğlu Onur , Kırmızıbayrak Petek Ballar
Published: September 2021

Induction of distinct cell death pathways is critical to deal with tumor heterogeneity and therapeutic resistance. In our previous study, we reported a promising saponin analog (AG-08) for cancer therapy inducing non-canonical necrotic cell death. Here, we describe that AG-08 forms unique supramolecular structures responsible for its biological activity. After internalization via non-canonical endocytosis pathway, these structures affect several cell signaling pathways including unfolded protein response, immune response, oxidative stress and heat stress. Moreover, we prepared 18 analogs to reveal the role of residues on the formation of supramolecular structures and biological activities. The results have demonstrated that unique structural features are required for particulate structures and unprecedented cell death mechanism. Although small molecule based supramolecular assemblies have widely been accepted as nuisance for drug discovery studies, our results indicate that they may provide a new research field for anti-cancer drug development studies.
Retrospective analysis of enhancer activity and transcriptome history
Authors: Boers Ruben , Boers Joachim , Tan Beatrice , Wassenaar Evelyne , Sanchez Erlantz Gonzalez , Sleddens Esther , Tenhagen Yasha , van Leeuwen Marieke E. , Mulugeta Eskeatnaf , Laven Joop , Creyghton Menno , Baarends Willy , van IJcken Wilfred F. J. , Gribnau Joost
Published: September 2021

Cell state changes in development and disease are controlled by gene regulatory networks, the dynamics of which are difficult to track in real time. Here, we utilize an inducible DCM-RNA-polymerase-subunit-b fusion protein, to label active genes and enhancers with a bacterial methylation mark that does not affect gene transcription and is propagated in S-phase. We applied this DCM-time-machine (DCM-TM) technology to study intestinal homeostasis, following enterocyte differentiation back in time, revealing rapid and simultaneous activation of enhancers and nearby genes during intestinal stem cell (ISC) differentiation. We provide new insights in the absorptive-secretory lineage decision in ISC differentiation, and show that ISCs retain a unique chromatin landscape required to maintain ISC identity and delineate future expression of differentiation associated genes. DCM-TM has wide applicability in tracking cell states, providing new insights in the regulatory networks underlying cell state changes in development and differentiation.
Disruption of c-MYC binding and chromosomal looping involving genetic variants associated with ankylosing spondylitis upstream of RUNX3 promoter
Authors: Cohen Carla J , Davidson Connor , Selmi Carlo , Bowness Paul , Knight Julian C , Wordsworth B Paul , Vecellio Matteo
Published: September 2021

Background

Ankylosing Spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex aetiology and high heritability, involving more than 100 genetic associations. These include several AS-associated single nucleotide polymorphisms (SNPs) upstream of RUNX3, which encodes the multifunctional RUNT-related transcription factor (TF) 3. The lead associated SNP rs6600247 (p= 2.6 x 10-15) lies ~13kb upstream of the RUNX3 promoter adjacent to a c-MYC TF binding-site. The effect of rs6600247 genotype on DNA binding and chromosome looping were investigated by electrophoretic mobility gel shift assays (EMSA), Western blotting-EMSA (WEMSA) and Chromosome Conformation Capture (3C).

Results

Interrogation of ENCODE published data showed open chromatin in the region overlapping rs6600247 in primary human CD14+ monocytes in contrast to Jurkat T cell line or primary T-cells. The rs6600247 AS-risk allele is predicted to specifically disrupt a c-MYC binding-site. Using a 50bp DNA probe spanning rs6600247 there was consistently less binding to the AS-risk “C” allele of both purified c-MYC protein and nuclear extracts (NE) from monocyte-like U937 cells. WEMSA on U937 NE and purified c-MYC protein confirmed these differences (n=2; p<0.05). 3C experiments demonstrated negligible interaction between the region encompassing rs6600247 and the RUNX3 promoter. A stronger interaction frequency was demonstrated between the RUNX3 promoter and the previously characterised AS-associated SNP rs4648889.

Conclusions

The lead SNP rs6600247, located in an enhancer-like region upstream of the RUNX3 promoter, modulates c-MYC binding. However, the region encompassing rs6600247 has rather limited physical interaction with the promoter of RUNX3. In contrast a clear chromatin looping event between the region encompassing rs4648889 and the RUNX3 promoter was observed. These data provide further evidence for complexity in the regulatory elements upstream of the RUNX3 promoter and the involvement of RUNX3 transcriptional regulation in AS.
The impact of fast radiation on the phylogeny ofBactrocerafruit flies
Authors: Valerio Federica , Zadra Nicola , Stabelli Omar Rota , Ometto Lino
Published: September 2021

True fruit flies (Tephritidae) include several species that cause extensive damage to agriculture worldwide. Among them, species of the genusBactroceraare widely studied to understand the traits associated to their invasiveness and ecology. Comparative approaches based on a reliable phylogenetic framework are particularly effective, but, to date, molecular phylogenies ofBactroceraare still controversial. Here, we employed a comprehensive genomic dataset to infer a robust backbone phylogeny of eleven representativeBactroceraspecies and two outgroups. We further provide the first genome scaled inference of their divergence using calibrated relaxed clock. The results of our analyses support a closer relationship ofB. dorsalistoB. latifronsthan toB. tryoni, in contrast to all mitochondrial-based phylogenies. By comparing different evolutionary models, we show that this incongruence likely derives from the fast and recent radiation of these species that occurred around 2 million years ago, which may be associated with incomplete lineage sorting and possibly (ongoing) hybridization. These results can serve as basis for future comparative analyses and highlight the utility of using large datasets and efficient phylogenetic approaches to study the evolutionary history of species of economic importance.