bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness and feasibility of convalescent blood transfusion to reduce COVID-19 fatality ratio
Authors: Huo Xi , Sun Xiaodan , Bragazzi Nicola , Wu Jianhong
Published: February 2021

Background:
As of December 2020, COVID-19 has spread all over the world with more than 81 million cases and more than 1.8 million deaths. The rapidly increasing number of patients mandates the consideration of potential treatments for patients under severe and critical conditions. Convalescent plasma (CP) treatment refers to the approach of infusing patients with plasma from recently recovered patients. CP appears to be a possible therapeutic option to manage patients suffering from severe or even lethal infectious disorders, in which ‘traditional therapies’ have failed to obtain any result.
Methods:
In the present study, we develop a mathematical model on the treatment-donation-stockpile dynamics for an optimal implementation of CP therapy to examine potential benefits and complications in the logistic realization of this therapy in a large-scale population. We parametrize the model with COVID-19 epidemics in Italy, and conduct scenario analyses to estimate outcomes of population-wide CP therapy and to examine the maximum number of CP donation processions per day.
Results:
Under the assumption that the efficacy of CP is 90%, we show that by the end of year 2020, initiating the population-wide CP therapy from April 2020 can save as many as 19 215 lives (ranging from 5000 to 28 000 depending on donor availability), while the demand for apheresis use is manageable in all scenarios: the maximum daily demand is 156 (ranging from 27 to 519 depending on donor availability) for the first outbreak wave and 1434 (ranging from 224 to 4817 depending on donor availability) for the second wave. Given that Italy has 61 centres with apheresis this maximum demand level corresponds to a daily average of 2.5 and 23.5 processions of CP donation being performed by each centre with respect to each outbreak wave.
Conclusions:
Our analyses show that population-wide CP therapy can contribute to curbing COVID-19-related deaths, and the logistic implementation is feasible for developed countries. The reduction of deaths can be very significant if the CP therapy is started earlier in the outbreak, and remains significant even if it is implemented during the outbreak peak time.
Bridging the gap between rectifying developables and tangent developables: a family of developable surfaces associated with a space curve
Authors: Seguin Brian , Chen Yi-chao , Fried Eliot
Published: February 2021

There are two familiar constructions of a developable surface from a space curve. The tangent developable is a ruled surface for which the rulings are tangent to the curve at each point and relative to this surface the absolute value of the geodesic curvature
κ

g

of the curve equals the curvature
κ
. The alternative construction is the rectifying developable. The geodesic curvature of the curve relative to any such surface vanishes. We show that there is a family of developable surfaces that can be generated from a curve, one surface for each function
k
that is defined on the curve and satisfies |
k
| ≤ 
κ
, and that the geodesic curvature of the curve relative to each such constructed surface satisfies
κ

g

 = 
k
.
Differences in developmental potential predict the contrasting patterns of dental diversification in characiform and cypriniform fishes
Authors: Jandzik David , Stock David W.
Published: February 2021

Morphological diversification during adaptive radiation may depend on factors external or internal to the lineage. We provide evidence for the latter in characiform fishes (tetras and piranhas), which exhibit extensive dental diversity. Phylogenetic character mapping supported regain of lost teeth as contributing to this diversity. To test for latent potential for dentition that would facilitate its evolutionary expansion, we overexpressed a tooth initiation signal, the tumour necrosis factor pathway ligandectodysplasin, in a model characiform, the Mexican tetra (Astyanax mexicanus). This manipulation resulted in extensive ectopic dentition, in contrast with its previously reported limited effect in the zebrafish (Danio rerio). Tooth location in the order Cypriniformes, to which the zebrafish belongs, is much more restricted than in characiforms, a pattern that may be explained by differences in the retention of ancestral developmental potential. Our results suggest that differences in evolvability between lineages may lead to contrasting patterns of diversification.
Sociability increases survival of adult female giraffes
Authors: Bond M. L. , Lee D. E. , Farine D. R. , Ozgul A. , König B.
Published: February 2021

Studies increasingly show that social connectedness plays a key role in determining survival, in addition to natural and anthropogenic environmental factors. Few studies, however, integrated social, non-social and demographic data to elucidate what components of an animal's socio-ecological environment are most important to their survival. Female giraffes (
Giraffa camelopardalis
) form structured societies with highly dynamic group membership but stable long-term associations. We examined the relative contributions of sociability (relationship strength, gregariousness and betweenness), together with those of the natural (food sources and vegetation types) and anthropogenic environment (distance from human settlements), to adult female giraffe survival. We tested predictions about the influence of sociability and natural and human factors at two social levels: the individual and the social community. Survival was primarily driven by individual- rather than community-level social factors. Gregariousness (the number of other females each individual was observed with on average) was most important in explaining variation in female adult survival, more than other social traits and any natural or anthropogenic environmental factors. For adult female giraffes, grouping with more other females, even as group membership frequently changes, is correlated with better survival, and this sociability appears to be more important than several attributes of their non-social environment.
Neural and social correlates of attitudinal brokerage: using the complete social networks of two entire villages
Authors: Youm Yoosik , Kim Junsol , Kwak Seyul , Chey Jeanyung
Published: February 2021

To avoid polarization and maintain small-worldness in society, people who act as attitudinal brokers are critical. These people maintain social ties with people who have dissimilar and even incompatible attitudes. Based on resting-state functional magnetic resonance imaging (n= 139) and the complete social networks from two Korean villages (n= 1508), we investigated the individual-level neural capacity and social-level structural opportunity for attitudinal brokerage regarding gender role attitudes. First, using a connectome-based predictive model, we successfully identified the brain functional connectivity that predicts attitudinal diversity of respondents' social network members. Brain regions that contributed most to the prediction included mentalizing regions known to be recruited in reading and understanding others’ belief states. This result was corroborated by leave-one-out cross-validation, fivefold cross-validation and external validation where the brain connectivity identified in one village was used to predict the attitudinal diversity in another independent village. Second, the association between functional connectivity and attitudinal diversity of social network members was contingent on a specific position in a social network, namely, the structural brokerage position where people have ties with two people who are not otherwise connected.
Spinal fluid antibodies against multiple sclerosis candidate bacteria in demyelinating disease
Authors: Eckman Emily , Laman Jon D. , Fischer Kael F. , Lopansri Bert , Martins Tom B. , Hill Harry R. , Kriesel John D.
Published: February 2021

A panel of 10 IgG enzyme-linked immunosorbent assays (ELISAs) were developed for the detection of anti-microbial immune responses in the cerebrospinal fluid (CSF) of patients with demyelinating diseases (DD). Selection of the anti-microbial ELISA assays was guided by previous RNA sequencing studies that established a multiple sclerosis (MS) microbial candidate list. Microbial antigens included on the ELISA panel were derived from Akkermansia muciniphila, Atopobium vaginae, Bacteroides fragilis, Lactobacillus paracasei, Odoribacter splanchnicus, Pseudomonas aeruginosa, Cutibacterium (Propionibacterium) acnes, Fusobacterium necrophorum, Porphyromonas gingivalis, and Streptococcus mutans. Spinal fluid responses from patients with demyelinating diseases (DD, N=14) were compared to those with other neurological diseases (OND, N=8), and non-MS (Control, N=13) control patients. Commercial positive and negative control CSF specimens were run with each assay. ELISA Index values were derived for each specimen against each of the 10 bacterial antigen preparations. Intrathecal production of anti-microbial antibodies was assessed by comparing CSF and comparably diluted serum. CSF reactivity was significantly higher in the DD group compared to the controls against Akkermansia, Atopobium, Bacteroides, Lactobacillus, Odoribacter, and Fusobacterium. Four of the 11 tested DD group subjects had elevated antibody indexes against at least one of the 10 bacterial antigens, suggesting intrathecal production of anti-bacterial antibodies. This CSF serological study supports the hypothesis that several of the previously identified MS candidate microbes may contribute to demyelination in some patients.
State-Anxiety Modulates the Effect of Emotion Cues on Visual Temporal Sensitivity in Autism Spectrum Disorder
Authors: Chakrabarty Mrinmoy , Atsumi Takeshi , Yaguchi Ayako , Fukatsu Reiko , Ide Masakazu
Published: February 2021

Atypical processing of stimulus inputs across a range of sensory modalities in autism spectrum disorders (ASD) are widely reported. Sensory processing is known to be influenced by bodily internal states such as physiological arousal and anxiety. Since a sizeable proportion of ASD individuals reportedly have co-morbid anxiety disorders that are linked with dysregulated arousal, we investigated if face-emotion arousal cues, influenced visual sensory sensitivity (indexed by temporal resolution) in an ASD group (n=20) compared to a matched group of typically-developed individuals (TD, n=21). We asked further if emotion-cued changes in visual sensitivity associated with individual differences in state- and trait-anxiety. Participants reported the laterality of the second of two consecutive Gaussian-blob flashes in a visual temporal order judgment task (v-TOJ), demanding higher-level visual processing. The key manipulation was presenting a task-irrelevant face emotion cue briefly at unexpected time points preceding the task-relevant flashes. Disgust vs Neutral emotion signals enhanced the visual temporal resolution in ASD individuals. Furthermore, individual state-anxiety scores correlated with the emotion-cued change of temporal resolution (Disgust vs Neutral) in the ASD group. Both these effects were absent in the TD group. The results show that individual state-anxiety levels significantly modulate the effect of emotions on visual temporal sensitivity in ASD individuals, which was absent in our TD sample. The findings support a nuanced approach to understand the disparate sensory features in ASD individuals, by factoring in the interplay of the individual reactivity to environmental affective information and the severity of anxiety.
Protocol for rapid implementation of a SARS-CoV-2 sero-survey during the 2020 COVID-19 pandemic – who, where, how?
Authors: Smith Daniel , Mac Valerie , Yang Irene , Butts Brittany , Hecker Morgan , Howell J. Christina , Ozturk Tugba , Pirmohammed Shama , Huang Hanfeng , Kippels Andrea , Brewster Glenna , Verble Danielle D , Jacobs Winnie , Hu William T. , Wharton Whitney
Published: February 2021

Introduction

The 2019 novel coronavirus disease (COVID-19) pandemic has had devastating consequences in the US, yet clinical research on its natural history and transmission outside hospitalized settings has faced tangible and intangible challenges due to uncertainty in testing, case ascertainment, and appropriate safety measures. To better understand temporal evolution of COVID-19 related serological and other immune responses during a pandemic, we designed and implemented a baseline cross-sectional study of asymptomatic community volunteers and first responders in metro-Atlanta before the predicted infection peak in 2020.

Methods

We recruited healthy community volunteers and first responders for health history, serology, and biobanking. Through an iterative process, we identified one location on our campus and one community location which were accessible, vacant, distant from COVID-19 testing sites, open for social distancing, private for informed consent, and operational for sanitation and ventilation. Research and cleaning supplies were obtained from other researchers and private online vendors due to shortages, and faculty directly participated in consenting and phlebotomy.

Results

A total of 369 participants completed the study visits over six full and three half days. Over half of Phase 1 (174/299, 58.2%) and Phase 2 (45/70, 64.3%) self-reported as healthcare workers, and there was a high percentage of participants reporting exposure to known COVID-19 cases (48.2% and 61.4%).

Conclusions

Rigorous prospective clinical research with informed consents and is possible during a pandemic. Effective recruitment for moderately large sample size is facilitated by direct faculty involvement, connections with the community, and non-financial support from colleagues and the institution.
Genome-wide association study reveals genetic risk factors for trigeminal neuralgia
Authors: Hale Andrew T. , He Jing , Akinnusotu Oluwatoyin , Sale Rebecca L. , Wang Janey , Bastarache Lisa , Gamazon Eric R.
Published: February 2021

Background

While many clinical risk factors of trigeminal neuralgia (TN) have been identified, the genetic basis of TN is largely unknown. Here, we perform the first genome-wide association study (GWAS) for TN using three independent DNA biobanks – BioVU, the UK Biobank, and Finngen.

Objective

To elucidate the genetic basis of TN.

Methods

Using GWAS summary statistics generated from BioVU, the UK Biobank, and Finngen, we performed fixed-effect meta-analysis across 490,912 individuals (1,188 TN cases and 489,724 controls) to identify genetic risk factors for TN. Genome-wide significance was defined as p < 5.0×10−8.

Results

We identify an intergenic locus on chromosome 1p22.2 flanked byZNF326andSNORD3Gcontaining 5 SNPs (rs77449572, rs543311093, rs35117749, rs71666259, and rs116010656) reaching genome-wide significance (p < 5.0 x 10−8), where rs77449572 is the sentinel variant (p = 1.72 x 10−9). The SNP rs77449572 overlaps an enhancer element in cortex-derived neurospheres. In addition, rs71666259 and rs116010656 are located in enhancer elements in embryonic stem cells (HUES48), suggesting potential functional consequences of this locus. We also identify a second locus on chromosome 5q35.1 containing sentinel variant rs62376947 reaching genome-wide significance (p = 2.49 x 10−8).

Conclusions

To our knowledge, we perform the first GWAS of TN. Future studies should be aimed at understanding the extent to which genetic variation stratifies response to neuropathic pain medication and whether genetic information may be used to identify patients who are likely to benefit (or not) from surgical intervention.
pyconsFold: A fast and easy tool for modelling and docking using distance predictions
Authors: Lamb J , Elofsson A
Published: February 2021

Motivation

Contact predictions within a protein has recently become a viable method for accurate prediction of protein structure. Using predicted distance distributions has been shown in many cases to be superior to only using a binary contact annotation. Using predicted inter-protein distances has also been shown to be able to dock some protein dimers.

Results

Here we present pyconsFold. Using CNS as its underlying folding mechanism and predicted contact distance it outperforms regular contact prediction based modelling on our dataset of 210 proteins. It performs marginally worse than the state of the art pyRosetta folding pipeline but is on average about 20 times faster per model. More importantly pyconsFold can also be used as a fold-and-dock protocol by using predicted inter-protein contacts to simultaneously fold and dock two protein chains.

Availability and implementation

pyconsFold is implemented in Python 3 with a strong focus on using as few dependencies as possible for longevity. It is available both as a pip package in Python 3 and as source code onGitHuband is published under the GPLv3 license.

Contact

arne@bioinfo.se

Supplemental material

Install instructions, examples and parameters can be found in the supplemental notes.

Availability of data

The data underlying this article together with source code are available on github, athttps://github.com/johnlamb/pyconsfold.
Living apart if you can – how genetically and developmentally controlled sex has shaped the evolution of liverworts
Authors: He Xiaolan , Flores Jorge R. , Sun Yu , Bowman John L.
Published: February 2021

Sexual differentiation in bryophytes occurs in the dominant gametophytic generation. Over half of bryophytes are dioicous, and this pattern in liverworts is even more profound as over 70% of species are dioicous. However, the evolutionary mechanisms leading to the prevalence of dioicy and the shifts of sexual systems between dioicy and monoicy have remained poorly known. These essential factors in reproductive biology are explored here in light of phylogenetics combined with evidence of genomic characterization of sex chromosomes and sex-determination, as well as cytology. Our analyses and discussions on liverworts are focused on: (1) ancestry and shifts in sexuality, (2) evolution of sex chromosomes and maintenance of haploid dioicy, and (3) environmental impact on the evolution of monoicism. We show that the dioicous condition is ancestral in liverworts, and the evolution of sexual systems is both conserved and stable with an ancient origin, but also highly dynamic in certain more recently diverged lineages. We assume that the haploid dioicy maintained in the course of evolution must be linked to the genetically controlled sex-determination, and transition from genetically to developmentally controlled sex determination, the evolution of monoicism, is driven by ephemeral and unstable environments. Monoicy is less stable in the long-term than dioicy, and thus, ultimately, dioicy is selected in liverworts. It is concluded that sexual dimorphism is maintained through a highly dynamic evolutionary process, sex chromosomes bearing distinct set of evolutionary forces that can have large impacts on genome evolution and may also promote speciation.
Numerical calculation of the light propagation in tapered optical fibers for optical neural interfaces
Authors: Mach-Batlle Rosa , Pisanello Marco , Pisano Filippo , De Vittorio Massimo , Pisanello Ferruccio , Ciracì Cristian
Published: February 2021

As implantable optical systems recently enabled new approaches to study the brain with optical radiations, tapered optical fibers emerged as promising implantable waveguides to deliver and collect light from sub-cortical structures of the mouse brain. They rely on a specific feature of multimodal fiber optics: as the waveguide narrows, the number of guided modes decreases and the radiation can gradually couple with the environment. This happens along a taper segment whose length can be tailored to match with the depth of functional structures of the mouse brain, and can extend for a few millimeters. This anatomical requirement results in optical systems which have an active area that is very long compared to the wavelength of the light they guide and their behavior is typically estimated by ray tracing simulations, because finite element methods are too computationally demanding. Here we present a computational technique that exploits the beam-envelope method and the cylindrical symmetry of the fibers to provide an efficient and exact calculation of the electric field along the fibers, which may enable the design of neural interfaces optimized to meet different goals.
Biomechanical control of meiotic chromosomal bouquet and germ cell morphogenesis by the zygotene cilium
Authors: Mytlis Avishag , Kumar Vineet , Tao Qiu , Deis Rachael , Hart Neta , Levy Karine , Masek Markus , Shawahny Amal , Ahmad Adam , Eitan Hagai , Nather Farouq , Adar-Levor Shai , Birnbaum Ramon Y. , Elia Natalie , Bachmann-Gagescu Ruxandra , Roy Sudipto , Elkouby Yaniv M.
Published: February 2021

The hallmark of meiosis is chromosomal pairing and synapsis via synaptonemal complexes, but chromosomal pairing also depends on cytoplasmic counterparts that tether and rotate telomeres on the nuclear envelope. Telomeres slide on perinuclear microtubules, shuffling chromosomes and mechanically driving their homology searches. Pull of telomeres towards the centrosome drives formation of the “zygotene chromosomal bouquet”. These telomere dynamics are essential for pairing and fertility, and the bouquet, discovered in 1900, is universally conserved. Nevertheless, how cytoplasmic counterparts of bouquet formation are mechanically regulated has remained enigmatic. Here, we report the “zygotene cilium” - a previously unrecognized cilium, in oocytes. We show in zebrafish that this cilium specifically connects to the bouquet centrosome, constituting a cable system of the cytoplasmic bouquet machinery. Furthermore, zygotene cilia extend throughout the germline cyst, a conserved germ cell organization. Using multiple ciliary mutants and laser-induced excision, we demonstrate that the zygotene cilium is essential for chromosomal bouquet and synaptonemal complex formation, germ cell morphogenesis, ovarian development and fertility. Mechanistically, we provide evidence that the cilium functions at least partly via anchoring the bouquet centrosome in order to counterbalance telomere rotation and pulling. We also show that the zygotene cilium is conserved in both male and female meiosis in zebrafish, as well as in mammals. Our work uncovers the novel concept of a cilium as a critical player in meiosis and sheds new light on reproduction phenotypes in ciliopathies. We propose a cellular paradigm that cilia can control chromosomal dynamics.
Scalable Bias-corrected Linkage Disequilibrium Estimation Under Genotype Uncertainty
Authors: Gerard David
Published: February 2021

Linkage disequilibrium (LD) estimates are often calculated genome-wide for use in many tasks, such as SNP pruning and LD decay estimation. However, in the presence of genotype uncertainty, naive approaches to calculating LD have extreme attenuation biases, incorrectly suggesting that SNPs are less dependent than in reality. These biases are particularly strong in polyploid organisms, which often exhibit greater levels of genotype uncertainty than diploids. A principled approach using maximum likelihood estimation with genotype likelihoods can reduce this bias, but is prohibitively slow for genome-wide applications. Here, we present scalable moment-based adjustments to LD estimates based on the marginal posterior distributions of the genotypes. We demonstrate, on both simulated and real data, that these moment-based estimators are as accurate as maximum likelihood estimators, and are almost as fast as naive approaches based only on posterior mean genotypes. This opens up bias-corrected LD estimation to genome-wide applications. Additionally, we provide standard errors for these moment-based estimators. All methods are implemented in theldseppackage on the Comprehensive R Archive Networkhttps://cran.r-project.org/package=ldsep.
A unified model of amino acid homeostasis in mammalian cells
Authors: Gauthier-Coles Gregory , Vennitti Jade , Zhang Zhiduo , Comb William C. , Javed Kiran , Broer Angelika , Broer Stefan
Published: February 2021

Homeostasis is one of the fundamental concepts in physiology. Despite remarkable progress in our molecular understanding of amino acid transport, metabolism and signalling, it remains unclear by what mechanisms cytosolic amino acid concentrations are maintained. We propose that amino acid transporters are the primary determinants of intracellular amino acid levels. We show that a cell’s endowment with amino acid transporters can be deconvoluted by a logical series of experiments. This was used to computationally simulate amino acid translocation across the plasma membrane. For two different cancer cell lines and human myotubes, transport simulation generates cytosolic amino acid concentrations that are close to those observedin vitro. Perturbations of the system were replicatedin silicoand could be applied to systems where only transcriptomic data are available. The methodology developed in this study is widely applicable to other transport processes and explain amino acid homeostasis at the systems-level.
Energetic and structural features of SARS-CoV-2 N-protein co-assemblies with nucleic acids
Authors: Zhao Huaying , Wu Di , Nguyen Ai , Li Yan , Adão Regina C. , Valkov Eugene , Patterson George H. , Piszczek Grzegorz , Schuck Peter
Published: February 2021

Nucleocapsid (N) protein of the SARS-CoV-2 virus packages the viral genome into well-defined ribonucleoprotein particles, but the molecular pathway is still unclear. N-protein is dimeric and consists of two folded domains with nucleic acid (NA) binding sites, surrounded by intrinsically disordered regions that promote liquid-liquid phase separation. Here we use biophysical tools to study N-protein interactions with oligonucleotides of different length, examining the size, composition, secondary structure, and energetics of the resulting states. We observe formation of supramolecular clusters or nuclei preceding growth into phase-separated droplets. Short hexanucleotide NA forms compact 2:2 N-protein/NA complexes with reduced disorder. Longer oligonucleotides expose additional N-protein interactions and multi-valent protein-NA interactions, which generate higher-order mixed oligomers and simultaneously promote growth of droplets. Phase separation is accompanied by a significant increase in protein secondary structure, different from that caused by initial NA binding, which may contribute to the assembly of ribonucleoprotein particles within molecular condensates.
Thinopyrum intermediumTiAP1 interacts with a chitin deacetylase fromBlumeria graminisf. sp.triticiand increases the resistance toBgtin wheat
Authors: Yang Yanlin , Fan Pan , Liu Jingxia , Xie Wenjun , Liu Na , Niu Zubiao , Li Quanquan , Song Jing , Tian Qiuju , Bao Yinguang , Wang Honggang , Feng Deshun
Published: February 2021

The biotrophic fungal pathogenBlumeria graminisf. sp.tritici(Bgt) is a crucial factor causing reduction of global wheat production. Wild wheat relatives, e.g.Thinopyrum intermedium,is one of the wild-used parents in wheat disease-resistant breeding. FromT.intermediumline, we identified the aspartic acid protein gene,TiAP1, which involved in resistance againstBgt. TiAP1 is a secreted protein that accumulates in large amounts at the infection sites of powdery mildew and extends to the intercellular space. Yeast two-hybrid showed that it interacted with the chitin deacetylase (BgtCDA1) ofBgt. The yeast expression, purification, andinvitrotest confirmed the chitin deacetylase activity of BgtCDA1. The bombardment and VIGS mediated host-induced gene silencing showedBgtCDA1promotes the invasion ofBgt. Transcriptome analysis showed the cell wall xylan metabolism, lignin biosynthesis-related, and defence genes involved in the signal transduction were upregulated in the transgenicTiAP1wheat induced byBgt. The TiAP1 in wheat may inactivate the deacetylation function of BgtCDA1, cause chitin oligomers expose to wheat chitin receptor, then trigger the wheat immune response to inhibit the growth and penetration ofBgt, and thereby enhance the tolerance of wheat to pathogens.
Ascertainment rate of SARS-CoV-2 infections from healthcare and community testing in the UK
Authors: Colman Ewan , Puspitarani Gavrila A. , Enright Jessica , Kao Rowland R.
Published: February 2021

The proportion of SARS-CoV-2 infections ascertained through healthcare and community testing is generally unknown and expected to vary depending on natural factors and changes in test-seeking behaviour. Here we use population surveillance data and reported daily case numbers in the United Kingdom to estimate the rate of case ascertainment. We mathematically describe the relationship between the ascertainment rate, the daily number of reported cases, population prevalence, and the sensitivity of PCR and Lateral Flow tests as a function time since exposure. Applying this model to the data, we estimate that 20-40% of SARS-CoV-2 infections in the UK were ascertained with a positive test with results varying by time and region. Cases of the Alpha variant were ascertained at a higher rate than the wild type variants circulating in the early pandemic, and higher again for the Delta variant and Omi-cron BA.1 sub-lineage, but lower for the BA.2 sub-lineage. Case ascertainment was higher in adults than in children. We further estimate the daily number of infections and compare this to mortality data to estimate that the infection fatality rate increased by a factor of 3 during the period dominated by the Alpha variant, and declined in line with the distribution of vaccines.
Oncogenic alterations in the p53 pathway abolish oscillatory competence
Authors: Xiong Lingyun , Garfinkel Alan
Published: February 2021

The tumor suppressor p53 displays concentration oscillations in response to DNA damage, a behavior that has been suggested to be essential to its anti-cancer function. Many genetic alterations in the p53 pathway have been shown to be oncogenic, whether by experiment or by clinical associations with various cancers. These oncogenic alterations include somatic mutations, copy number variations and inherited polymorphisms. Using a differential equation model of p53-Mdm2 dynamics, we employ Hopf bifurcation analysis to show that all of the oncogenic perturbations have a common effect, to abolish the oscillatory competence of p53, thereby impairing its tumor suppressor function. In this analysis, these diverse genetic alterations, widely observed in human cancers, have a unified mechanistic explanation.

Significance

In human cancers, the p53 tumor suppressor pathway is frequently altered by diverse genetic changes. An integrated understanding of these oncogenic alterations is currently lacking. We show that all oncogenic alterations in the p53 pathway abolish the oscillatory competence of p53, a property that is essential for cell cycle arrest upon stress, for effective DNA damage response and for maintaining genome integrity. This unified dynamical explanation of distinct cancer driver events that converge on a key cancer hallmark pathway has practical implications for anti-cancer therapies.
The 3-D structure of fibrous material is fully restorable from its X-ray diffraction pattern
Authors: Iwamoto Hiroyuki
Published: February 2021

X-ray fiber diffraction is potentially a powerful technique to study the structure of fibrous materials, such as DNA and synthetic polymers. However, only rotationally averaged diffraction patterns can be recorded, and it is difficult to correctly interpret them without the knowledge of esoteric diffraction theories. Here we demonstrate that, in principle, the non-rotationally averaged 3-D structure of the material can be restored from its fiber diffraction pattern. The method is a simple puzzle-solving process, and in ideal cases, it does not require any prior knowledge about the structure, such as helical symmetry. We believe that the proposed method has a potential to transform the fiber diffraction to a 3-D imaging technique, and will be useful for a wide field of life and materials sciences.
Comparative analysis of mammal genomes unveils key genomic variability for human lifespan
Authors: Farré X. , Molina R. , Barteri F. , Timmers P.R.H.J. , Joshi P.K. , Oliva B. , Acosta S. , Esteve-Altava B. , Navarro A. , Muntané G.
Published: February 2021

Mammals vary 100-fold in their maximum lifespan. This enormous variation is the result of the adaptations of each species to their own biological trade-offs and ecological conditions. Comparative genomics studies have demonstrated that the genomic factors underlying the lifespans of species and the longevity of individuals are shared across the tree of life. Here, we set out to compare protein-coding regions across the mammalian phylogeny, aiming to detect individual amino acid changes shared by the most long-lived mammal species and genes whose rates of protein evolution correlate with longevity. We discovered a total of 2,737 amino acid changes in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (p=0.003). The detected genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 amino acids, located in 996 different genes, showed a significant association with maximum lifespan in a phylogenetically controlled test. Interestingly, most of the detected amino acids positions do not vary in extant human populations (>81.2%) or have allele frequencies below 1% (99.78%), Consequently, almost none could have been detected by Genome-Wide Association Studies (GWAS). Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected by chance, successfully demonstrating for the first time that comparative genomics can be used to enhance the interpretation of human GWAS. Finally, we show that the human longevity-associated proteins coded by the detected genes are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.
Reconciling Inherent Interfacial Compatibility Conflict Enhances Adhesive Infiltration and Resolves Dentin Bonding Durability
Authors: Luo Qiaojie , Chen Yadong , Xu Jiajia , Shu Chang , Li Zimeng , Zhu Weipu , Shen Youqing , Li Xiaodong
Published: February 2021

Wet bonding is a basic technique used daily in clinics for tooth-restoration fixation. However, only 50% of the bonding lasts more than 5 years and thus patients must visit the dentists repeatedly. This is attributed to the limited infiltration of adhesives into the demineralized dentin (DD) matrix during wet-bonding. Herein, we show that reconciling interfacial compatibility conflict between the DD matrix and the critical hydrophobic adhesive molecules via hydrophobizing the DD matrix enables the adhesives to thoroughly infiltrate and uniformly distribute within the DD matrix. Thus, the bonding of the hydrophobic DD matrix using commercial dentin adhesives achieves the bonding strength 2-6 times higher than that of the non-treated DD matrix. When a hydrophobic adhesive is applied on the hydrophobic DD matrix, a flawless hybrid layer is produced as observed by nanoleakage investigation. A long-term bonding strength comes up to 7.3 fold that of the control group and very importantly, with no attenuation after 12 months. This study clarifies the basic cause of poor wet-bonding durability and demonstrates a paradigm in adhesive dentistry to overcome the long-existing bonding durability problem associated with inadequate adhesive infiltration into the DD matrix. This provides a new angle of view to resolve clinical dentin bonding durability problem and will significantly promote adhesive dentistry.

Highlights

Inherent interfacial compatibility conflict between demineralized dentin matrix and hydrophobic molecules of dentin adhesives is the basic cause for the dentin bonding durability problem.

Reconciling the interfacial compatibility conflict markedly facilitates adhesive infiltration in the demineralized dentin matrix and greatly enhances bonding effectiveness.

High interfacial compatibility produces a flawless hybrid layer and ideal bonding effectiveness and durability.

Graphical Abstract

For wet bonding, poor infiltration of adhesives within the DD matrix inevitably produces numerous defects throughout the hybrid layer, which always leads to the failure of restoration. Via hydrophobizing the DD matrix, reconciling interfacial compatibility conflict between the DD matrix and the hydrophobic adhesive monomers overcomes durability problems associated with the infiltration of adhesives into the DD matrix producing a flawless hybrid layer and providing ideal bonding effectiveness and durability.
Beyond fitness: selection and information flow through the constructive steps in lifecycles
Authors: Smith Eric
Published: February 2021

The replicator is the fundamental abstraction of evolutionary genetics. Only for replicators do Darwin’s concept of fitness as differential reproductive success, and the formalization by Fisher and Price in terms of apportionment of descendant populations to ancestors, coincide without ambiguity or potential conflict. The organization of the Price equation, causal interpretations of Fisher’s Fundamental Theorem and its relatives, and the abstraction of fitness as the sole channel through which information flows in from environments to form the adapted states of evolving populations, all follow from properties of replicators imposed artificially on the genetics of more complex lifecycles. Here it is shown how to generalize this role of the replicator to the autocatalytic flows in the generators of Stoichiometric Populations Processes, and to generalize from the unique summary statistic of fitness to a class of summary statistics that appear as regression coefficients against the autocatalytic flows associated with reproduction, including replication but also including constructive operations beyond simple copying. Both the statistical construction and the causal interpretation of Fisher’s Theorem and the Price Equation generalize from replicators and fitness to the wider class of regressions.Ad hoccorrections for mis-specified fitness models, which the conventional Price equation groups with “environment” effects, become part of a Fisher covariance on the basis of flows, which takes on a consistent causal interpretation in terms of an expanded concept of selection recognizing distributed information. A measure is derived for the information in the trajectory of a population evolving under a stoichiometric stochastic process, as the large-deviation function for that trajectory from a null model. The interpretation of fitness and other regression coefficients as channels for causation and information flow is derived from their inner product with the gradient of the trajectory entropy.
Checkpoint proteins in patients with precancer and cervical cancer
Authors: Kayukova Elena , Sholokhov Leonid , Belokrinitskaya Tatiana , Tereshkov Pavel
Published: February 2021

The efficiency of immuno-oncological drugs in treatment cervical cancer is not high. The research of new immunological targets in cervical cancer is actual.

The aim was to study the local level of checkpoint proteins of immune cycle in patients with cervical cancer of different stages (sCD25, 4-1BB, B7.2, TGF-b1, CTLA-4, PD-L1, PD-1, Tim-3, LAG-3, Galectin-9, sCD27, PD-L2).

Materials and research methods. The objects of study were the patients with precancer (n=13) and cervical cancer (n=49). The control group consisted of 13 gynecologically healthy women. The material of study was cervical epithelium obtained by cervical brush. The research method was flow cytometry. Test parameters: sCD25, 4-1BB, B7.2, TGF-b1, CTLA-4, PD-L1, PD-1, Tim-3, LAG-3, Galectin-9, sCD27, PD-L2. Statistical analysis of the data was carried out using nonparametric statistics using the Mann – Whitney U-test. The results of the study.

The levels of sCD25, B7.2, PDL1, Tim-3, sCD27, PD-L2 were increased in the comparison groups relation to the control (p <0.05). The differential criterion for invasive cervical cancer may be an increase in the level of LAG-3 in the cervical epithelium by 43% (p <0.05).The levels of PD-L1, PD-1, sCD27 and PD-L2 were increased opposite the levels LAG-3 and Galectin-9 were decreased in patients with metastatic cervical cancer(p <0.05).
A Safe and Effective Mucosal RSV Vaccine Consisting of RSV Phosphoprotein and Flagellin Variant
Authors: Zhao Bali , Yang Jingyi , He Bing , Li Xian , Yan Hu , Liu Shuning , Yang Yi , Zhou Dihan , Liu Bowen , Fan Xuxu , Zhong Maohua , Zhang Ejuan , Zhang Fan , Zhang Yue , Chen Yao-Qing , Jiang Shibo , Yan Huimin
Published: February 2021

Respiratory syncytial virus (RSV) is a major cause of serious acute lower respiratory tract infection in infants and the elderly. No licensed RSV vaccine available thus far calls for the development of vaccines with new target(s) and vaccination strategies. Here, we constructed a recombinant protein, designated P-KFD1, comprised of RSV phosphoprotein (P) andE. coliK12 strain-derived flagellin variant KFD1. Intranasal (i.n.) immunization with P-KFD1 inhibits RSV replication in both upper and lower respiratory tract, and protects mice against lung disease without vaccine-enhanced disease (VED). The P-specific CD4+T cells provoked by P-KFD1 i.n. immunization, either reside in or migrate to respiratory tract, mediate protection against RSV infection. Sc-RNA seq and carboxyfluorescein succinimidyl ester (CFSE) labeled cell transfer further characterized the Th1 and Th17 responses induced by P-KFD1. Finally, we found the anti-viral protection depends on either IFN-γ or IL-17A. Collectively, P-KFD1 is promising as a safe and effective mucosal vaccine candidate to prevent RSV infection.

HIGHLIGHTS

A new subunit RSV vaccine candidate with new target and vaccination strategy, P-KFD1, is designed and generated

Intranasal immunization with P-KFD1 protects mice against RSV infection and averts vaccine-enhanced disease

Sc-RNA seq and CFSE-labelled cell transfer identified characteristics of the protective CD4+T cells

Local and peripheral CD4+T cells provide protection against RSV infection dependent on either IFN-γ or IL-17A
Repetitive Mild Head Trauma Induces Activity-Mediated Lifelong Brain Deficits in a NovelDrosophilaModel
Authors: Behnke Joseph A. , Ye Changtian , Setty Aayush , Moberg Kenneth H. , Zheng James Q.
Published: February 2021

Mild head trauma, including concussion, can lead to chronic brain dysfunction and degeneration but the underlying mechanisms remain poorly understood. Here, we developed a novel head impact system to investigate the long-term effects of mild head trauma on brain structure and function, as well as the underlying mechanisms inDrosophila melanogaster. We find thatDrosophilasubjected to repetitive head impacts develop long-term deficits, including impaired startle-induced climbing, progressive brain degeneration, and shortened lifespan, all of which are substantially exacerbated in female flies. Interestingly, head impacts elicit an elevation in neuronal activity and its acute suppression abrogates the detrimental effects in female flies. Together, our findings validateDrosophilaas a suitable model system for investigating the long-term effects of mild head trauma, suggest an increased vulnerability in brain injury in female flies, and indicate that early altered neuronal excitability may be a key mechanism linking mild brain trauma to chronic degeneration.
Comprehensive Analysis of Ubiquitously Expressed Genes in Human, From a Data-Driven Perspective
Authors: Gu Jianlei , Dai Jiawei , Lu Hui , Zhao Hongyu
Published: February 2021

Comprehensive characterization of spatial and temporal gene expression patterns in humans is critical for uncovering regulatory codes of the human genome and understanding molecular mechanisms of human diseases. The ubiquitously expressed genes (UEGs) refer to those genes expressed across a majority, if not all, phenotypic and physiological conditions of an organism. It is known that many human genes are broadly expressed across tissues. However, most previous UEG studies have only focused on providing a list of UEGs without capturing their global expression patterns, thus limiting the potential use of UEG information. In this article, we propose a novel data-driven framework to leverage the extensive collection of ∼40,000 human transcriptomes to derive a list of UEGs and their corresponding global expression patterns, which offers a valuable resource to further validate and characterize human UEGs. Our results suggest that about half (12,234; 49.01%) of the human genes are expressed in at least 80% of human transcriptomes and the median size of the human transcriptome is 16,342 (65.44%). This suggests that the average difference in gene content between human transcriptomes is only 16.43%. Through gene clustering, we identified a set of UEGs, named LoVarUEGs, that have stable expression across human transcriptomes and can be used as internal reference genes for expression measurement. To further demonstrate the usefulness of this resource, we evaluated the uniqueness of repression for 16 previously predicted disallowed genes in islets beta cells and found that seven of these genes showed relatively more varied expression patterns, suggesting that the repression of these genes may not be unique to islets beta cells. We have made our resource publicly available athttps://github.com/macroant/HumanUEGs.
Reward enhances online participants’ engagement with a demanding auditory task
Authors: Bianco Roberta , Mills Gordon , de Kerangal Mathilde , Rosen Stuart , Chait Maria
Published: February 2021

Online recruitment platforms are increasingly utilized for experimental research. Crowdsourcing is associated with numerous benefits but also notable constraints, including lack of control over participants’ environment and engagement. In the context of auditory experiments, these limitations may be particularly detrimental to threshold-based tasks that require effortful listening. Here, we ask whether incorporating a performance-based monetary bonus will improve speech reception performance of online participants. In two experiments, participants performed an adaptive matrix-type speech-in-noise task (where listeners select two key words out of closed sets). In Experiment 1, our results revealed worse performance in online (N = 49) compared with in-lab (N = 81) groups. Specifically, relative to the in-lab cohort, significantly fewer participants in the online group achieved very low (< -17dB) thresholds. In Experiment 2 (N = 200), we show that a monetary reward improved listeners’ threshold to levels similar to those observed in the lab setting. Overall the results suggest that providing a small performance-based bonus increases participants’ task-engagement, facilitating a more accurate estimation of auditory ability under challenging listening conditions.