bluuebunny/crossref_metadata_2025 huggingface dataset:
A longitudinal analysis of puberty-related cortical development
Authors: Vijayakumar Nandita , Youssef George , Allen Nicholas B , Anderson Vicki , Efron Daryl , Hazell Philip , Mundy Lisa , Nicholson Jan M , Patton George , Seal Marc L , Simmons Julian G , Whittle Sarah , Silk Tim
Published: November 2020

The brain undergoes extensive structural changes during adolescence, concurrent to puberty-related physical and hormonal changes. While animal research suggests these biological processes are related to one another, our knowledge of brain development in humans is largely based on age-related processes. Thus, the current study characterized puberty-related changes in human brain structure, by combining data from two longitudinal neuroimaging cohorts. Beyond normative changes in cortical thickness, we examined whether individual differences in the rate of pubertal maturation (or “pubertal tempo”) was associated with variations in cortical trajectories. Participants (N = 192; scans = 366) completed up to three waves of MRI assessments between 8.5 and 14.5 years of age, as well as questionnaire assessments of pubertal stage at each wave. Generalized additive mixture models were used to characterize trajectories of cortical development. Results revealed widespread linear puberty-related changes across much of the cortex. Many of these changes, particularly within the frontal and parietal cortices, were independent of age-related development. Males exhibiting faster pubertal tempo demonstrated greater thinning in the precuneus and frontal cortices than same-aged and -sex peers. Findings suggest that the unique influence of puberty on cortical development may be more extensive than previously identified, and also emphasize important individual differences in the coupling of these developmental processes.
Utility of polygenic embryo screening for disease depends on the selection strategy
Authors: Lencz Todd , Backenroth Daniel , Granot-Hershkovitz Einat , Green Adam , Gettler Kyle , Cho Judy H. , Weissbrod Omer , Zuk Or , Carmi Shai
Published: November 2020

Polygenic risk scores (PRSs) have been offered since 2019 to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. Here we predict, based on the liability threshold model, the expected reduction in complex disease risk following polygenic embryo screening for a single disease. Our main finding is that a strong determinant of the potential utility of such screening is the selection strategy, a factor that has not been previously studied. Specifically, when only embryos with a very high PRS are excluded, the achieved risk reduction is minimal. In contrast, selecting the embryo with the lowest PRS can lead to substantial relative risk reductions, given a sufficient number of viable embryos. For example, a relative risk reduction of ≈50% for schizophrenia can be achieved by selecting the embryo with the lowest PRS out of five viable embryos. We systematically examine the impact of several factors on the utility of screening, including the variance explained by the PRS, the number of embryos, the disease prevalence, the parental PRSs, and the parental disease status. When quantifying the utility, we consider both relative and absolute risk reductions, as well as population-averaged and per-couple risk reductions. We also examine the risk of pleiotropic effects. Finally, we confirm our theoretical predictions by simulating “virtual” couples and offspring based on real genomes from schizophrenia and Crohn’s disease case-control studies. We discuss the assumptions and limitations of our model, as well as the potential emerging ethical concerns.
Cortical feedback and gating in odor discrimination and generalization
Authors: Tavoni Gaia , Chen Kersen David E. , Balasubramanian Vijay
Published: November 2020

A central question in neuroscience is how context changes perception of sensory stimuli. In the olfactory system, for example, experiments show that task demands can drive divergence and convergence of cortical odor responses, likely underpinning olfactory discrimination and generalization. Here, we propose a simple statistical mechanism for this effect based on unstructured feedback from the central brain to the olfactory bulb, which represents the context associated with an odor, and sufficiently selective cortical gating of sensory inputs. Strikingly, the model predicts that both convergence and divergence of cortical odor patterns should increase when odors are initially more similar, an effect reported in recent experiments. The theory in turn predicts reversals of these trends following experimental manipulations and in neurological conditions that increase cortical excitability.
emiRIT: A text-mining based resource for microRNA information
Authors: Roychowdhury Debarati , Gupta Samir , Qin Xihan , Arighi Cecilia N. , Vijay-Shanker K.
Published: November 2020

Motivation

microRNAs (miRNAs) are essential gene regulators and their dysregulation often leads to diseases. Easy access to miRNA information is crucial for interpreting generated experimental data, connecting facts across publications, and developing new hypotheses built on previous knowledge. Here, we present emiRIT, a text mining-based resource, which presents miRNA information mined from the literature through a user-friendly interface.

Results

We collected 149,233 miRNA-PubMed ID pairs from Medline between January 1997 to May 2020. emiRIT currently containsmiRNA-generegulation (60,491 relations);miRNA-disease (cancer)(12,300 relations);miRNA-biological process and pathways(23,390 relations); and circulatorymiRNAs in extracellular locations(3,782 relations). Biological entities and their relation to miRNAs were extracted from Medline abstracts using publicly available and in-house developed text mining tools, and the entities were normalized to facilitate querying and integration. We built a database and an interface to store and access the integrated data, respectively.

Conclusion

We provide an up-to-date and user-friendly resource to facilitate access to comprehensive miRNA information from the literature on a large-scale, enabling users to navigate through different roles of miRNA and examine them in a context specific to their information needs. To assess our resource’s information coverage, in the absence of gold standards, we have conducted two case studies focusing on the target and differential expression information of miRNAs in the context of diseases. Database URL:https://research.bioinformatics.udel.edu/emirit/
Developing a broadly applicablepyrF-based genetic manipulation system inAcinetobacter baumannii
Authors: Xu Run , Gao Can , Wu Shuqi , Su Mengjiao , Sun Chengfu , Jia Xu , Wang Rui
Published: November 2020

Acinetobacter baumanniiis an emergency pathogenic bacterium for its multidrug-resistance and high mortality rates after infection. In-depth genetic analysis ofA. baumanniivirulence and drug-resistant genes is highly desirable. Existing methods for genetic manipulation ofA. baumanniimainly rely on the use of antibiotic as the selectable marker, and thesacB/sucrose as the counter-selectable marker, which is inconvenient and inappropriate for all research ofA. baumannii. Based on the highly conservedpyrFgene and its conserved 500bp-flanking sequence, we quickly and easily generated thepyrF-deleted mutants as the uracil auxotrophic host strain in three model strains and 11 clinical strains. ThepyrF-carried vectors constructed for gene editing with pyrF/5-FOA as the counter-selection were conveniently and time-saving in thesepyrF-deleted mutants. Utilizing thepyrF-based genetic manipulation system, we easily and efficiently modified thecasgene and CRISPR sequence of I-F CRISPR-Cas system inA. baumanniiAYE, and detected the CRISPR interference and adaptation in these mutants. In summary, thepyrF-based genetic manipulation system could be broadly applicable used for efficiently maker-less gene editing in mostA. baumanniistrains.
Nodosome inhibition as a novel broad-spectrum antiviral strategy against arboviruses and SARS-CoV-2
Authors: Limonta Daniel , Dyna-Dagman Lovely , Branton William , Makio Tadashi , Wozniak Richard W. , Power Christopher , Hobman Tom C.
Published: November 2020

In the present report, we describe two small molecules with broad-spectrum antiviral activity. These drugs block formation of the nodosome. The studies were prompted by the observation that infection of human fetal brain cells with Zika virus (ZIKV) induces expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a host factor that was found to promote ZIKV replication and spread. A drug that targets NOD2 was shown to have potent broad-spectrum antiviral activity against other flaviviruses, alphaviruses and SARS-CoV-2, the causative agent of COVID-19. Another drug that inhibits the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) which functions downstream of NOD2, also decreased replication of these pathogenic RNA viruses. The broad-spectrum action of nodosome targeting drugs is mediated, at least in part, by enhancement of the interferon response. Together, these results suggest that further preclinical investigation of nodosome inhibitors as potential broad-spectrum antivirals is warranted.
Finger Sweat Analysis Enables Short Interval Metabolic Biomonitoring in Humans
Authors: Brunmair Julia , Niederstaetter Laura , Neuditschko Benjamin , Bileck Andrea , Slany Astrid , Janker Lukas , Feuerstein Max Lennart , Langbauer Clemens , Gotsmy Mathias , Zanghellini Jürgen , Meier-Menches Samuel M. , Gerner Christopher
Published: November 2020

Metabolic biomonitoring in humans is typically based on the sampling of blood, plasma or urine. Although established in the clinical routine, these sampling procedures are often associated with a variety of compliance issues and are impractical for performing time-course studies. The analysis of the minute amounts of sweat sampled from the fingertip enables a solution to this challenge. Sweat sampling from the fingertip is non-invasive and robust and can be accomplished repeatedly by untrained personnel. This matrix represents a rich source for metabolomic phenotyping, which is exemplified by the detection of roughly 50’000 features per sample. Moreover, the determined limits of detection demonstrate that the ingestion of 200 μg of a xenobiotic may be sufficient for its detection in sweat from the fingertip. The feasibility of short interval sampling of sweat from the fingertips was confirmed in three time-course studies after coffee consumption or ingestion of a caffeine capsule, successfully monitoring all known caffeine metabolites. Fluctuations in the rate of sweat production were accounted for by mathematical modelling to reveal individual rates of caffeine uptake, metabolism and clearance. Biomonitoring using sweat from the fingertip has far reaching implications for personalised medical diagnostics and biomarker discovery.
Allosteric Hotspots in the Main Protease of SARS-CoV-2
Authors: Strömich Léonie , Wu Nan , Barahona Mauricio , Yaliraki Sophia N.
Published: November 2020

Abstract

Inhibiting the main protease of SARS-CoV-2 is of great interest in tackling the COVID-19 pandemic caused by the virus. Most efforts have been centred on inhibiting the binding site of the enzyme. However, considering allosteric sites, distant from the active or orthosteric site, broadens the search space for drug candidates and confers the advantages of allosteric drug targeting. Here, we report the allosteric communication pathways in the main protease dimer by using two novel fully atomistic graph theoretical methods: Bond-to-bond propensity analysis, which has been previously successful in identifying allosteric sites withouta prioriknowledge in benchmark data sets, and, Markov transient analysis, which has previously aided in finding novel drug targets in catalytic protein families. We further score the highest ranking sites against random sites in similar distances through statistical bootstrapping and identify four statistically significant putative allosteric sites as good candidates for alternative drug targeting.
Visualising Cholesterol in Brain by On-Tissue Derivatisation and Quantitative Mass Spectrometry Imaging
Authors: Angelini Roberto , Yutuc Eylan , Wyatt Mark F , Newton Jillian , Yusuf Fowzi Adam , Griffiths Lauren , Cooze Benjamin Jordan , El Assad Dana , Frache Gilles , Rao Wei , Allen Luke B. , Korade Zeljka , Nguyen Thu TA , Rathnayake Rathnayake AC , Cologna Stephanie M , Howell Owain W , Clench Malcolm R , Wang Yuqin , Griffiths William J
Published: November 2020

Despite being a critical molecule for neurobiology and brain health, mass spectrometry imaging (MSI) of cholesterol has been under reported compared to other lipids, due to the difficulty in ionising the sterol molecule. In the present work we have employed an on-tissue enzyme-assisted derivatisation strategy to improve detection of cholesterol in brain tissue sections. We report distribution and levels of cholesterol across specific brain structures of the mouse brain, in a model of Niemann-Pick type C1 (NPC1) disease, and during brain development. MSI revealed how cholesterol changes during development and that in the adult is highest in pons and medulla of the brain stem. Cholesterol was significantly reduced in the corpus callosum and other brain regions in theNpc1null mouse, confirming hypomyelination at the molecular level. Our study demonstrates the potential of MSI to the study of sterols in neuroscience.
An antibiotic-resistance conferring mutation in a neisserial porin: Structure, ion flux, and ampicillin binding
Authors: Bartsch A. , Ives C.M. , Kattner C. , Pein F. , Diehn M. , Tanabe M. , Munk A. , Zachariae U. , Steinem C. , Llabrés S.
Published: November 2020

Gram-negative bacteria cause the majority of highly drug-resistant bacterial infections. To cross the outer membrane of the complex Gram-negative cell envelope, antibiotics permeate through porins, trimeric channel proteins that enable the exchange of small polar molecules. Mutations in porins contribute to the development of drug-resistant phenotypes. In this work, we show that a single point mutation in the porin PorB fromNeisseria meningitidis, the causative agent of bacterial meningitis, can strongly affect the binding and permeation of beta-lactam antibiotics. Using X-ray crystallography, high-resolution electrophysiology, atomistic biomolecular simulation, and liposome swelling experiments, we demonstrate differences in drug binding affinity, ion selectivity and drug permeability of PorB. Our work further reveals distinct interactions between the transversal electric field in the porin eyelet and the zwitterionic drugs, which manifest themselves under applied electric fields in electrophysiology and are altered by the mutation. These observations may apply more broadly to drug-porin interactions in other channels. Our results improve the molecular understanding of porin-based drug-resistance in Gram-negative bacteria.
The ApiAP2 factor PfAP2-HC is an integral component of heterochromatin in the malaria parasitePlasmodium falciparum
Authors: Carrington Eilidh , Cooijmans Roel H. M. , Keller Dominique , Toenhake Christa G. , Bártfai Richárd , Voss Till S.
Published: November 2020

Malaria parasites undergo a highly complex life cycle in the human host and the mosquito vector. The ApiAP2 family of sequence-specific DNA-binding proteins plays a dominant role in parasite development and life cycle progression. Of the ApiAP2 factors studied to date, most act as transcription factors regulating stage-specific gene expression. Here, we characterised a new ApiAP2 factor inPlasmodium falciparum(PF3D7_1456000) that we termed PfAP2-HC. Via detailed investigation of several single or double genetically engineered parasite lines, we demonstrate that PfAP2-HC specifically binds to heterochromatin throughout the genome. Intriguingly, PfAP2-HC does not bind DNAin vivoand recruitment of PfAP2-HC to heterochromatin is independent of its DNA-binding domain but strictly dependent on heterochromatin protein 1. Furthermore, our results suggest that PfAP2-HC functions neither in the regulation of gene expression nor in heterochromatin formation or maintenance. In summary, our findings reveal that PfAP2-HC constitutes a core component of heterochromatin in malaria parasites. They furthermore identify unexpected properties of ApiAP2 factors and suggest substantial functional divergence among the members of this important family of regulatory proteins.
A novel Mn-dependent peroxidase contributes to tardigrade anhydrobiosis
Authors: Yoshida Yuki , Satoh Tadashi , Ota Chise , Tanaka Sae , Horikawa Daiki D. , Tomita Masaru , Kato Koichi , Arakawa Kazuharu
Published: November 2020

Tardigrades are microscopic animals that are capable of tolerating extreme environments by entering a desiccated ametabolic state known as anhydrobiosis. While antioxidative stress genes, antiapoptotic pathways and tardigrade-specific intrinsically disordered proteins have been implicated in the anhydrobiotic machinery, conservation of these mechanisms is not universal within the phylum Tardigrada, suggesting the existence of overlooked components. Here, we show that a novel Mn-dependent peroxidase is an important factor in tardigrade anhydrobiosis. Through comparative time-series transcriptome analysis ofRamazzottius varieornatusspecimens exposed to desiccation or ultraviolet light, we first identified several novel gene families without similarity to existing sequences that are induced rapidly after stress exposure. Among these, a single gene family with multiple orthologs that is highly conserved within the phylum Tardigrada and enhances oxidative stress tolerance when expressed in human cells was identified. Crystallographic study of this protein suggested Zn or Mn binding at the active site, and we further confirmed that this protein has Mn-dependent peroxidase activityin vitro. Our results demonstrated novel mechanisms for coping with oxidative stress that may be a fundamental mechanism of anhydrobiosis in tardigrades. Furthermore, localization of these sets of proteins in the Golgi apparatus suggests an indispensable role of the Golgi stress response in desiccation tolerance.
Potent SARS-CoV-2 neutralizing antibodies selected from a human antibody library constructed decades ago
Authors: Qiang Min , Ma Peixiang , Li Yu , Liu Hejun , Harding Adam , Min Chenyu , Liu Lili , Yuan Meng , Ji Qun , Tao Pingdong , Shi Xiaojie , Li Zhean , Wang Fulian , Zhang Yu , Wu Nicholas C. , Lee Chang-Chun D. , Zhu Xueyong , Gilbert-Jaramillo Javier , Saxena Abhishek , Huang Xingxu , Wang Hou , James William , Dwek Raymond A. , Wilson Ian A. , Yang Guang , Lerner Richard A.
Published: November 2020

Combinatorial antibody libraries not only effectively reduce antibody discovery to a numbers game, but enable documentation of the history of antibody responses in an individual. The SARS-CoV-2 pandemic has prompted a wider application of this technology to meet the public health challenge of pandemic threats in the modern era. Herein, we used a combinatorial human antibody library constructed 20 years before the COVID-19 pandemic to discover three highly potent antibodies that selectively bind SARS-CoV-2 spike protein and neutralize authentic SARS-CoV-2 virus. Compared to neutralizing antibodies from COVID-19 patients with generally low somatic hypermutation (SHM), these antibodies contain over 13-22 SHMs, many of which are involved in specific interactions in crystal structures with SARS-CoV-2 spike RBD. The identification of these somatically mutated antibodies in a pre-pandemic library raises intriguing questions about the origin and evolution of human immune responses to SARS-CoV-2.
Acrylamide Fragment Inhibitors that Induce Unprecedented Conformational Distortions in Enterovirus 71 3C and SARS-CoV-2 Main Protease
Authors: Qin Bo , Craven Gregory B. , Hou Pengjiao , Lu Xinran , Child Emma S. , Morgan Rhodri M. L. , Armstrong Alan , Mann David J. , Cui Sheng
Published: November 2020

RNA viruses are critically dependent upon virally encoded proteases that cleave the viral polyproteins into functional mature proteins. Many of these proteases are structurally conserved with an essential catalytic cysteine and this offers the opportunity to irreversibly inhibit these enzymes with electrophilic small molecules. Here we describe the successful application of quantitative irreversible tethering (qIT) to identify acrylamide fragments that selectively target the active site cysteine of the 3C protease (3Cpro) of Enterovirus 71, the causative agent of hand, foot and mouth disease in humans, altering the substrate binding region. Further, we effectively re-purpose these hits towards the main protease (Mpro) of SARS-CoV-2 which shares the 3C-like fold as well as similar catalytic-triad. We demonstrate that the hit fragments covalently link to the catalytic cysteine of Mproto inhibit its activity. In addition, we provide the first demonstration that targeting the active site cysteine of Mprocan also have profound allosteric effects, distorting secondary structures required for formation of the active dimeric unit of Mpro. These new data provide novel mechanistic insights into the design of EV71 3Cproand SARS-CoV-2 Mproinhibitors and identify acrylamide-tagged pharmacophores for elaboration into more selective agents of therapeutic potential.
The worldwide invasion ofDrosophila suzukiiis accompanied by a large increase of transposable element load and a small number of putatively adaptive insertions
Authors: Mérel Vincent , Gibert Patricia , Buch Inessa , Rada Valentina Rodriguez , Estoup Arnaud , Gautier Mathieu , Fablet Marie , Boulesteix Matthieu , Vieira Cristina
Published: November 2020

Transposable Elements (TEs) are ubiquitous and mobile repeated sequences. They are major determinants of host fitness. Here, we portrayed the TE content of the spotted wing flyDrosophila suzukii. Using a recently improved genome assembly, we reconstructed TE sequencesde novo, and found that TEs occupy 47% of the genome and are mostly located in gene poor regions. The majority of TE insertions segregate at low frequencies, indicating a recent and probably ongoing TE activity. To explore TE dynamics in the context of biological invasions, we studied variation of TE abundance in genomic data from 16 invasive and six native populations (ofD. suzukii). We found a large increase of the TE load in invasive populations correlated with a reduced Watterson estimate of genetic diversitya proxy of effective population size. We did not find any correlation between TE contents and bio-climatic variables, indicating a minor effect of environmentally induced TE activity. A genome-wide association study revealed thatca. 5,000 genomic regions are associated with TE abundance. We did not find, however, any evidence in such regions of an enrichment for genes known to interact with TE activity (e.g. transcription factor encoding genes or genes of the piRNA pathway). Finally, the study of TE insertion frequencies revealed 15 putatively adaptive TE insertions, six of them being likely associated with the recent invasion history of the species.
Genome-wide analysis of long noncoding RNAs, 24-nt siRNAs, DNA methylation and H3K27me3 marks in Brassica rapa and related species
Authors: Mehraj Hasan , Shea Daniel J. , Takahashi Satoshi , Miyaji Naomi , Akter Ayasha , Seki Motoaki , Dennis Elizabeth S. , Ryo Fujimoto , Osabe Kenji
Published: November 2020

Long noncoding RNAs (lncRNAs) are RNA fragments that generally do not code for a protein but are involved in epigenetic gene regulation. In this study, lncRNAs of Brassica rapa were classified into long intergenic noncoding RNAs, natural antisense RNAs, and intronic noncoding RNAs and their expression were analyzed in relation to genome-wide 24-nt small interfering RNAs (siRNAs), DNA methylation, and histone H3 lysine 27 trimethylation marks (H3K27me3). More than 65% of the lncRNAs analyzed consisted of one exon, and more than 55% overlapped with inverted repeat regions (IRRs). Overlap of lncRNAs with IRRs or genomic regions encoding for 24-nt siRNAs resulted in increased DNA methylation levels and when both were present, there were further increase in DNA methylation levels. LncRNA did not overlap greatly with H3K27me3 marks, but the expression level of intronic noncoding RNAs that did coincide with H3K27me3 marks was higher than without H3K27me3 marks. The Brassica genus comprises important vegetables and oil seed crops grown across the world. Brassica rapa is a diploid (AA genome) thought to be one of the ancestral species of both B. juncea (AABB genome) and B. napus (AACC) through genome merging (allotetrapolyploidization). Complex genome restructuring and epigenetic alterations are thought to be involved in these allotetrapolyploidization events, but the detailed mechanism is not known. Comparison of lncRNAs between B. rapa and B. nigra, B. oleracea, B. juncea, and B. napus showed the highest conservation with B. oleracea. This study presents a comprehensive analysis of the epigenome structure of the B. rapa at multi-epigenetic levels (siRNAs, DNA methylation, H3K27me3, and lncRNAs) and offers insights into the function of lncRNA in the Brassica genus.
Badger territoriality maintained despite disturbance of major road construction
Authors: Gaughran Aoibheann , Mullen Enda , MacWhite Teresa , Maher Peter , Kelly David J. , Kelly Ruth , Good Margaret , Marples Nicola M.
Published: November 2020

Road ecology has traditionally focused on the impact of in-situ and functional roads on wildlife. However, road construction also poses a major, yet understudied, threat and any implications for key aspects of animal behaviour are unknown. There are also concerns that environmental disturbances, including major roadworks, can disrupt badger territoriality, promoting the spread of tuberculosis to cattle. To address these knowledge gaps, the ranging behaviour of a medium-density Irish badger population was monitored, using GPS-tracking collars, before, during and after a major road realignment project that bisected the study area. We estimated badgers’ home range sizes, nightly distances travelled and the distance and frequency of extra-territorial excursions during each phase of the study and quantified any changes to these parameters. We show that roadworks had a very limited effect on ranging behaviour. A small increase in nightly distance during the roadworks did not translate into an increase in home range size, nor an increase in the distance or frequency of extra-territorial excursions during the roadworks. In addition, suitable mitigation measures to prevent badger deaths appeared to ensure that normal patterns of ranging behaviour continued once the new road was in place. Our analysis supports the view that road construction did not cause badgers to change their ranging behaviour in ways likely to increase the spread of tuberculosis.
Differing impacts of global and regional responses on SARS-CoV-2 transmission cluster dynamics
Authors: Magalis Brittany Rife , Ramirez-Mata Andrea , Zhukova Anna , Mavian Carla , Marini Simone , Lemoine Frederic , Prosperi Mattia , Gascuel Olivier , Salemi Marco
Published: November 2020

Although the global response to COVID-19 has not been entirely unified, the opportunity arises to assess the impact of regional public health interventions and to classify strategies according to their outcome. Analysis of genetic sequence data gathered over the course of the pandemic allows us to link the dynamics associated with networks of connected individuals with specific interventions. In this study, clusters of transmission were inferred from a phylogenetic tree representing the relationships of patient sequences sampled from December 30, 2019 to April 17, 2020. Metadata comprising sampling time and location were used to define the global behavior of transmission over this earlier sampling period, but also the involvement of individual regions in transmission cluster dynamics. Results demonstrate a positive impact of international travel restrictions and nationwide lockdowns on global cluster dynamics. However, residual, localized clusters displayed a wide range of estimated initial secondary infection rates, for which uniform public health interventions are unlikely to have sustainable effects. Our findings highlight the presence of so-called “super-spreaders”, with the propensity to infect a larger-than-average number of people, in countries, such as the USA, for which additional mitigation efforts targeting events surrounding this type of spread are urgently needed to curb further dissemination of SARS-CoV-2.
Doxycycline inhibits α-synuclein-associated pathologiesin vitroandin vivo
Authors: Dominguez-Meijide Antonio , Parrales Valeria , Vasili Eftychia , González-Lizárraga Florencia , König Annekatrin , Lázaro Diana F. , Lannuzel Annie , Haik Stéphane , Del Bel Elaine , Chehín Rosana , Raisman-Vozari Rita , Michel Patrick P , Bizat Nicolas , Outeiro Tiago Fleming
Published: November 2020

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn). Doxycycline, a tetracyclic antibiotic shows neuroprotective effects, initially proposed to be due to its anti-inflammatory properties. More recently, an additional mechanism by which doxycycline may exert its neuroprotective effects has been proposed as it has been shown that it inhibits amyloid aggregation. Here, we studied the effects of doxycycline on aSyn aggregationin vivo, in vitroand in a cell free system using real-time quaking induced conversion (RT-QuiC). Our results show that doxycycline decreases the number and size of aSyn aggregates in cells. In addition, doxycycline inhibits the aggregation and seeding of recombinant aSyn, and attenuates the production of mitochondrial-derived reactive oxygen species. Finally, we found doxycycline induces a cellular redistribution of the aggregates in an animal model of PD that is associated with a recovery of dopaminergic function. In summary, we provide strong evidence that doxycycline treatment may be an effective strategy against synucleinopathies.
Mitochondrial pathway polygenic risk scores are associated with Alzheimer’s Disease
Authors: Paliwal Devashi , McInerney Tim W. , Pa Judy , Swerdlow Russell H. , Easteal Simon , Andrews Shea J. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2020

INTRODUCTION

Genetic, animal and epidemiological studies involving biomolecular and clinical endophenotypes implicate mitochondrial dysfunction in Alzheimer’s disease (AD) pathogenesis. Polygenic risk scores (PRS) provide a novel approach to assess biological pathway-associated disease risk by combining the effects of variation at multiple, functionally related genes.

METHODS

We investigated associations of PRS for genes involved in 12 mitochondrial pathways (pathway-PRS) related to AD in 854 participants from Alzheimer’s Disease Neuroimaging Initiative.

RESULTS

Pathway-PRS for four mitochondrial pathways are significantly associated with increased AD risk: (i) response to oxidative stress (OR: 2.01 [95% Cl: 1.71, 2.37]); (ii) mitochondrial transport (OR: 1.81 [95% Cl: 1.55, 2.13]); (iii) hallmark oxidative phosphorylation (OR: 1.23 [95% Cl: 1.07, 1.41]); and (iv) mitochondrial membrane potential regulation (OR: 1.18 [95% Cl: 1.03, 1.36]).

DISCUSSION

Therapeutic approaches targeting these pathways may have potential for modifying AD pathogenesis. Further investigation is required to establish a causal role for these pathways in AD pathology.
DNA G-quadruplexes for native mass spectrometry in potassium: a database of validated structures in electrospray-compatible conditions
Authors: Ghosh Anirban , Largy Eric , Gabelica Valérie
Published: November 2020

G-quadruplex DNA structures have become attractive drug targets, and native mass spectrometry can provide detailed characterization of drug binding stoichiometry and affinity, potentially at high throughput. However, the G-quadruplex DNA polymorphism poses problems for interpreting ligand screening assays. In order to establish standardized MS-based screening assays, we studied 28 sequences with documented NMR structures in (usually 100 mM) K+, and report here their circular dichroism (CD), melting temperature (Tm), NMR spectra and electrospray mass spectra in 1 mM KCl/100 mM TMAA. Based on these results, we make a short-list of sequences that adopt the same structure in the MS assay as reported by NMR, and provide recommendations on using them for MS-based assays. We also built an R-based open-source application to build and consult a database, wherein further sequences can be incorporated in the future. The application handles automatically most of the data processing, and allows generating custom figures and reports. The database is included in theg4dbrpackage (https://github.com/EricLarG4/g4dbr) and can be explored online (https://ericlarg4.github.io/G4_database.html).
Hedgehog signalling regulates patterning of the murine and human dentitions through Gas1 co-receptor function
Authors: Seppala Maisa , Thivichon-Prince Beatrice , Xavier Guilherme M. , Shaffie Nina , Sangani Indiya , Birjandi Anahid A. , Rooney Joshua , Lau Jane N. S. , Dhalivar Rajveer , Rossi Ornella , Riaz Adeel , Stonehouse-Smith Daniel , Wang Yiran , Viriot Laurent , Cobourne Martyn T.
Published: November 2020

The mammalian dentition exhibits wide numerical and morphological variation between different species. The regulation of dental pattern is achieved through complex reiterative molecular signalling interactions that occur through multiple stages of tooth development. We show that mice with loss-of-function in the Hedgehog co-receptor Gas1 have variation in size, morphology and number of teeth within the molar dentition. Specifically, premolar-like supernumerary teeth are present with high penetrance, arising through survival and continued development of vestigial tooth germs. We further demonstrate that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt signalling in vestigial tooth germs through facilitation of Shh signalling. Moreover, regulation of tooth number is independent of the additional Hedgehog co-receptors Cdon and Boc. Interestingly, further reduction of Shh pathway activity in aGas1mutant background leads to fusion of the molar field and ultimately, developmental arrest of tooth development rather than exacerbating the supernumerary phenotype. Finally, we demonstrate defective coronal morphology in the molar dentition of human subjects carryingGAS1missense mutations, suggesting that regulation of Hedgehog signalling through GAS1 is also essential for normal patterning of the human dentition.
Reciprocal social ties drive stability within a social network
Authors: Dakin Roslyn , Clunis Paisley , Cornthwaite Emily M. , Ryder T. Brandt
Published: November 2020

Social reciprocity is thought to be the most important driver of cooperation among non-kin, but its effects within complex social networks where individuals choose their partners have not been studied. Here, we test whether reciprocation can explain social dynamics in a bird species where males form coalitions to court females, the wire-tailed manakin (Pipra filicauda). In our study population, approximately a third of male-male social interactions involve one male leaving his territory to interact and display with the owner of another territory; this directional behaviour provides benefits to the recipient at a cost to the visiting male. We characterize social ties among pairs of territory holders according to the directionality of their interactions, and show here that territory holding males engaged in far more reciprocated (bidirectional) partnerships with other territory holders than expected by chance. Reciprocated partnerships were also stronger (i.e., the partners interacted more frequently) than non-reciprocated partnerships, controlling for spatial proximity of the territories. An individual-level analysis revealed that a male’s social contribution to a given partner was predictive of the number of social interactions he received from that same partner. Finally, we show that reciprocation predicted the long-term stability of social partnerships one year later. Together, these results demonstrate that reciprocity is associated with stability in complex social networks where partner choice is flexible.

LAY SUMMARY

When animals are free to choose their partners, how does reciprocity influence social dynamics?

In the wire-tailed manakin, males form coalitions with other males to help attract mates. We tracked male social networks and found that some males form reciprocal partnerships where each male leaves its territory to display at the other’s territory. These bidirectional partnerships are particularly strong and stable, indicating that reciprocity is associated with stability in complex social networks.
A Cell Atlas of Microbe-Responsive Processes in the Zebrafish Intestine
Authors: Willms Reegan J. , Jones Lena Ocampo , Hocking Jennifer C. , Foley Edan
Published: November 2020

Gut microbial products direct growth, differentiation, and development in the animal host. Disruptions to host-microbe interactions have profound health consequences, that include onset of chronic inflammatory illnesses. However, we lack system-wide understanding of cell-specific responses to the microbiome. We profiled transcriptional activity in individual cells from the intestine, and associated tissue, of zebrafish larvae that we raised in the presence or absence of a microbiome. We uncovered extensive cellular heterogeneity in the conventional zebrafish intestinal epithelium, including previously undescribed cell types with known mammalian homologs. By comparing conventional to germ-free profiles, we mapped microbial impacts on transcriptional activity in each cell population. We revealed intricate degrees of cellular specificity in host responses to the microbiome that included regulatory effects on patterning, metabolic and immune activity. For example, we showed that removal of microbes hindered pro-angiogenic signals in the developing vasculature, resulting in impaired intestinal vascularization. Our work provides a high-resolution atlas of intestinal cellular composition in the developing fish gut and details the effects of the microbiome on each cell type. Furthermore, we provide a web-based resource for single-cell gene expression visualization under conventional and germ-free conditions to facilitate exploration of this dataset.
Discordance between the predicted vs. the actually recognized CD8+ T cell epitopes of HCMV pp65 antigen and aleatory epitope dominance
Authors: Lehmann Alexander , Zhang Ting , Reche Pedro A , Lehmann Paul V.
Published: November 2020

CD8+ T cell immune monitoring aims at measuring the numbers and functions of antigen-specific CD8+ T cell populations engaged during immune responses, providing insights into the magnitude and quality of cell-mediated immunity operational in a test subject. The selection of peptides forex vivoCD8+ T cell detection is critical, however, because for each restricting HLA class I molecule present in a human individual there is a multitude of potential epitopes within complex antigens, and HLA diversity between the test subjects predisposes CD8+ T cell responses to individualized epitope recognition profiles. We report here on a brute force CD8+ T cell epitope mapping approach for the human cytomegalovirus (HCMV) pp65 antigen on ten HLA-A*02:01-matched HCMV infected human subjects. In this approach, in each test subject, every possible CD8+ T cell epitope was systematically tested; that is 553 individual peptides that walk the sequence of the HCMV pp65 protein in steps of single amino acids. Highly individualized CD8+ T cell response profiles with aleatory epitope recognition patterns were observed. We compared the actually detected epitope utilization in each individual with epitope prediction ranking for the shared HLA-A*02:01 allele, and for additional HLA class I alleles expressed by each individual. No correlation was found between epitopes’ ranking on the prediction scale and their actual immune dominance. The data suggest that accurate CD8+ T cell immune monitoring might depend on the agnostic reliance on mega peptide pools, or brute force mapping, rather than individualized epitope predictions.
Genetic demultiplexing of pooled single-cell RNA-sequencing samples in cancer facilitates effective experimental design
Authors: Weber Lukas M. , Hippen Ariel A. , Hickey Peter F. , Berrett Kristofer C. , Gertz Jason , Doherty Jennifer Anne , Greene Casey S. , Hicks Stephanie C.
Published: November 2020

Background

Pooling cells from multiple biological samples prior to library preparation within the same single-cell RNA sequencing experiment provides several advantages, including lower library preparation costs and reduced unwanted technological variation, such as batch effects. Computational demultiplexing tools based on natural genetic variation between individuals provide a simple approach to demultiplex samples, which does not require complex additional experimental procedures. However, these tools have not been evaluated in cancer, where somatic variants, which could differ between cells from the same sample, may obscure the signal in natural genetic variation.

Results

Here, we performedin silicobenchmark evaluations by combining raw sequencing reads from multiple single-cell samples in high-grade serous ovarian cancer, which has a high copy number burden, and lung adenocarcinoma, which has a high tumor mutational burden. Our results confirm that genetic demultiplexing tools can be effectively deployed on cancer tissue using a pooled experimental design, although high proportions of ambient RNA from cell debris reduce performance.

Conclusions

This strategy provides significant cost savings through pooled library preparation. To facilitate similar analyses at the experimental design phase, we provide freely accessible code and a reproducible Snakemake workflow built around the best-performing tools found in ourin silicobenchmark evaluations, available athttps://github.com/lmweber/snp-dmx-cancer.
Genomic and phenotypic analysis of COVID-19-associated pulmonary aspergillosis isolates ofAspergillus fumigatus
Authors: Steenwyk Jacob L. , Mead Matthew E. , de Castro Patrícia Alves , Valero Clara , Damasio André , dos Santos Renato A. C. , Labella Abigail L. , Li Yuanning , Knowles Sonja L. , Raja Huzefa A. , Oberlies Nicholas H. , Zhou Xiaofan , Cornely Oliver A. , Fuchs Frieder , Koehler Philipp , Goldman Gustavo H. , Rokas Antonis
Published: November 2020

The ongoing global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) first described from Wuhan, China. A subset of COVID-19 patients has been reported to have acquired secondary infections by microbial pathogens, such as fungal opportunistic pathogens from the genusAspergillus. To gain insight into COVID-19 associated pulmonary aspergillosis (CAPA), we analyzed the genomes and characterized the phenotypic profiles of four CAPA isolates ofAspergillus fumigatusobtained from patients treated in the area of North Rhine-Westphalia, Germany. By examining the mutational spectrum of single nucleotide polymorphisms, insertion-deletion polymorphisms, and copy number variants among 206 genes known to modulateA. fumigatusvirulence, we found that CAPA isolate genomes do not exhibit major differences from the genome of the Af293 reference strain. By examining virulence in an invertebrate moth model, growth in the presence of osmotic, cell wall, and oxidative stressors, and the minimum inhibitory concentration of antifungal drugs, we found that CAPA isolates were generally, but not always, similar toA. fumigatusreference strains Af293 and CEA17. Notably, CAPA isolate D had more putative loss of function mutations in genes known to increase virulence when deleted (e.g., in theFLEAgene, which encodes a lectin recognized by macrophages). Moreover, CAPA isolate D was significantly more virulent than the other three CAPA isolates and theA. fumigatusreference strains tested. These findings expand our understanding of the genomic and phenotypic characteristics of isolates that cause CAPA.
Structurally distinct duplex telomere repeat-binding proteins inUstilago maydisexecute specialized, non-overlapping functions in telomere recombination and telomere protection
Authors: Yu Eun Young , Zahid Syed , Hsu Min , Sutherland Jeanette , Holloman William K. , Lue Neal F.
Published: November 2020

Duplex telomere binding proteins exhibit considerable structural and functional diversity in different phyla. Herein we address the distinct properties and functions of two Myb-containing, duplex telomere repeat-binding factors inUstilago maydis, a basidiomycete fungus that is evolutionarily distant from the standard budding and fission yeasts. The two telomere-binding proteins inU. maydis, namedUmTrf1 andUmTrf2, have different domain organizations and belong to distinct protein families with different phylogenetic distributions. Despite these differences, they exhibit comparable affinities and similar sequence specificity for the canonical, 6-base-pair telomere repeats. Deletion oftrf1triggers preferential loss of long telomere tracts, suggesting a role for the encoded protein in promoting telomere replication. Trf1 loss also partially suppresses the ALT-like phenotypes ofku70-deficient mutants, suggesting a novel role for a telomere protein in stimulating ALT-related pathways. In keeping with these ideas, we found that purified Trf1 can modulate the helicase activity of Blm, a conserved telomere replication and recombination factor. In contrast,trf2appears to be essential and transcriptional repression of this gene leads to severe growth defects and profound telomere aberrations that encompass telomere length heterogeneity, accumulation of extrachromosomal telomere repeats such as C-circles, and high levels of single-stranded telomere DNA. These observations support a critical role forUmTrf2 in telomere protection. Together, our findings point to a unique, unprecedented division of labor between the two major duplex telomere repeat-binding factors inUstilago maydis. Comparative analysis ofUmTrf1 homologs in different phyla reveals a high degree of functional diversity for this protein family, and provides a case study for how a sequence-specific DNA binding protein can acquire and lose functions at different chromosomal locations.