bluuebunny/crossref_metadata_2025 huggingface dataset:
Aluminosilicate haloes preserve complex life approximately 800 million years ago
Authors: Anderson Ross P. , Tosca Nicholas J. , Cinque Gianfelice , Frogley Mark D. , Lekkas Ioannis , Akey Austin , Hughes Gareth M. , Bergmann Kristin D. , Knoll Andrew H. , Briggs Derek E. G.
Published: June 2020

Mudstone-hosted microfossils are a major component of the Proterozoic fossil record, particularly dominating the record of early eukaryotic life. Early organisms possessed no biomineralized parts to resist decay and controls on their fossilization in mudstones are poorly understood. Consequently, the Proterozoic fossil record is compromised—we do not know whether changing temporal/spatial patterns of microfossil occurrences reflect evolution or the distribution of favourable fossilization conditions. We investigated fossilization within the approximately 1000 Ma Lakhanda Group (Russia) and the approximately 800 Ma Svanbergfjellet and Wynniatt formations (Svalbard and Arctic Canada). Vertical sections of microfossils and surrounding matrices were extracted from thin sections by focused ion beam milling. Elemental mapping and synchrotron-based infrared microspectroscopy revealed that microfossils are surrounded by haloes rich in aluminium, probably hosted in kaolinite. Kaolinite has been implicated in Cambrian Burgess Shale-type (BST) fossilization and is known to slow the growth of degraders. The Neoproterozoic mudstone microfossil record may be biased to tropical settings conducive to kaolinite formation. These deposits lack metazoan fossils even though they share fossilization conditions with younger BST deposits that are capable of preserving non-mineralizing metazoans. Thus metazoans, at least those typically preserved in BST deposits, were probably absent from sedimentary environments before approximately 800 Ma.
Preservation of erniettomorph fossils in clay-rich siliciclastic deposits from the Ediacaran Wood Canyon Formation, Nevada
Authors: Hall J. G. , Smith E. F. , Tamura N. , Fakra S. C. , Bosak T.
Published: June 2020

Three-dimensionally preserved Ediacaran fossils occur globally within sandstone beds. Sandy siliciclastic deposits of the Ediacaran Wood Canyon Formation (WCF) in the Montgomery Mountains, Nevada, contain two fossil morphologies with similar shapes and sizes: one exhibits mm-scale ridges and a distinct lower boundary and the other is devoid of these diagnostic features. We interpret these as taphomorphs of erniettomorphs, soft-bodied organisms with uncertain taxonomic affinities. We explore the cast-and-mould preservation of both taphomorphs by petrography, Raman spectroscopy, X-ray fluorescence microprobe and X-ray diffraction. All fossils and the surrounding sedimentary matrix contain quartz grains, iron-rich chlorite and muscovite. The ridged fossils contain about 70% larger quartz grains compared to the ridgeless taphomorph, indicating a lower abundance of clay minerals in the ridged fossil. Chlorite and muscovite likely originated from smectite and kaolinite precursors that underwent lower greenschist facies metamorphism. Kaolinite and smectite are inferred to have been abundant in sediments around the ridged fossil, which enabled the preservation of a continuous, distinct, clay- and kerogen-rich bottom boundary. The prevalence of quartz in the ridged fossils of the WCF and in erniettomorphs from other localities also suggests a role for this mineral in three-dimensional preservation of erniettomorphs in sandstone and siltstone deposits.
The origin and rise of complex life: progress requires interdisciplinary integration and hypothesis testing
Authors: Wood Rachel , Donoghue Philip C. J. , Lenton Timothy M. , Liu Alexander G. , Poulton Simon W.
Published: June 2020

Understanding of the triggers and timing of the rise of complex life
ca
2100 to 720 million years ago has expanded dramatically in recent years. This theme issue brings together diverse and novel geochemical and palaeontological data presented as part of the Royal Society ‘
The origin and rise of complex life: integrating models
,
geochemical and palaeontological data
’ discussion meeting held in September 2019. The individual papers offer prescient insights from multiple disciplines. Here we summarize their contribution towards the goal of the meeting; to create testable hypotheses for the differing roles of changing climate, oceanic redox, nutrient availability, and ecosystem feedbacks across this profound, but enigmatic, transitional period.
Identification and characterization of a new soybean promoter induced byPhakopsora pachyrhizi, the causal agent of Asian soybean rust
Authors: Cabre Lisa , Peyrard Stephane , Sirven Catherine , Gilles Laurine , Pelissier Bernard , Ducerf Sophie , Poussereau Nathalie
Published: June 2020

Background

Phakopsora pachyrhiziis a biotrophic fungal pathogen responsible for the Asian soybean rust disease causing important yield losses in tropical and subtropical soybean-producing countries.P. pachyrhizitriggers important transcriptional changes in soybean plants during infection, with several hundreds of genes being either up- or downregulated.

Results

Based on published transcriptomic data, we identified a predicted chitinase gene, referred to asGmCHIT1, that was upregulated in the first hours of infection. We first confirmed this early induction and showed that this gene was expressed as early as 8 hours afterP. pachyrhizi inoculation. To investigate the promoter ofGmCHIT1, transgenic soybean plants expressing the green fluorescence protein (GFP) under the control of theGmCHIT1promoter were generated. Following inoculation of these transgenic plants withP. pachyrhizi, GFP fluorescence was detected in a limited area located around appressoria, the fungal penetration structures. Fluorescence was also observed after mechanical wounding whereas no variation in fluorescence of pGmCHIT1:GFP transgenic plants was detected after a treatment with an ethylene precursor or a methyl jasmonate analogue.

Conclusion

We identified a soybean chitinase promoter exhibiting an early induction byP. pachyrhizilocated in the first infected soybean leaf cells. Our results on the induction ofGmCHIT1promoter byP. pachyrhizicontribute to the identification of a new pathogen inducible promoter in soybean and beyond to the development of a strategy for the Asian soybean rust disease control using biotechnological approaches.
Modeling the structure of the frameshift stimulatory pseudoknot in SARS-CoV-2 reveals multiple possible conformers
Authors: Omar Sara Ibrahim , Zhao Meng , Sekar Rohith Vedhthaanth , Moghadam Sahar Arbabi , Tuszynski Jack A. , Woodside Michael T.
Published: June 2020

The coronavirus causing the COVID-19 pandemic, SARS-CoV-2, uses −1 programmed ribosomal frameshifting (−1 PRF) to control the relative expression of viral proteins. As modulating −1 PRF can inhibit viral replication, the RNA pseudoknot stimulating −1 PRF may be a fruitful target for therapeutics treating COVID-19. We modeled the unusual 3-stem structure of the stimulatory pseudoknot of SARS-CoV-2 computationally, using multiple blind structural prediction tools followed by μs-long molecular dynamics simulations. The results were compared for consistency with nuclease-protection assays and single-molecule force spectroscopy measurements of the SARS-CoV-1 pseudoknot, to determine the most likely conformations. We found several possible conformations for the SARS-CoV-2 pseudoknot, all having an extended stem 3 but with different packing of stems 1 and 2. Several conformations featured rarely-seen threading of a single strand through the junction formed between two helices. These structural models may help interpret future experiments and support efforts to discover ligands inhibiting −1 PRF in SARS-CoV-2.
The ontology of the anatomy and development of the solitary ascidianCiona
Authors: Hotta Kohji , Dauga Delphine , Manni Lucia
Published: June 2020

Ciona robusta(Ciona intestinalistype A), a model organism for biological studies, belongs to ascidians, the main class of tunicates, which are the closest relatives of vertebrates. InCiona, a project on the ontology of both development and anatomy is ongoing for several years. Its goal is to standardize a resource relating each anatomical structure to developmental stages. Today, the ontology is codified until the hatching larva stage. Here, we present its extension throughout the swimming larva stages, the metamorphosis, until the juvenile stages. For standardizing the developmental ontology, we acquired different time-lapse movies, confocal microscope images and histological serial section images for each developmental event from the hatching larva stage (17.5 hour post fertilization) to the juvenile stage (7 days post fertilization). Combining these data, we defined 12 new distinct developmental stages (from Stage 26 to Stage 37), in addition to the previously defined 26 stages, referred to embryonic development. The new stages were grouped into four Periods named: Adhesion, Tail Absorption, Body Axis Rotation, and Juvenile. To build the anatomical ontology, 203 anatomical entities were identified, defined according to the literature, and annotated, taking advantage from the high resolution and the complementary information obtained from confocal microscopy and histology. The ontology describes the anatomical entities in hierarchical levels, from the cell level (cell lineage) to the tissue/organ level. Comparing the number of entities during development, we found two rounds on entity increase: in addition to the one occurring after fertilization, there is a second one during the Body Axis Rotation Period, when juvenile structures appear. Vice versa, one-third of anatomical entities associated with the embryo/larval life were significantly reduced at the beginning of metamorphosis. Data was finally integrated within the web-based resource “TunicAnatO”, which includes a number of anatomical images and a dictionary with synonyms. This ontology will allow the standardization of data underpinning an accurate annotation of gene expression and the comprehension of mechanisms of differentiation. It will help in understanding the emergence of elaborated structures during both embryogenesis and metamorphosis, shedding light on tissue degeneration and differentiation occurring at metamorphosis.
Mucin-derivedO-glycans supplemented to diet mitigate diverse microbiota perturbations
Authors: Pruss K. M. , Marcobal A. , Southwick A.M. , Dahan D. , Smits S.A. , Ferreyra J.A. , Higginbottom S.K. , Sonnenburg E.D. , Kashyap P.C. , Choudhury B. , Bode L. , Sonnenburg J. L.
Published: June 2020

Microbiota-accessible carbohydrates (MACs) are powerful modulators of microbiota composition and function. These substrates are often derived from diet, such as complex polysaccharides from plants or human milk oligosaccharides (HMOs) during breastfeeding. Host-derived mucus glycans on gut-secreted mucin proteins may serve as a continuous endogenous source of MACs for resident microbes; here we investigate the potential role of purified, orally-administered mucus glycans in maintaining a healthy microbial community. In this study, we liberated and purifiedO-linked glycans from porcine gastric mucin and assessed their efficacy in shaping the recovery of a perturbed microbiota in a mouse model. We found that porcine mucin glycans (PMGs) and HMOs enrich for taxonomically similar resident microbes. We demonstrate that PMGs aid recovery of the microbiota after antibiotic treatment, suppressC. difficileabundance, delay the onset of diet-induced obesity, and increase relative abundance of residentAkkermansia muciniphila. In silicoanalysis revealed that genes associated with mucus utilization are abundant and diverse in prevalent gut commensals and rare in enteric pathogens, consistent with these glycan-degrading capabilities being selected for during host development and throughout evolution of the host-microbe relationship. Importantly, we identify mucus glycans as a novel class of prebiotic compounds that can be used to mitigate perturbations to the microbiota and provide benefits to host physiology.
A comparative study of supervised machine learning algorithms for the prediction of long-range chromatin interactions
Authors: Vanhaeren Thomas , Divina Federico , García-Torres Miguel , Gómez-Vela Francisco , Vanhoof Wim , Martínez García Pedro Manuel
Published: June 2020

The role of three-dimensional genome organization as a critical regulator of gene expression has become increasingly clear over the last decade. Most of our understanding of this association comes from the study of long range chromatin interaction maps provided by Chromatin Conformation Capture-based techniques, which have greatly improved in recent years. Since these procedures are experimentally laborious and expensive,in silicoprediction has emerged as an alternative strategy to generate virtual maps in cell types and conditions for which experimental data of chromatin interactions is not available. Several methods have been based on predictive models trained on one-dimensional (1D) sequencing features, yielding promising results. However, different approaches vary both in the way they model chromatin interactions and in the machine learning-based strategy they rely on, making it challenging to carry out performance comparison of existing methods. In this study, we use publicly available 1D sequencing signals to model chromatin interactions in two human cell lines and evaluate the prediction performance of 5 popular machine learning algorithms: decision trees, random forests, gradient boosting, support vector machines and multi-layer perceptron. Our approach accurately predicts long-range interactions and reveals that gradient boosting significantly outperforms the other four algorithms, yielding accuracies of ~ 95%. We show that chromatin features in close genomic proximity to the anchors cover most of the predictive information. Moreover, we demonstrate that gradient boosting models trained with different subsets of chromatin features, unlike the other methods tested, are able to produce accurate predictions. In this regard, and besides architectural proteins, transcription factors are shown to be highly informative. Our study provides a framework for the systematic prediction of long-range chromatin interactions, identifies gradient boosting as the best suited algorithm for this task and highlights cell-type specific binding of transcription factors at the anchors as important determinants of chromatin wiring.
Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses
Authors: Scekic-Zahirovic Jelena , Sanjuan-Ruiz Inmaculada , Kan Vanessa , Megat Salim , De Rossi Pierre , Dieterlé Stéphane , Cassel Raphaelle , Kessler Pascal , Wiesner Diana , Tzeplaeff Laura , Demais Valérie , Muller Hans-Peter , Picchiarelli Gina , Mishra Nibha , Dirrig-Grosch Sylvie , Kassubek Jan , Rasche Volker , Ludolph Albert , Boutillier Anne-Laurence , Polymenidou Magdalini , Lagier-Tourenne Clotilde , Liebscher Sabine , Dupuis Luc
Published: June 2020

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS, lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a profound increase in neuronal activity in the frontal cortex ofFusknock-in micein vivo. Importantly, RNAseq analysis suggested involvement of defects in inhibitory neurons, that was confirmed by ultrastructural and morphological defects of inhibitory synapses and increased synaptosomal levels of mRNAs involved in inhibitory neurotransmission. Thus, cytoplasmic FUS triggers inhibitory synaptic deficits, leading to increased neuronal activity and behavioral phenotypes. FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, but also in other neurodegenerative diseases with FUS mislocalization.
Taking Fright: The Decline of Australian Pied OystercatchersHaematopus longirostrisat South Ballina Beach, New South Wales
Authors: Totterman Stephen
Published: June 2020

This study reviewed data from the Richmond River Area Pied Oystercatcher Protection Program 1997–2013 and Richmond River Area Shorebird Protection Program 2014–2018, on the far north coast of the State of New South Wales (NSW), Australia. The Australian Pied OystercatcherHaematopus longirostrisbreeding population size for South Ballina Beach has decreased from 15–16 pairs in 1994–1996 to 7–9 pairs in 2016–2018. This is despite control of the European Red FoxVulpes vulpessuccessfully reducing depredation of eggs and chicks and > 207 oystercatchers fledging from beaches in the Richmond River area in 1997–2018. The negative trend for South Ballina is contrasted with the positive trend for Bombing Range Beach, where the population size has increased from 4–5 pairs in 2002–2004 to 8–9 pairs in 2016–2018. Vehicle-based recreation has increased at South Ballina in the past two decades versus Bombing Range has remained closed to the public. It is proposed that human recreation disturbance is preventing recruitment into the South Ballina oystercatcher breeding population. Without strong protection of habitat from such disturbance, the NSW oystercatcher breeding population size is predicted to continue to decrease.
Enteroendocrine cells sense bacterial tryptophan catabolites to activate enteric and vagal neuronal pathways
Authors: Ye Lihua , Bae Munhyung , Cassilly Chelsi D. , Jabba Sairam V. , Thorpe Daniel W. , Martin Alyce M , Lu Hsiu-Yi , Wang Jinhu , Thompson John D. , Lickwar Colin R. , Poss Kenneth D. , Keating Damien J. , Jordt Sven-Eric , Clardy Jon , Liddle Rodger A. , Rawls John F.
Published: June 2020

The intestinal epithelium senses nutritional and microbial stimuli using epithelial sensory enteroendocrine cells (EECs). EECs can communicate nutritional information to the nervous system, but similar mechanisms for microbial information are unknown. Usingin vivoreal-time measurements of EEC and nervous system activity in zebrafish, we discovered that the bacteriaEdwardsiella tardaspecifically activates EECs through the receptor transient receptor potential ankyrin A1 (Trpa1) and increases intestinal motility in an EEC-dependent manner. Microbial, pharmacological, or optogenetic activation of Trpa1+EECs directly stimulates vagal sensory ganglia and activates cholinergic enteric neurons through 5-HT. We identified a subset of indole derivatives of tryptophan catabolism produced byE. tardaand other gut microbes that potently activates zebrafish EEC Trpa1 signaling and also directly stimulates human and mouse Trpa1 and intestinal 5-HT secretion. These results establish a molecular pathway by which EECs regulate enteric and vagal neuronal pathways in response to specific microbial signals.
Towards a better understanding of the low recall of insertion variants with short-read based variant callers
Authors: Delage Wesley , Thevenon Julien , Lemaitre Claire
Published: June 2020

Since 2009, numerous tools have been developed to detect structural variants (SVs) using short read technologies. Insertions >50 bp are one of the hardest type to discover and are drastically underrepresented in gold standard variant callsets. The advent of long read technologies has completely changed the situation. In 2019, two independent cross technologies studies have published the most complete variant callsets with sequence resolved insertions in human individuals. Among the reported insertions, only 17 to 37% could be discovered with short-read based tools. In this work, we performed an in-depth analysis of these unprecedented insertion callsets in order to investigate the causes of such failures. We have first established a precise classification of insertion variants according to four layers of characterization: the nature and size of the inserted sequence, the genomic context of the insertion site and the breakpoint junction complexity. Because these levels are intertwined, we then used simulations to characterize the impact of each complexity factor on the recall of several SV callers. Simulations showed that the most impacting factor was the insertion type rather than the genomic context, with various difficulties being handled differently among the tested SV callers, and they highlighted the lack of sequence resolution for most insertion calls. Our results explain the low recall by pointing out several difficulty factors among the observed insertion features and provide avenues for improving SV caller algorithms and their combinations.

Contact

wesley.delage@irisa.fr
DYNC1LI2 regulates localization of the chaperone-mediated autophagy-receptor LAMP2A and improves cellular homeostasis in cystinosis
Authors: Rahman Farhana , Johnson Jennifer L. , Zhang Jinzhong , He Jing , Cherqui Stephanie , Catz Sergio D.
Published: June 2020

The dynein motor protein complex is required for retrograde transport but the functions of the intermediate-light chains that form the cargo-binding complex are not elucidated and the importance of individual subunits in the maintenance of cellular homeostasis is unknown. Here, using mRNA arrays and protein analysis, we show that the dynein subunit, intermediate chain 2 (DYNC1LI2) is downregulated in cystinosis, a lysosomal storage disorder caused by genetic defects in the lysosomal cystine transporter, cystinosin. Reconstitution of the expression of DYNC1LI2 inCtns-/-cells re-established endolysosomal dynamics. Defective vesicular trafficking in cystinotic cells was rescued by DYNC1LI2 expression which correlated with decreased endoplasmic reticulum stress manifested as decreased expression levels of the chaperone Grp78. Mitochondrial fragmentation in cystinotic fibroblasts was also rescued by DYNC1LI2. Survival of cystinotic cells to oxidative stress insult was increased by DYNC1LI2 reconstitution but not by its paralog DYNC1LI1, which also failed to decrease ER stress levels and mitochondrial fragmentation. Restoring DYNC1LI2 expression rescued the localization of the chaperone-mediated autophagy receptor, LAMP2A, and restored cellular homeostasis of cystinotic proximal tubule cells, the primary cell type affected in cystinosis. DYNC1LI2 failed to rescue phenotypes in cystinotic cells when LAMP2A was downregulated or when co-expressed with dominant negative (DN) RAB7 or DN-RAB11, which impair LAMP2A trafficking. DYNC1LI2 emerges as a new target to repair underlying trafficking and CMA defects in cystinosis, a mechanism that is not restored by currently used lysosomal depletion therapies.
The Potential ofCapsicum annumExtracts to PreventLactococcosisin Tilapia
Authors: Ndashe Kunda , Ngh’ake Stellah , Pola Emelda , Sakala Emmanuel Masautso , Kabwali Emmanuel , Moonga Ladslav , Kefi Alexander Shula , Hang’ombe Bernard Mudenda
Published: June 2020

The capsaicin was extracted in-house from locally purchased chili pepper (Capsicum annum) using the conventional solvent extraction method. Varying concentrations of capsaicin were mixed with Lactococcus garvieae each and inoculated on Mueller Hinton agar to determine the minimum bactericidal concentration. Four groups of 100 fish each were injected with either 1) Capsaicin, 2) bacteria and capsaicin, 3) bacteria and 4) normal saline (negative control). The fish were observed for 7 days post treatment and experiment was repeated three times. Protection against infection was measured by the lack of clinical disease and survivability of the fish during period of experimentation. The minimum bactericidal concentration of capsaicin on growth ofLactococcus garvieaewas 0.1967mg/ml. Significantly, more fish in the bacteria and capsaicin group survived (p<0.0001) compared to those injected with bacteria only. The findings suggest that chili pepper extract can preventLactococcus garvieaeinfection in tilapia.
Towards robust and replicable sex differences in the intrinsic brain function of autism
Authors: Floris Dorothea L. , Filho José O. A. , Lai Meng-Chuan , Giavasis Steve , Oldehinkel Marianne , Mennes Maarten , Charman Tony , Tillmann Julian , Dumas Guillaume , Ecker Christine , Dell’Acqua Flavio , Banaschewski Tobias , Moessnang Carolin , Baron-Cohen Simon , Durston Sarah , Loth Eva , Murphy Declan G. M. , Buitelaar Jan K. , Beckmann Christian F. , Milham Michael P. , Di Martino Adriana
Published: June 2020

Background

Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data.

Methods

We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR).

Results

Discovery analyses in ABIDE revealed significant main effects across the intrinsic functional connectivity (iFC) of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples – EU-AIMS LEAP.

Limitations

Given the lack ofa prioriharmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability.

Conclusions

Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.
Arhopalus rusticus(Coleoptera: Cerambycidae): a new vector for pine wood nematode,Bursaphelenchus xylophilus(Nematoda: Aphelenchoididae)
Authors: Wang Yang , Mao Yunfei , Chen Fengmao , Wang Lichao , song Juan , Zhou Lifeng
Published: June 2020

In the study on the transmission of pine wood nematodes byArhopalus rusticus, we research the ability and characteristics ofArhopalus rusticusto transmit pine wood nematodes. A total of 288Arhopalus rusticus(female 142, male 146) were collected and 20 (female 8, male 12) of them were able to carry pine wood nematodes. Results shown that 12 beetles can transmit pine wood nematodes.Arhopalus rusticusdoes not eat the pine bark, but eat the pine needles. Pine wood nematodes are transmitted through the feeding bite mark on the pine needles. In addition experiments further confirmed that pine wood nematodes could transmit through pine needles.
Environmental and genetic contributions to imperfectwMel-likeWolbachiatransmission and frequency variation
Authors: Hague Michael T.J. , Mavengere Heidi , Matute Daniel R. , Cooper Brandon S.
Published: June 2020

Maternally transmittedWolbachiabacteria infect about half of all insect species. They usually show imperfect maternal transmission and often produce cytoplasmic incompatibility (CI). Irrespective of CI,Wolbachiafrequencies tend to increase when rare only if they benefit host fitness. SeveralWolbachia, includingwMel that infectsDrosophila melanogastercause weak or no CI and persist at intermediate frequencies. On the island of São Tomé off West Africa, the frequencies ofwMel-likeWolbachiainfectingD. yakuba(wYak) andD. santomea(wSan) fluctuate, and the contributions of imperfect maternal transmission, fitness effects, and CI to these fluctuations are unknown. We demonstrate spatial variation inwYak frequency and transmission on São Tomé. Concurrent field estimates of imperfect maternal transmission do not predict spatial variation inwYak frequencies, which are highest at high altitudes where maternal transmission is the most imperfect. Genomic and genetic analyses provide little support forD. yakubaeffects onwYak transmission. Instead, rearing at cool temperatures reduceswYak titer and increases imperfect transmission to levels observed on São Tomé. Using mathematical models ofWolbachiafrequency dynamics and equilibria, we infer temporally variable imperfect transmission or spatially variable effects on host fitness and reproduction are required to explainwYak frequencies. In contrast, spatially stablewSan frequencies are plausibly explained by imperfect transmission, modest fitness effects, and weak CI. Our results provide insight into causes ofwMel-like frequency variation in divergent hosts. Understanding this variation is crucial to explainWolbachiaspread and to improvewMel biocontrol of human disease in transinfected mosquito systems.
The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding
Authors: Qiao Baofu , de la Cruz Monica Olvera
Published: June 2020

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection.

Abstract Figure

TOC:

The SARS-CoV-2 spike protein-ACE2 complex showing the polybasic cleavage sites
Combinatorial phosphorylation modulates the structure and function of the G protein gamma subunit in yeast
Authors: Toosi Zahra Nassiri , Su Xinya , Choudhury Shilpa , Li Wei , Pang Yui Tik , Gumbart James C. , Torres Matthew P.
Published: June 2020

Protein intrinsically disordered regions (IDRs) are often targets of combinatorial post-translational modifications (PTMs) that serve to regulate protein structure and/or function. Emerging evidence suggests that the N-terminal tails of G protein γ subunits – essential components of heterotrimeric G protein complexes – are intrinsically disordered, highly phosphorylated governors of G protein signaling. Here, we demonstrate that the yeast Gγ Ste18 undergoes combinatorial, multi-site phosphorylation within its N-terminal IDR. Phosphorylation at S7 is responsive to GPCR activation and osmotic stress while phosphorylation at S3 is responsive to glucose stress and is a quantitative indicator of intracellular pH. Each site is phosphorylated by a distinct set of kinases and both are also interactive, such that phosphomimicry at one site affects phosphorylation on the other. Lastly, we show that phosphorylation produces subtle yet clear changes in IDR structure and that different combinations of phosphorylation modulate the activation rate and amplitude of the scaffolded MAPK Fus3. These data place Gγ subunits among the growing list of intrinsically disordered proteins that exploit combinatorial post-translational modification to govern signaling pathway output.
‘Phase Zero’ clinical study platform combining broadband Vis/near-infrared spectroscopy and electrophysiology to study human brain organoid models of neurodevelopmental disorders
Authors: Dutta Anirban , Karanth Sneha Sudhakar , Bhattacharya Mahasweta , Liput Michal , Augustyniak Justyna , Cheung Mancheung , Stachowiak Ewa K. , Stachowiak Michal K.
Published: June 2020

Homeostatic control of neuronal excitability by modulation of synaptic inhibition (I) and excitation (E) of the principal neurons is important during brain maturation. The fundamental features of in-utero brain developmental, including local synaptic E-I ratio and bioenergetics, can be modeled by cerebral organoids (CO) that have exhibited highly regular nested oscillatory network events. Therefore, we evaluated a ‘Phase Zero’ clinical study platform combining broadband Vis/near-infrared(NIR) spectroscopy and electrophysiology to study E-I ratio based on the spectral exponent of local field potentials and bioenergetics based on the activity of mitochondrial Cytochrome-C Oxidase (CCO). We found a significant effect of the age of the healthy controls iPSC CO from 23 days to 3 months on the CCO activity (χ2(2,N=10)=20,p=4.5400e-05), and spectral exponent between 30–50Hz (χ2(2,N=16)=13.88,p=0.001). Also, a significant effect of drugs, choline (CHO), idebenone (IDB), R-alpha-lipoic acid plus acetyl-L-carnitine (LCLA), was found on the CCO activity (χ2(3,N=10)=25.44,p = 1.2492e-05), spectral exponent between 1–20Hz (χ2(3,N=16)=43.5,p=1.9273e-09) and 30–50Hz (χ2(3,N=16)=23.47, p=3.2148e-05) in 34 days old CO from schizophrenia (SCZ) patients iPSC. We present a multidimensional approach combining electrophysiology and Vis-NIR spectroscopy to complement traditional drug design approaches that can advance the system towards a normative parameter space.
Super-resolution segmentation network for reconstruction of packed neurites
Authors: Hang Zhou , Tingwei Quan , Qing Huang , Tian Liu , Tingting Cao , Shaoqun Zeng
Published: June 2020

Neuron reconstruction can provide the quantitative data required for measuring the neuronal morphology and is crucial in the field of brain research. However, the difficulty in reconstructing packed neuritis, wherein massive labor is required for accurate reconstruction in most cases, has not been resolved. In this work, we provide a fundamental pathway for solving this challenge by proposing the use of the super-resolution segmentation network (SRSNet) that builds the mapping of the neurites in the original neuronal images and their segmentation in a higher-resolution space. SRSNet focuses on enlarging the distances between the boundaries of the packed neurites producing the high-resolution segmentation images. Thus, in the construction of the training datasets, only the traced skeletons of neurites are required, which vastly increase the usability of SRSNet. From the results of the experiments conducted in this work, it has been observed that SRSNet achieves accurate reconstruction of packed neurites where the other state-of-the-art methods fail.
Cholinergic upregulation by optogenetic stimulation of nucleus basalis after photothrombotic stroke in forelimb somatosensory cortex improves endpoint and motor but not sensory control of skilled reaching in mice
Authors: Agha Behroo Mirza , Akbary Roya , Ghasroddashti Arashk , Nazari-Ahangarkolaee Mojtaba , Whishaw Ian Q. , Mohajerani Majid H.
Published: June 2020

A network of cholinergic neurons in the basal forebrain innerve the forebrain and are proposed to contribute to a variety of functions including attention, and cortical plasticity. This study examined the contribution of the nucleus basalis cholinergic projection to the sensorimotor cortex on recovery on a skilled reach-to-eat task following photothrombotic stroke in the forelimb region of the somatosensory cortex. Mice were trained to perform a single-pellet skilled reaching task and their pre and poststroke performance, from Day 4 to Day 28 poststroke, was assessed frame-by-frame by video analysis with end point, movement and sensorimotor integration measures. Somatosensory forelimb lesions produced impairments in endpoint and movement component measures of reaching and increased the incidence of fictive eating, a sensory impairment in mistaking a missed reach for a successful reach. Upregulated acetylcholine (ACh) release, as measured by local field potential recording, elicited via optogenetic stimulation of the nucleus basalis improved recovery of reaching and improved movement scores but did not affect a sensorimotor integration impairment poststroke. The results show that the mouse cortical forelimb somatosensory region contributes to forelimb motor behavior and suggest that ACh upregulation could serve as an adjunct to behavioral therapy for the acute treatment of stroke.
Proximity Labeling-assisted Identification of Endogenous Kinase Substrates
Authors: Niinae Tomoya , Imami Koshi , Sugiyama Naoyuki , Ishihama Yasushi
Published: June 2020

Mass spectrometry-based phosphoproteomics can identify more than 10,000 phosphorylated sites in a single experiment. But, despite the fact that enormous phosphosite information has been accumulated in public repositories, protein kinase-substrate relationships remain largely unknown. Here, we describe a method to identify endogenous substrates of kinases by means of proximity labeling. We used a proximity-dependent biotin identification approach, called BioID, in combination with kinase-perturbed phosphoproteomics profiling and phosphorylation sequence motifs derived fromin vitrokinase assay to find molecules that interact with a target kinase, that show altered phosphorylation in response to kinase perturbation, and that are directly phosphorylated by the kinasein vitro; i.e., endogenous kinase substrates. Application of this methodology to casein kinase 2 (CK2) and protein kinase A (PKA) identified 33 and 52 putative substrates, respectively. We also show that known cancer-associated missense mutations near phosphosites of substrates affect phosphorylation by CK2 or PKA, and thus might alter downstream signaling in cancer cells bearing these mutations.

This study extends our knowledge of kinase-substrate networks by proposing a new large-scale approach to identify endogenous substrates of kinases.
Changes in Solo and Partnered Sexual Behaviors during the COVID-19 Pandemic: Findings from a U.S. Probability Survey
Authors: Hensel Devon J. , Rosenberg Molly , Luetke Maya , Fu Tsung-chieh , Herbenick Debby
Published: June 2020

Background

Research demonstrates that pandemics adversely impact sexual and reproductive health (SRH), but few have examined their impact on people’s participation in sex. We examined self-reported changes in solo and sexual behaviors in U.S. adults during early stages of the public health response to COVID-19.

Methods

We conducted an online, nationally representative, cross-sectional survey of U.S. adults (N=1010; aged 18-94 years; 62% response rate) from April 10-20, 2020. We used weighted multinomial logistic regression to examine past month self-reported changes (decreased, stable or increased) in ten solo and partnered sexual behaviors. Predictor variables included: having children at home, past month depressive symptoms, (ACHA 3-item scale), past month loneliness (UCLA 3-Item Loneliness scale), COVID-19 protection behaviors (adapted 12-item scale), perceived COVID-19 consequences (adapted 10-item scale) and COVID-19 knowledge (adapted 10-item scale).

Results

Nearly half of all adults reported some kind of change – most commonly, a decrease – in their sexual behavior in the past month. Having elementary aged children at home, past month depressive symptoms and loneliness and enacting more COVID-19 protective behaviors were associated with both reduced partnered bonding behaviors, such as hugging, cuddling, holding hands and kissing, as well as reduced partnered sexual behaviors, such as oral sex, partnered genital touching and vaginal sex. Greater COVID-19 risk perception and greater COVID-19 knowledge were associated with mixed effects in behavior outcomes.

Conclusions

Our data illustrate the very personal ways in which different pandemic-associated factors may create or inhibit opportunities for solo and partnered sex. The centrality of sexuality to health and well-being – even during pandemics – means that a critical piece of public health prevention and management responses should is ensuring that services and resource that support positive sexual decision making remain open and available.
Proteomic Profiling in Biracial Cohorts Implicates DC-SIGN as a Mediator of Genetic Risk in COVID-19
Authors: Katz Daniel H. , Tahir Usman A. , Ngo Debby , Benson Mark , Bick Alexander G. , Pampana Akhil , Gao Yan , Keyes Michelle J. , Correa Adolfo , Sinha Sumita , Shen Dongxiao , Yang Qiong , Robbins Jeremy M. , Chen Zsu-Zsu , Cruz Daniel E. , Peterson Bennet , Natarajan Pradeep , Vasan Ramachandran S. , Smith J. Gustav , Wang Thomas J. , Wilson James G. , Gerszten Robert E.
Published: June 2020

Brief Summary

COVID-19 is one of the most consequential pandemics in the last century, yet the biological mechanisms that confer disease risk are incompletely understood. Further, heterogeneity in disease outcomes is influenced by race, though the relative contributions of structural/social and genetic factors remain unclear.1,2Very recent unpublished work has identified two genetic risk loci that confer greater risk for respiratory failure in COVID-19: theABOlocus and the 3p21.31 locus.3To understand how these loci might confer risk and whether this differs by race, we utilized proteomic profiling and genetic information from three cohorts including black and white participants to identify proteins influenced by these loci. We observed that variants in theABOlocus are associated with levels of CD209/DC-SIGN, a known binding protein for SARS-CoV and other viruses,4as well as multiple inflammatory and thrombotic proteins, while the 3p21.31 locus is associated with levels of CXCL16, a known inflammatory chemokine.5Thus, integration of genetic information and proteomic profiling in biracial cohorts highlights putative mechanisms for genetic risk in COVID-19 disease.
Estimation of effects of contact tracing and mask adoption on COVID-19 transmission in San Francisco: a modeling study
Authors: Worden Lee , Wannier Rae , Blumberg Seth , Ge Alex Y. , Rutherford George W. , Porco Travis C.
Published: June 2020

The current COVID-19 pandemic has spurred concern about what interventions may be effective at reducing transmission. The city and county of San Francisco imposed a shelter-in-place order in March 2020, followed by use of a contact tracing program and a policy requiring use of cloth face masks. We used statistical estimation and simulation to estimate the effectiveness of these interventions in San Francisco. We estimated that self-isolation and other practices beginning at the time of San Francisco’s shelter-in-place order reduced the effective reproduction number of COVID-19 by 35.4% (95% CI, −20.1%–81.4%). We estimated the effect of contact tracing on the effective reproduction number to be a reduction of approximately 44% times the fraction of cases that are detected, which may be modest if the detection rate is low. We estimated the impact of cloth mask adoption on reproduction number to be approximately 8.6%, and note that the benefit of mask adoption may be substantially greater for essential workers and other vulnerable populations, residents return to circulating outside the home more often. We estimated the effect of those interventions on incidence by simulating counterfactual scenarios in which contact tracing was not adopted, cloth masks were not adopted, and neither contact tracing nor cloth masks was adopted, and found increases in case counts that were modest, but relatively larger than the effects on reproduction numbers. These estimates and model results suggest that testing coverage and timing of testing and contact tracing may be important, and that modest effects on reproduction numbers can nonetheless cause substantial effects on case counts over time.
Poorly known aspects of flattening the curve of COVID-19
Authors: Debecker Alain , Modis Theodore
Published: June 2020

This work concerns the too-often mentioned flattening of the curve of COVID-19. The diffusion of the virus is analyzed with logistic-curve fits on the 25 countries most affected at the time of the writing and in which the diffusion curve was more than 95% completed. A negative correlation observed between the final number of infections and the slope of the logistic curve corroborates a result obtained long time ago via an extensive simulation study. There is both theoretical arguments and experimental evidence for the existence of such correlations. The flattening of the curve results in a retardation of the curve’s midpoint, which entails an increase in the final number of infections. It is possible that more lives are lost at the end by this process. Our analysis also permits evaluation of the various governments’ interventions in terms of rapidity of response, efficiency of the actions taken (the amount of flattening achieved), and the number of days by which the curve was delayed. Not surprisingly, early decisive response proves to be the optimum strategy among the countries studied.
COVID-19 and associations with frailty and multimorbidity: a prospective analysis of UK Biobank participants
Authors: Woolford S J , D’Angelo S , Curtis E M , Parsons C M , Ward K A , Dennison E M , Patel H P , Cooper C , Harvey N C
Published: June 2020

Background

Frailty and multimorbidity have been suggested as risk factors for severe COVID-19 disease.

Aims

We investigated whether frailty and multimorbidity were associated with risk of hospitalisation with COVID-19 in the UK Biobank.

Methods

502,640 participants aged 40-69 years at baseline (54-79 years at COVID-19 testing) were recruited across UK 2006-10. A modified assessment of frailty using Fried’s classification was generated from baseline data. COVID-19 test results (England) were available 16/03/2020-01/06/2020, mostly taken in hospital settings. Logistic regression was used to discern associations between frailty, multimorbidity and COVID-19 diagnoses, adjusting for sex, age, BMI, ethnicity, education, smoking and number of comorbidity groupings, comparing COVID-19 positive, COVID-19 negative and non-tested groups.

Results

4,510 participants were tested for COVID-19 (positive=1,326, negative=3,184). 497,996 participants were not tested. Compared to the non-tested group, after adjustment, COVID-19 positive participants were more likely to be frail (OR=1.3 [95% CI=1.1, 1.7]), report slow walking speed (OR=1.3 [1.1, 1.6]), report two or more falls in the past year (OR=1.3 [1.0, 1.5]) and be multimorbid (≥4 comorbidity groupings vs 0-1: OR=1.9 [1.5, 2.3]). However, similar strength of associations were apparent when comparing COVID-19 negative and non-tested groups. Furthermore, frailty and multimorbidity were not associated with COVID-19 diagnoses, when comparing COIVD-19 positive and COVID-19 negative participants.

Discussion and conclusions

Frailty and multimorbidity do not appear to aid risk stratification, in terms of a positive versus negative results of COVID-19 testing. Investigation of the prognostic value of these markers for adverse clinical sequelae following COVID-19 disease is urgently needed.