bluuebunny/crossref_metadata_2025 huggingface dataset:
Endometriosis And Chronic Pelvic Pain Have Similar Impact On Women, But Time To Diagnosis Is Decreasing: An Australian Survey
Authors: Armour Mike , Sinclair Justin , Ng Cecilia H M , Hyman Mikayla S , Lawson Kenny , Smith Caroline A , Abbott Jason
Published: June 2020

Chronic pelvic pain (CPP) affects a significant number of women worldwide. Internationally, people with endometriosis report significant negative impact across many areas of their life. We aimed to use an online survey using the EndoCost tool to determine if there was any difference in the impact of CPP in those with vs. those without a confirmed diagnosis of endometriosis, and if there was any change in diagnostic delay since the introduction of clinical guidelines in 2005. 409 responses were received; 340 with a diagnosis of endometriosis and 69 with no diagnosis. People with CPP, regardless of diagnosis, reported moderate to severe dysmenorrhea and non-cyclical pelvic pain. Dyspareunia was also common. Significant negative impact was reported for social, academic, and sexual/romantic relationships in both cohorts. In the endometriosis cohort there was a mean diagnostic delay of eight years, however there was a reduction in both the diagnostic delay (p<0.001) and number of doctors seen before diagnosis (p<0.001) in those presenting more recently. Both endometriosis and CPP have significant negative impact. Whilst there is a decrease in the time to diagnosis, there is an urgent need for improved treatment options and support for women with the disease once the diagnosis is made.
Exosomal microRNAs Drive Thrombosis in COVID-19
Authors: Gambardella Jessica , Sardu Celestino , Morelli Marco Bruno , Messina Vincenzo , Castellanos Vanessa , Marfella Raffaele , Maggi Paolo , Paolisso Giuseppe , Wang Xujun , Santulli Gaetano
Published: June 2020

Thrombotic and thromboembolic complications have been shown to play a critical role in the clinical outcome of COVID-19. Emerging evidence has shown that exosomal miRNAs are functionally involved in a number of physiologic and pathologic processes. However, neither exosomes nor miRNAs have been hitherto investigated in COVID-19. To test the hypothesis that exosomal miRNAs are a key determinant of thrombosis in COVID-19, we enrolled patients positive for COVID-19. Circulating exosomes were isolated from equal amounts of serum and levels of exosomal miRNAs were quantified. We divided our population in two groups based on the serum level of D-dimer on admission. Strikingly, we found that exosomal miR-424 was significantly upregulated whereas exosomal miR-103a, miR-145, and miR-885 were significantly downregulated in patients in the high D-dimer group compared to patients in the low D-Dimer group (p<0.0001).
The effectiveness of interventions to reduce COVID-19 transmission in a large urban jail
Authors: Malloy Giovanni S. P. , Puglisi Lisa , Brandeau Margaret L. , Harvey Tyler D. , Wang Emily A.
Published: June 2020

Objectives

To estimate the impact of various mitigation strategies on COVID-19 transmission in a U.S. jail beyond those offered in national guidelines.

Methods

We developed a stochastic dynamic transmission model of COVID-19 in one large urban U.S. jail among staff and incarcerated individuals. We divided the outbreak into four intervention phases: the start of the outbreak, depopulation of the jail, increased proportion of people in single cells, and asymptomatic testing. We used the next generation method to estimate the basic reproduction ratio, R0, in each phase. We estimated the fraction of new cases, hospitalizations, and deaths averted by these interventions along with the standard measures of sanitization, masking, and social distancing interventions.

Results

For the first outbreak phase, the estimated R0 was 8.23 (95% CrI: 5.01-12.90), and for the subsequent phases, R0,phase 2 = 3.58 (95% CrI: 2.46-5.08), R0,phase 3 = 1.72 (95% CrI: 1.41-2.12), and R0,phase 4 = 0.45 (95% CrI: 0.32-0.59). In total, the jail’s interventions prevented approximately 83% of projected cases and hospitalizations and 89% of deaths over 83 days.

Conclusions

Depopulation, single celling, and asymptomatic testing within jails can be effective strategies to mitigate COVID-19 transmission in addition to standard public health measures.

Policy Implications

Decision-makers should prioritize reductions in the jail population, single celling, and testing asymptomatic populations, as additional measures to manage COVID-19 within correctional settings.
An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance inMycobacterium tuberculosis
Authors: Furió Victoria , Moreno-Molina Miguel , Chiner-Oms Álvaro , Villamayor Luis M , Torres-Puente Manuela , Comas Iñaki
Published: June 2020

Efforts to eradicate tuberculosis are hampered by the rise and spread of antibiotic resistance. Several large-scale projects have aimed to specifically link clinical mutations to resistance phenotypes, but they were limited in both their explanatory and predictive powers. Here, we combine functional genomics and phylogenetic associations using clinical strain genomes to decipher the architecture of isoniazid resistance and search for new resistance determinants. This approach has allowed us to confirm the main target route of the antibiotic, determine the clinical relevance of redox metabolism as an isoniazid resistance mechanism and identify novel candidate genes harboring resistance mutations in strains with previously unexplained isoniazid resistance. This approach can be useful for characterizing how the tuberculosis bacilli acquire resistance to new antibiotics and how to forestall them.
High-order mutants reveal an essential requirement for peroxidases but not laccases in Casparian strip lignification
Authors: Rojas-Murcia Nelson , Hématy Kian , Lee Yuree , Emonet Aurélia , Ursache Robertas , Fujita Satoshi , De Bellis Damien , Geldner Niko
Published: June 2020

The invention of lignin has been at the heart of plants’ capacity to colonize land, allowing them to grow tall, transport water within their bodies and protect themselves against various stresses. Consequently, this polyphenolic polymer, that impregnates the cellulosic plant cell walls, now represents the second most abundant polymer on Earth, after cellulose itself. Yet, despite its great physiological, ecological and economical importance, our knowledge of lignin biosynthesisin vivo, especially the crucial last steps of polymerization within the cell wall, remains vague. Specifically, the respective roles and importance of the two main polymerizing enzymes classes, laccases and peroxidases have remained obscure. One reason for this lies in the very high numbers of laccases and peroxidases encoded by 17 and 73 homologous genes, respectively, in the Arabidopsis genome. Here, we have focused on a specific lignin structure, the ring-like Casparian strips (CS) within the endodermis of Arabidopsis roots. By reducing the number of possible candidate genes using cellular resolution expression and localization data and by boosting the levels of mutants that can be stacked using CRISPR/Cas9, we were able to knock-out more than half of all laccases in the Arabidopsis genome in a nonuple mutant – abolishing the vast majority of laccases with detectable endodermal-expression. Yet, we were unable to detect even slight defects in CS formation. By contrast, we were able to induce a complete absence of CS formation in a quintuple peroxidase mutant. Our findings are in stark contrast to the strong requirement of xylem vessels for laccase action and indicate that lignin in different cell types can be polymerized in very distinct ways. We speculate that cells lignify differently depending on whether they deposit lignin in a localized or ubiquitous fashion, whether they stay alive during and after lignification as well as the composition of the cell wall.
Pervasive RNA secondary structure in the genomes of SARS-CoV-2 and other coronaviruses – an endeavour to understand its biological purpose
Authors: Simmonds P.
Published: June 2020

The ultimate outcome of the COVID-19 pandemic is unknown and is dependent on a complex interplay of its pathogenicity, transmissibility and population immunity. In the current study, SARS coronavirus 2 (SARS-CoV-2) was investigated for the presence of large scale internal RNA base pairing in its genome. This property, termed genome scale ordered RNA structure (GORS) has been previously associated with host persistence in other positive-strand RNA viruses, potentially through its shielding effect on viral RNA recognition in the cell. Genomes of SARS-CoV-2 were remarkably structured, with minimum folding energy differences (MFEDs) of 15%, substantially greater than previously examined viruses such as HCV (MFED 7-9%). High MFED values were shared with all coronavirus genomes analysed created by several hundred consecutive energetically favoured stem-loops throughout the genome. In contrast to replication-association RNA structure, GORS was poorly conserved in the positions and identities of base pairing with other sarbecoviruses – even similarly positioned stem-loops in SARS-CoV-2 and SARS-CoV rarely shared homologous pairings, indicative of more rapid evolutionary change in RNA structure than in the underlying coding sequences. Sites predicted to be base-paired in SARS-CoV-2 showed substantially less sequence diversity than unpaired sites, suggesting that disruption of RNA structure by mutation imposes a fitness cost on the virus which is potentially restrictive to its longer evolution. Although functionally uncharacterised, GORS in SARS-CoV-2 and other coronaviruses represent important elements in their cellular interactions that may contribute to their persistence and transmissibility.
BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance
Authors: Donoghue Lauren J. , Markovetz Matthew R. , Morrison Cameron B. , McFadden Kathryn M. , Rogers Troy D. , Button Brian , Ehre Camille , Hill David B. , Grubb Barbara R. , Kelada Samir N. P.
Published: June 2020

Airway mucociliary clearance (MCC) is required for host defense and often diminished in chronic lung diseases. Effective clearance depends upon coordinated actions of the airway epithelium and a mobile mucus layer. Dysregulation of the primary secreted airway mucin proteins, MUC5B and MUC5AC, is associated with a reduction in the rate of MCC; however, how other secreted proteins impact the integrity of the mucus layer and MCC remains unclear. We previously identified the geneBpifb1/Lplunc1as a regulator of airway MUC5B levels using genetic approaches. Here, we show that BPIFB1 is required for normal mucociliary clearancein vivousingBpifb1knockout (KO) mice. Reduced MCC inBpifb1KO mice occurred in the absence of defects in sodium or chloride ion transport or reduced ciliary beat frequency. BPIFB1 loss resulted in airway mucus flakes with significantly increased complex viscosity, a key biophysical property of mucus known to impact MCC. Finally, we detected colocalization of BPIFB1 and MUC5B in secretory granules in mice and in the protein mesh of secreted mucus in human airway cultures. Collectively, our findings demonstrate that BPIFB1 is an important component of the mucociliary apparatus in mice and a key component of the mucus protein network.
The genetic basis of adaptation in phenology in an introduced population of Black Cottonwood (Populus trichocarpa, Torr. & Gray)
Authors: Apuli Rami-Petteri , Richards Thomas , Rendon Martha , Karacic Almir , Wästljung Ann-Christin Rönnberg , Ingvarsson Pär K.
Published: June 2020

Entering and exiting winter dormancy presents important trade-offs between growth and survival at northern latitudes and many forest trees display local adaptation across latitude. Transfers of a species outside its native range introduce the species to novel combinations of environmental conditions potentially requiring different combinations of alleles to optimize growth.

We performed genome wide association analyses and a selection scan in aP. trichocarpamapping population derived from crossings between clones collected across the native range and introduced into Sweden. GWAS analyses were performed using phenotypic data collected across two field seasons and in a controlled phytotron experiment.

We uncovered 629 putative candidate genes associated with spring and autumn phenology traits as well as with growth. Many regions harboring variation significantly associated with the initiation of leaf shed and leaf autumn coloring appeared to have been evolving under positive selection in the native environments ofP. trichocarpa.

A comparison between the candidate genes identified with results from earlier GWAS analyses performed in the native environment found a smaller overlap for spring phenology traits than for autumn phenology traits, aligning well with earlier observations that spring phenology transitions have a more complex genetic basis that autumn phenology transitions.
SMC and the bactofilin/PadC scaffold have distinct yet redundant functions in chromosome segregation and organization inMyxococcus xanthus
Authors: Anand Deepak , Schumacher Dominik , Søgaard-Andersen Lotte
Published: June 2020

In bacteria, ParABSsystems and structural maintenance of chromosome (SMC) condensin-like complexes are important for chromosome segregation and organization. The rod-shapedMyxococcus xanthuscells have a unique chromosome arrangement in which a scaffold composed of three bactofilins (BacNOP) and PadC positions the essential ParB·parSsegregation complexes and the DNA segregation ATPase ParA in the subpolar regions. Here, we identify the Smc and ScpAB subunits of the SMC complex inM. xanthusand demonstrate that SMC is conditionally essential with mutants containingsmcorscpABdeletions being temperature sensitive. Lack of SMC caused defects in chromosome segregation and organization. Lack of the BacNOP/PadC scaffold caused chromosome segregation defects but was not essential. Inactivation of SMC was synthetic lethal with lack of the BacNOP/PadC scaffold. Lack of SMC interfered with formation of the BacNOP/PadC scaffold while lack of this scaffold did not interfere with chromosome association by SMC. Altogether, our data support that three systems cooperate to enable chromosome segregation inM. xanthus, whereby ParABSconstitutes the basic machinery and SMC and the BacNOP/PadC scaffold have distinct yet redundant roles in this process with SMC supporting individualization of daughter chromosomes and BacNOP/PadC making the ParABS system operate more robustly
Inchworm stepping of Myc-Max heterodimer protein diffusion along DNA
Authors: Dai Liqiang , Yu Jin
Published: June 2020

Oncogenic protein Myc serves as a transcription factor to control cell metabolisms. Myc dimerizes via leucine zipper with its associated partner protein Max to form a heterodimer structure, which then binds target DNA sequences to regulate gene transcription. The regulation depends on by Myc-Max binding to DNA and searching for target sequences via diffusional motions along DNA. Here, we conduct structure-based molecular dynamics (MD) simulations to investigate the diffusion dynamics of the Myc-Max heterodimer along DNA. We found that the heterodimer protein slides on the DNA in a rotation-uncoupled manner in coarse-grained simulations, as its two helical DNA binding basic regions (BRs) alternate between open and closed conformations via inchworm stepping motions. In such motions, the two BRs of the heterodimer step across the DNA strand one by one, with step sizes up about half of a DNA helical pitch length. Atomic MD simulations of the Myc-Max heterodimer in complex with DNA have also been conducted. Hydrogen bond interactions reveal between the two BRs and two complementary DNA strands, respectively. In the non-specific DNA binding, the BR shows an onset of stepping on one association DNA strand and dissociating from the complementary strand. Overall, our simulation studies suggest that the inchworm stepping motions of the Myc-Max heterodimer can be achieved during the protein diffusion along DNA.
Adaptive mechanoproperties characterize glioblastoma fitness for invasion
Authors: Monzo Pascale , Crestani Michele , Chong Yuk Kien , Hennig Katharina , Ghisleni Andrea , Li Qingsen , Richichi Cristina , Maiuri Paolo , Balland Martial , Sheetz Michael P. , Pelicci Giuliana , Ang Beng Ti , Tang Carol , Gauthier Nils C.
Published: June 2020

Glioblastoma are heterogeneous tumors composed of highly invasive and highly proliferative clones. Heterogeneity in invasiveness could emerge from discrete biophysical properties linked to specific molecular expression. We identified clones of patient-derived glioma propagating cells that were either highly proliferative or highly invasive and compared their cellular architecture, migratory and biophysical properties. We discovered that invasiveness was linked to cellular fitness. The most invasive cells were stiffer, developed higher mechanical forces on the substrate and moved stochastically. The mechanochemical-induced expression of the formin FMN1 conferred invasive strength that was confirmed in patient samples. Moreover, FMN1 ectopic expression in less invasive clones increased fitness parameters. Mechanistically, FMN1 acts from the microtubule lattice, counteracting microtubule bundling and promoting a robust cell-body cohesion leading to highly invasive hurdling motility.

One Sentence Summary

FMN1 increases cell mechanics and invasiveness.
Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV
Authors: Stukalov Alexey , Girault Virginie , Grass Vincent , Karayel Ozge , Bergant Valter , Urban Christian , Haas Darya A. , Huang Yiqi , Oubraham Lila , Wang Anqi , Hamad M. Sabri , Piras Antonio , Hansen Fynn M. , Tanzer Maria C. , Paron Igor , Zinzula Luca , Enghleitner Thomas , Reinecke Maria , Lavacca Teresa M. , Ehmann Rosina , Wölfel Roman , Jores Jörg , Kuster Bernhard , Protzer Ulrike , Rad Roland , Ziebuhr John , Thiel Volker , Scaturro Pietro , Mann Matthias , Pichlmair Andreas
Published: June 2020

The global emergence of SARS-CoV-2 urgently requires an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1–10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. We therefore conducted a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactome of both viruses, as well as their influence on transcriptome, proteome, ubiquitinome and phosphoproteome in a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon SARS-CoV-2 and SARS-CoV infections at different layers and identified unique and common molecular mechanisms of these closely related coronaviruses. The TGF-β pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy by SARS-CoV-2 ORF3. The extensive dataset (available athttps://covinet.innatelab.org) highlights many hotspots that can be targeted by existing drugs and it can guide rational design of virus- and host-directed therapies, which we exemplify by identifying kinase and MMPs inhibitors with potent antiviral effects against SARS-CoV-2.
Modeling invasion patterns in the glioblastoma battlefield
Authors: Conte Martina , Casas-Tinto Sergio , Soler Juan
Published: June 2020

Glioblastoma is the most aggressive tumor of the central nervous system, due to its great infiltration capacity. Understanding the mechanisms that regulate the Glioblastoma invasion front is a major challenge with preeminent potential clinical relevance. In the in1ltration front, the key features of its dynamics relate to biochemical and biomechanical aspects, which result in extended cellular protrusions, known as tumor microtubes. The coordination of metalloproteinase expression, extracellular matrix degradation, and integrin activity emerges as leading mechanism that facilitates Glioblastoma expansion and in1ltration in uncontaminated brain regions. We propose a novel multidisciplinary approach, based on in vivo experiments in Drosophila and mathematical models, for the proteins dynamics at the front of Glioblastoma, with a predictive value of the tumor progression.
Is YouTube® promoting the exotic pet trade? Analysis of the global public perception of popular YouTube® videos featuring threatened exotic animals
Authors: Moloney Georgia , Tuke Jonathan , Dal Grande Eleonora , Nielsen Torben , Chaber Anne-Lise
Published: June 2020

The exploitation of threatened exotic species via social media challenges efforts to regulate the exotic pet trade and consequently threatens species conservation. To investigate how such content is perceived by the global community, sentiment analysis techniques were employed to explore variations in attitudes expressed through text and emoji usage in public comments associated with 346 popular YouTube® videos starring exotic wild cats or primates in captive or domestic situations. Although a negative trend in mean text sentiment was observed in 2015 for primates, an otherwise consistent positive mean sentiment text and emoji score through time was revealed in response to both exotic wild cat and primate videos, implying the societal normalisation and acceptance of exotic pets. These findings highlight the urgency for effective YouTube® policy changes and content management to promote public education and conservation awareness, whilst extinguishing false legitimisation and potential demand for the exotic pet trade.
Effects of date fruit (Phoenix dactylifera) on sperm cell morphology and reproductive hormonal profiles in cypermethrin-induced male infertility
Authors: Azubuike Ubah Simon , Adikpe Agbonu Oluwa , Kwinjoh Columbus Philemon , Owoicho Abah Kenneth , Chika Chibuogwu Ijeoma , Eneojo Abalaka Samson , Bankole Abayomi Samuel , Ikechukwu Enem Simon , Etudaye Ajayi Itopa
Published: June 2020

Date fruits are endowed with medicinal values, including boosting the male fertility status, but with meagre empirical evidence. Thus, the current study was designed to assess the ameliorative and potential adverse effects of date fruit extracts (Phoenix dactylifera) on cypermethrin-induced male infertility. The study was conducted in two phases using adult male Wistar rats (n = 42, 180 – 220 g and aged 14 - 16 weeks). The first phase was a single oral dose toxicity study to ascertain the suitability of date fruit extract and cypermethrin administered at 250 mg/kg and 60 mg/kg, respectively. The second phase, which included four treatment groups of six animals per group, assessed the effects of date fruits on cypermethrin-induced infertility. At the termination of the experiment, semen was collected by epididymal extraction for the assessment of sperm abnormalities, motility, mass activity, semen pH, and percentage live. Serum samples were also collected for testosterone and follicle stimulating hormone (FSH) profiling, and the collected data was subjected to statistical analysis. The group administered only cypermethrin showed a decrease in percentage motility, live, mass activity and an increase in total abnormalities over the control group while the group exposed to only date fruits extracts showed increased percentage motility, live, mass activity and a decrease in total abnormalities over the control. The results of a combined administration of date fruit extracts and cypermethrin on a separate group showed a consistently reduced percentage of anatomically abnormal sperm cells and a general improvement of sperm motility and mass activity. There was no significant difference in the weight of the Wister rats in all the groups (p > 0.05). However, testosterone and FSH levels were significantly reduced (p < 0.05) by date fruit extract treatment. The current report provides evidence of the potential ameliorative effects of date fruit extracts in cypermethrin-induced male infertility and cautions excessive use or abuse since some adverse effects were observed.
Diversification of mammalian deltaviruses by host shifting
Authors: Bergner Laura M. , Orton Richard J. , Broos Alice , Tello Carlos , Becker Daniel J. , Carrera Jorge E. , Patel Arvind H. , Biek Roman , Streicker Daniel G.
Published: June 2020

Hepatitis delta virus (HDV) is an unusual RNA agent that replicates using host machinery but exploits hepatitis B virus (HBV) to mobilize its spread within and between hosts. In doing so, HDV enhances the virulence of HBV. How this seemingly improbable hyper-parasitic lifestyle emerged is unknown, but underpins the likelihood that HDV and related deltaviruses may alter other host-virus interactions. Here, we show that deltaviruses diversify by transmitting between mammalian species. Among 96,695 RNA sequence datasets, deltaviruses infected bats, rodents and an artiodactyl from the Americas, but were absent from geographically overrepresented Old World representatives of each mammalian order, suggesting a relatively recent diversification within the Americas. Consistent with diversification by host shifting, both bat and rodent-infecting deltaviruses were paraphyletic and co-evolutionary modeling rejected co-speciation with mammalian hosts. In addition, a two-year field study showed common vampire bats in Peru were infected by two divergent deltaviruses, indicating multiple introductions to a single host species. One vampire bat-associated deltavirus was detected in the saliva of up to 35% of individuals, formed phylogeographically compartmentalized clades, and infected a sympatric bat, illustrating horizontal transmission within and between species on ecological timescales. Consistent absence of HBV-like viruses in two deltavirus-infected bat species indicated acquisitions of novel viral associations during the divergence of bat and human-infecting deltaviruses. Our analyses support an American zoonotic origin of HDV and reveal prospects for future cross-species emergence of deltaviruses. Given their peculiar life history, deltavirus host shifts will have different constraints and disease outcomes compared to ordinary animal pathogens.

Significance Statement

Satellites are virus-like agents which require both a host and a virus to complete their life cycle. The only human-infecting satellite is hepatitis delta virus (HDV), which exacerbates liver disease in patients co-infected with hepatitis B virus (HBV). How HDV originated is a longstanding evolutionary puzzle. Using terabase-scale data mining, co-evolutionary analyses, and field studies in bats, we show that deltaviruses can jump between highly divergent host species. Our results further suggest that the contemporary association between HDV and HBV likely arose following zoonotic transmission from a yet undiscovered animal reservoir in the Americas. Plastic host and virus associations open prospects that deltaviruses might alter the virulence of multiple viruses in multiple host species.
A subpopulation of astrocyte progenitors defined by Sonic hedgehog signaling
Authors: Gingrich Ellen , Case Kendra , Garcia A. Denise R.
Published: June 2020

The molecular signaling pathway, Sonic hedgehog (Shh), is critical for the proper development of the central nervous system. The requirement for Shh signaling in neuronal and oligodendrocyte development in the developing embryo are well established. Here, we show that Shh signaling also operates in a subpopulation of progenitor cells that generate cortical astrocytes. In the neonatal brain, cells expressing the Shh target gene,Gli1, are found in the subventricular zone (SVZ), a germinal zone harboring astrocyte progenitor cells. Using a genetic inducible fate mapping strategy, we show that these cells give rise to half of the cortical astrocyte population, suggesting that the cortex harbors astrocytes from different lineages. Shh activity in SVZ progenitor cells is transient but recurs in a subpopulation of mature astrocytes localized in layers IV and V in a manner independent of their lineage. These data identify a novel role for Shh signaling in cortical astrocyte development and support a growing body of evidence pointing to astrocyte heterogeneity.
Directional translocation resistance of Zika xrRNA
Authors: Suma Antonio , Coronel Lucia , Bussi Giovanni , Micheletti Cristian
Published: June 2020

xrRNAs from flaviviruses survive in host cells for their exceptional dichotomic response to the unfolding action of different enzymes. They can be unwound, and hence copied, by replicases, and yet can resist degradation by exonucleases. How the same stretch of xrRNA can encode such diverse responses is an open question. Here, by using atomistic models and translocation simulations, we uncover an elaborate and directional mechanism for how stress propagates when the two xrRNA ends, 5′ and 3′, are driven through a pore. Pulling the 3′ end, as done by replicases, elicits a progressive unfolding; pulling the 5′ end, as done by exonucleases, triggers a counterintuitive molecular tightening. Thus, in what appears to be a remarkable instance of intra-molecular tensegrity, the very pulling of the 5′ end is what boosts resistance to translocation and consequently to degradation. The uncovered mechanistic principle might be co-opted to design molecular meta-materials.
jouvence, a new human H/ACA snoRNA involves in the control of cell proliferation and differentiation
Authors: El-Khoury Flaria , Bignon Jérôme , Martin Jean-René
Published: June 2020

Small nucleolar RNAs (snoRNAs) are non-coding RNAs conserved from archeobacteria to mammals. In humans, various snoRNAs have been associated with pathologies as well as with cancer. Recently inDrosophila, a new snoRNA namedjouvencehas been involved in lifespan. Since snoRNAs are well conserved through evolution, both structurally and functionally,jouvenceorthologue has been identified in human, allowing hypothesizing thatjouvencecould display a similar function (increasing healthy lifespan) in human. Here, we report the characterization of the human snoRNA-jouvence, which was not yet annotated in the genome. We show, both in stably cancerous cell lines and in primary cells, that its overexpression stimulates the cell proliferation. In contrast, its knockdown, by siRNA leads to an opposite phenotype, a decrease in cell proliferation. Transcriptomic analysis reveals that overexpression ofjouvenceleads to a dedifferentiation signature of the cells, a cellular effect comparable to rejuvenation. Inversely, the knockdown ofjouvenceleads to a decrease of genes involved in ribosomes biogenesis and spliceosome in agreement with the canonical role of a H/ACA box snoRNA. In this context,jouvencecould represent a now tool to fight against the deleterious effect of aging, as well as a new target in cancer therapy.
Reward-predictive cues elicit maladaptive reward seeking in adolescent rats
Authors: Marshall Andrew T. , Maidment Nigel T. , Ostlund Sean B.
Published: June 2020

Impulsive behavior during adolescence may stem from a developmental imbalance between motivational and impulse control systems, producing greater urges to pursue reward and weakened capacities to inhibit such actions. Here, we developed a Pavlovian-instrumental transfer (PIT) protocol to assay rats’ ability to suppress cue-motivated reward seeking based on changes in reward expectancy. Traditionally, PIT studies focus on how reward-predictive cues motivate instrumental reward-seeking behavior (lever pressing). However, cues signaling imminent reward delivery also elicit countervailing focal-search responses (food-cup approach). We first examined how reward expectancy (cue-reward probability) influences expression of these competing behaviors. Adult male rats increased rates of lever pressing when presented with cues signaling lower probabilities of reward but focused their activity at the food cup on trials with cues that signaled higher probabilities of reward. We then compared adolescent and adult male rats in their responsivity to cues signaling different reward probabilities. In contrast to adults, adolescent rats did not flexibly adjust their pattern of responding based on the expected likelihood of reward delivery but increased their rate of lever pressing for both weak and strong cues. These findings indicate that impulse control over cue-motivated behavior is fundamentally dysregulated during adolescence, providing a model for studying neurobiological mechanisms of adolescent impulsivity.
Spatially-specific working memory activity in the human superior colliculus
Authors: Rahmati Masih , DeSimone Kevin , Curtis Clayton E. , Sreenivasan Kartik K.
Published: June 2020

Theoretically, working memory (WM) representations are encoded by population activity of neurons with distributed tuning across the stored feature. Here, we leverage computational neuroimaging approaches to map the topographic organization of human superior colliculus (SC) and model how population activity in SC encodes WM representations. We first modeled receptive field properties of voxels in SC, deriving a detailed topographic organization resembling that of the primate SC. Neural activity within male and female human SC persisted throughout a retention interval of several types of modified memory-guided saccade tasks. Assuming an underlying neural architecture of the SC based on its retinotopic organization, we used an encoding model to show that the pattern of activity in human SC represents locations stored in WM. Our tasks and models allowed us to dissociate the locations of visual targets and the motor metrics of memory-guided saccades from the spatial locations stored in WM, thus confirming that human SC represents true WM information. These data have several important implications. They add the SC to a growing number of cortical and subcortical brain areas that form distributed networks supporting WM functions. Moreover, they specify a clear neural mechanism by which topographically organized SC encodes WM representations.

Significance Statement

Using computational neuroimaging approaches, we mapped the topographic organization of human superior colliculus (SC) and modeled how population activity in SC encodes working memory (WM) representations, rather than simpler visual or motor properties that have been traditionally associated with the laminar maps in the primate SC. Together, these data both position the human SC into a distributed network of brain areas supporting WM and elucidate the neural mechanisms by which the SC supports WM.
Spatiotemporal dimensions of a reproductive life history trait in a spiny lizard radiation (Squamata: Phrynosomatidae)
Authors: Velasco Julián A. , Campillo-García Gustavo , Pinto-Ledezma Jesús , Flores-Villela Oscar
Published: June 2020

The ecological and evolutionary factors underlying life history trait variation is one of the most interesting topics in biology. Although many studies have evaluated either macroevolutionary or macroecological patterns of life history traits across several taxonomic groups, only few studies have attempted to integrate both dimensions in a single analytical framework. Here, we study how parity mode evolved across multiple scales in the radiation of spiny lizards (Squamata: Phrynosomatidae). We adopted macroecological and macroevolutionary approaches to explore how climate across spatial and temporal scales drives the evolution of viviparity in this lizard radiation. We find support for a weak signature of current climates on the geographical distribution of oviparous and viviparous species. By contrast, we detected that evolutionary transitions from oviparity to viviparity reach a peak during the MidMiocene Climatic Optimum — a period with a profound climate change event. We suggest that this abrupt climatic cooling promoted evolutionary transitions to viviparity simultaneously across three clades in the spiny lizard radiation. The decoupling in macroecological and macroevolutionary patterns found here suggests that past climate change has played a larger role than current climates in the spatial and temporal diversification of this reproductive life history trait.
Dynamic expression and localization of the LIN-2/7/10 protein scaffolding complex duringC. elegansvulval development
Authors: Gauthier Kimberley D. , Rocheleau Christian E.
Published: June 2020

The evolutionarily conserved LIN-2 (CASK)/LIN-7 (Lin7A-C)/LIN-10 (APBA1) complex plays an important role in regulating spatial organization of membrane proteins and signaling components. InC. elegans,the complex is essential for development of the vulva by promoting the localization of the sole Epidermal Growth Factor Receptor (EGFR) orthologue, LET-23, to the basolateral membrane of the vulva precursor cells (VPCs) where it can specify the vulval cell fate. However, the expression and localization of the LIN-2/7/10 complex, and how the complex regulates receptor localization, are not known. Here we describe anin vivoanalysis of the complex inC. elegansVPCs. Only LIN-7 colocalizes with LET-23 EGFR at the basolateral membrane, while the LIN-2/7/10 complex components instead colocalize at cytoplasmic foci, consistent with Golgi or endosomes. LIN-10 recruits LIN-2, which in turn recruits LIN-7. We demonstrate that the complex formsin vivowith particularly strong interaction and colocalization between LIN-2 and LIN-7. Our data suggest that the LIN-2/7/10 complex forms on endomembrane compartments where it likely targets LET-23 EGFR to the basolateral membrane, and point to distinct regulation between LIN-2/7 and LIN-10.

Summary Statement

LIN-10 recruits LIN-2 and LIN-7 to Golgi or recycling endosomes, consistent with targeting rather than tethering the epidermal growth factor receptor to the basolateral membrane inC. elegans.
Loss of O-GlcNAcylation on MeCP2 Thr 203 Leads to Neurodevelopmental Disorders
Authors: Cheng Juanxian , Zhao Zhe , Chen Liping , Du Ruijing , Wu Yan , Zhu Qian , Fan Ming , Duan Xiaotao , Wu Haitao
Published: June 2020

Mutations of the X-linked methyl-CpG-binding protein 2 (MECP2) gene in humans are responsible for most cases of Rett syndrome (RTT), an X-linked progressive neurological disorder. While genome-wide screens in clinical trials reveal several putative RTT-associated mutations onMECP2, their causative relevance regarding the functional regulation of MeCP2 on the etiologic sites at the protein level require more evidence. In this study, we demonstrate that MeCP2 is dynamically modified by O-linked-β-N-acetylglucosamine (O-GlcNAc) at threonine 203 (T203), an etiologic site in RTT patients. Disruption of the O-GlcNAcylation of MeCP2 specifically at T203 impairs dendrite development and spine maturation in cultured hippocampal neurons, and disrupts neuronal migration, dendritic spine morphogenesis and dysfunction of synaptic transmission in the developing and juvenile mouse cerebral cortex. Mechanistically, genetic disruption of O-GlcNAcylation at T203 on MeCP2 decreases neuronal activity-induced induction ofBdnftranscription. Our study highlights the critical role of MeCP2 T203 O-GlcNAcylation in neural development and synaptic transmission potentiallyviaBDNF.
Associations of Global Country Profiles and Modifiable Risk Factors with COVID-19 Cases and Deaths
Authors: Burden Samuel Joseph , Rademaker Josefien , Weedon Benjamin David , Whaymand Luke , Dawes Helen , Jones Alexander
Published: June 2020

Modifiable risk factors affect SARS-CoV-2 infection and mortality raising the possibility that lifestyle modification could play a role. This has not been studied at a global level. We analysed publicly available data from countries reporting COVID-19 cases and deaths. Associations of modifiable risk factors with total cases and excess deaths were determined with and without adjustment for confounders. 4,670,832 cases and 311,384 deaths were reported by 181 countries by 18th May 2020. Wealthier countries had the greatest caseload. Obesity was the primary modifiable risk factor for infection and greater age, male sex, physical inactivity and low salt consumption were associated with excess deaths. Obesity was less influential on mortality than physical inactivity. Globally, obesity confers vulnerability to SARS-CoV-2 infection and physical inactivity likely explains the greater mortality in the obese. High salt consumption may induce reductions in tissue ACE2 expression and subsequently reduce mortality rates.
Knowledge, Attitudes, and Fear of COVID-19 during the Rapid Rise Period in Bangladesh
Authors: Hossain Mohammad Anwar , Hossain K M Amran , Walton Lori Maria , Uddin Zakir , Haque Md. Obaidul , Kabir Md. Feroz , Arafat S. M. Yasir , Sakel Mohamed , Faruqui Rafey , Jahid Ikbal Kabir , Hossain Zahid
Published: June 2020

Objectives

To determine the level of Knowledge, Attitude, and Practice (KAP) related to COVID-19 preventive health habits and perception of Fear towards COVID-19 in subjects living in Bangladesh.

Design

Prospective, cross-sectional survey of (n= 2157) male and female subjects, 13-90 years of age, living in Bangladesh.

Methods

Ethical Approval and Trial registration were obtained prior to the commencement of the study. Subjects who volunteered to participate and signed the informed consent were enrolled in the study and completed the “Fear of COVID-19 Scale” (FCS).

Results

Twenty-eight percent (28.69%) of subjects reported one or more COVID-19 symptoms and 21.4% of subjects reported one or more comorbidities. Knowledge scores were slightly higher in males (8.75± 1.58) than females (8.66± 1.70). Knowledge was significantly correlated with age (p<.005), an education level (p<.001), Attitude (p<.001), and urban location (p=<.001). Knowledge scores showed an inverse correlation with Fear scores (p=<.001). Eighty-three percent (83.7%) of subjects with COVID-19 symptoms reported wearing a mask in public and 75.4% of subjects reported staying away from crowded places. Subjects with one or more symptoms reported higher Fear compared to subjects without (18.73± 4.6; 18.45± 5.1).

Conclusions

Overall, Bangladeshis reported a high prevalence of self-isolation, positive preventive health behaviors related to COVID-19, and moderate to high fear levels. Higher Knowledge and Practice were found in males, higher education levels, older age, and urban location. “Fear” of COVID-19 was more prevalent in female and elderly subjects. Positive “Attitude” was reported for the majority of subjects, reflecting the belief that COVID-19 was controllable and containable.

Ethical approval

Ethical permission obtained from the Institutional review board (BPA-IPRR/IRB/29/03/2020/021) of Institute of Physiotherapy, Rehabilitation, and Research (IPRR), the academic organization of the Bangladesh Physiotherapy Association.

WHO Trial registry

The trial registration obtained prospectively from a primary trial registry of WHO (CTRI/2020/04/024413).

Data Availability

The data are available regarding this study and can be viewed upon request
A germline PALB2 pathogenic variant identified in a pediatric high-grade glioma
Authors: Zhong Yiming , Schubert Jeffrey , Wu Jinhua , Xu Feng , Lin Fumin , Cao Kajia , Zelley Kristin , Luo Minjie , Foster Jessica B. , Cole Kristina A. , MacFarland Suzanne P. , Resnick Adam C. , Storm Phillip B. , Li Marilyn M.
Published: June 2020

PALB2 (partner and localizer of BRCA2) gene encodes a protein that colocalizes with BRCA2 in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. PALB2 plays a critical role in maintaining genome integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. It has a known loss-of-function disease mechanism. Biallelic PALB2 pathogenic variants have been described in autosomal recessive Fanconi anemia. Heterozygous pathogenic variants in PALB2 are associated with increased risk for female and male breast cancer and pancreatic cancer (Science 324: 217; Cancer Res 71: 2222–2229; N Engl J Med 371: 497–506). Heterozygous germline PALB2 mutations have also been observed in patients with medulloblastoma (Lancet Oncol 19: 785–798). However, PALB2-related cancer predisposition to high-grade gliomas has not been reported. Here we report a germline PALB2 pathogenic variant (c.509_510delGA, p.Arg170Ilefs*14, NM_024675.3) found in a pediatric patient with high-grade glioma. This variant was first identified by tumor sequencing using the Children's Hospital of Philadelphia (CHOP) Comprehensive Solid Tumor Panel and then confirmed to be a germline change using the CHOP Comprehensive Hereditary Cancer Panel on DNA from a blood sample of this patient. Parental studies showed that this variant was paternally inherited. Further studies are needed to illustrate if pathogenic variants in PALB2 convey increased risk to developing brain tumor. This case also highlights the potential of identifying germline mutation through tumor sequencing.
A new approach to phason disorder for a decagonal quasicrystal: the moment series expansion of the tiling distribution function for AlCuRh
Authors: Bugański Ireneusz , Strzałka Radoslaw , Wolny Janusz
Published: June 2020

A method is proposed of calculating the geometric term of the structure factor for quasicrystals, which enables incorporation of the phason disorder. The scheme is based on the series expansion of the structure factor with moments of the distribution function as coefficients. A distribution function is a mathematical object that is constructed for reference vertices of the tiles in the quasilattice. It encloses the entire structural information of the underlying quasilattice, together with the inherent disorder, necessary to calculate the diffraction pattern. By tuning the value of the distribution moments through the refinement procedure, it is possible to obtain a very good agreement of this new model of the decagonal AlCuRh phase with the experimental data, reflected in the crystallographicRfactor of 6.08%. The characteristic bias of the calculated diffraction peak intensities observed for the low-intensity reflections is significantly diminished, confirming its origin being, to some extent, related to phason disorder. Additionally, it is no longer necessary to use the general Debye–Waller factor for phasons, as the new formula accommodates this type of structural disorder. However, the best result was obtained for the model combining the new approach with the Gaussian corrective term.
Defining the hematite topotaxial crystal growth in magnetite–hematite phase transformation
Authors: Braga de Oliveira Flávia , Álvares da Silva Gilberto , Graça Leonardo Martins
Published: June 2020

Magnetite and hematite iron oxides are minerals of great economic and scientific importance. The oxidation of magnetite to hematite is characterized as a topotaxial reaction in which the crystallographic orientations of the hematite crystals are determined by the orientation of the magnetite crystals. Thus, the transformation between these minerals is described by specific orientation relationships, called topotaxial relationships. This study presents electron-backscatter diffraction analyses conducted on natural octahedral crystals of magnetite partially transformed into hematite. Inverse pole figure maps and pole figures were used to establish the topotaxial relationships between these phases. Transformation matrices were also applied to Euler angles to assess the diffraction patterns obtained and confirm the identified relationships. A new orientation condition resulting from the magnetite–hematite transformation was characterized, defined by the parallelism between the octahedral planes {111} of magnetite and rhombohedral planes \{10\bar {1}1\} of hematite. Moreover, there was a coincidence between one of the octahedral planes of magnetite and the basal {0001} plane of hematite, and between dodecahedral planes {110} of magnetite and prismatic planes \{11\bar {2}0\} of hematite. All these three orientation conditions are necessary and define a growth model for hematite crystals from a magnetite crystal. A new topotaxial relationship is also proposed: (111)Mag || (0001)Hem and (\bar {1}\bar {1}1)_{\rm Mag} || (10\bar {1}1)_{\rm Hem}.