bluuebunny/crossref_metadata_2025 huggingface dataset:
Life course longitudinal growth and risk of knee osteoarthritis at age 53 years: evidence from the 1946 British birth cohort study
Authors: Staines Katherine A. , Hardy Rebecca , Samvelyan Hasmik J. , Ward Kate A. , Cooper Rachel
Published: August 2020

Objectives

To examine the relationship between height gain across childhood and adolescence with knee osteoarthritis in the MRC National Survey of Health and Development (NSHD).

Methods

Data are from 3035 male and female participants of the NSHD. Height was measured at ages 2, 4, 6, 7, 11 and 15 years, and self-reported at ages 20 and 26 years. Associations between (i) height at each age (ii) height gain during specific life periods (iii) Super-Imposition by Translation And Rotation (SITAR) growth curve variables of height size, tempo and velocity, and knee osteoarthritis at 53 years were tested.

Results

In sex-adjusted models, taller height at 4 and 6 years were modestly associated with decreased odds of knee osteoarthritis at age 53 (ORs per 1cm increase in height at age 6: 0.97 and age 4: 0.98 (95% CI: 0.95-1.00)). These associations were attenuated after adjustment for potential confounders. Similarly, taller adult achieved height measured at 26 and 53 years of age were associated with decreased odds of knee osteoarthritis (OR per 1cm increase in height: 0.98 (95% CI 0.96 to 1.00)). No associations were found between height gain during specific life periods or the SITAR growth curve variables and odds of knee osteoarthritis.

Conclusions

There was some limited evidence to suggest that taller height in childhood is associated with decreased odds of knee osteoarthritis at age 53 years in this cohort. This work enhances our understanding of osteoarthritis predisposition and the contribution of life course height to this.
A Bayesian estimate of the COVID-19 infection fatality ratio in Brazil based on a random seroprevalence survey
Authors: Marra Valerio , Quartin Miguel
Published: August 2020

We infer the infection fatality ratio (IFR) of SARS-CoV-2 in Brazil by combining three datasets. We compute the prevalence via the population-based seroprevalence survey EPICOVID19-BR. For the fatalities we obtain the absolute number using the public Painel Coronavírus dataset and the age-relative number using the public SIVEP-Gripe dataset. The time delay between the development of antibodies and subsequent fatality is estimated via the SIVEP-Gripe dataset. We obtain the IFR via Bayesian inference for each survey stage and 27 federal states. We include the effect of fading IgG antibody levels by marginalizing over the time after contagion at which the test gives a negative result with a flat prior on the interval [40, 80] days. We infer a country-wide average IFR (maximum posterior and 95% CI) of 0.97% (0.82–1.14%) and age-specific IFR: 0.028% (0.024–0.036%) [< 30 years], 0.21% (0.17–0.25%) [30–49 years], 1.06% (0.88–1.31%) [50–69 years], 2.9% (2.5–3.7%) [≥ 70 years].
Potentially zoonotic gastrointestinal nematodes co-infecting free ranging non-human primates in Kenyan urban centres
Authors: Mbuthia Peris , Murungi Edwin , Owino Vincent , Akinyi Mercy , Eastwood Gillian , Nyamota Richard , Lekolool Isaac , Jeneby Maamun
Published: August 2020

Background

Natural infections with soil transmitted nematodes occur in non-human primates (NHPs) and have the potential to cross primate-species boundaries and cause diseases of significant public health concern. Despite their presence in most urban centres in Kenya, comprehensive studies on their gastrointestinal parasites are scant.

Objective

Conduct a cross-sectional survey to identify zoonotic nematodes in free-ranging NHPs found within four selected urban and peri-urban centres in Kenya.

Methods

A total of 86 NHPs: 41 African green monkeys [AGM] (Chlorocebus aethiops), 30 olive baboons (Papio anubis), 5 blue monkeys (Cercopithecus mitis stuhlmanni) and 10 red tailed monkeys (Cercopithecus ascanius) were sampled once in situ and released back to their habitat. Microscopy was used to identify nematodes egg and larvae stages in the samples. Subsequently, PCR coupled with high-resolution melting (PCR-HRM) analysis and sequencing were used to identify nodule worms.

Results

NHPs inhabiting densely populated urban environs in Kenya were found infected with a rich diversity of nematodes including three potentially zoonotic nematodes including Oesophagostomum stephanostomum, Oesophagostomum bifurcum and Trichostrongylus colubriformis and co-infections were common.

Conclusion

Phylogenetic analysis showed that O. stephanostomum from red tailed and blue monkeys have a close evolutionary relatedness to human isolates suggesting the zoonotic potential of this parasite. Moreover, we also report the first natural co-infection of O. bifurcum and O. stephanostomum in free-ranging AGMs.
Targeting pentose phosphate pathway for SARS-CoV-2 therapy
Authors: Bojkova Denisa , Costa Rui , Bechtel Marco , Ciesek Sandra , Michaelis Martin , Cinatl Jindrich
Published: August 2020

It becomes more and more obvious that deregulation of host metabolism play an important role in SARS-CoV-2 pathogenesis with implication for increased risk of severe course of COVID-19. Furthermore, it is expected that COVID-19 patients recovered from severe disease may experience long-term metabolic disorders. Thereby understanding the consequences of SARS-CoV-2 infection on host metabolism can facilitate efforts for effective treatment option. We have previously shown that SARS-CoV-2-infected cells undergo a shift towards glycolysis and that 2-deoxy-D-glucose (2DG) inhibits SARS-CoV-2 replication. Here, we show that also pentose phosphate pathway (PPP) is remarkably deregulated. Since PPP supplies ribonucleotides for SARS-CoV-2 replication, this could represent an attractive target for an intervention. On that account, we employed the transketolase inhibitor benfooxythiamine and showed dose-dependent inhibition of SARS-CoV-2 in non-toxic concentrations. Importantly, the antiviral efficacy of benfooxythiamine was further increased in combination with 2DG.
Efficient 5-OP-RU-induced enrichment of Mucosal-associated invariant T cells in the murine lung does not enhance control of aerosolMycobacterium tuberculosisinfection
Authors: Vorkas Charles Kyriakos , Levy Olivier , Skular Miroslav , Li Kelin , Aubé Jeffrey , Glickman Michael S.
Published: August 2020

Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset in mammals that recognize microbial vitamin B metabolites presented by the evolutionarily conserved MHC I-related molecule MR1. Emerging data suggest that MAIT cells may be an attractive target for vaccine-induced protection against bacterial infections because of their rapid cytotoxic responses at mucosal services to a widely conserved bacterial ligand. In this study, we tested whether a MAIT cell priming strategy could protect against aerosolMycobacterium tuberculosis(Mtb) infection in mice. Intranasal co-stimulation with the lipopeptide TLR 2/6 agonist, Pam2Cys (P2C), and the synthetic MR1 ligand, 5-OP-RU, resulted in robust expansion of MAIT cells in lung. Although MAIT cell priming significantly enhanced MAIT cell activation and expansion early afterMtbchallenge, these MAIT cells did not restrictMtbbacterial load. MAIT cells were depleted later in infection, with decreased detection of granzyme B+and IFNγ+MAIT cells relative to uninfected P2C/5-OP-RU-treated mice. Decreasing the infectious inoculum, varying the time between priming and aerosol infection, and testing MAIT cell priming in NOS2 deficient mice all failed to reveal an effect of P2C/5-OP-RU induced MAIT cells onMtbcontrol. We conclude that intranasal MAIT cell priming in mice induces early MAIT cell activation and expansion afterMtbexposure, without attenuatingM. tuberculosisgrowth, suggesting thatMtbevades MAIT cell-dependent immunity.
Genome-scale mapping reveals complex regulatory activities of RpoN inYersinia pseudotuberculosis
Authors: Mahmud F.A.K.M. , Nilsson K. , Fahlgren A. , Navais R. , Choudhry R. , Avican K. , Fallman M.
Published: August 2020

RpoN, an alternative sigma factor commonly known as sigma 54, is implicated in persistent stages ofYersinia pseudotuberculosisinfections in which genes associated with this regulator are upregulated. We here combined phenotypic and genomic assays to provide insight into its role and function in this pathogen. RpoN was found essential forY. pseudotuberculosisvirulence in mice, andin vitrofunctional assays showed that it controls biofilm formation and motility. Mapping genome-wide associations ofY. pseudotuberculosisRpoN using chromatin immunoprecipitation coupled with next-generation sequencing identified an RpoN-binding motif located at 103 inter- and intragenic sites on both sense and anti-sense strands. Deletion ofrpoNhad a large impact on gene expression, including down-regulation of genes encoding proteins involved in flagellar assembly, chemotaxis, and quorum sensing. There were also clear indications of cross talk with other sigma factors, together with indirect effects due to altered expression of other regulators. Matching differential gene expression with locations of the binding sites implicated around 130 genes or operons potentially activated or repressed by RpoN. Mutagenesis of selected intergenic binding sites confirmed both positive and negative regulatory effects of RpoN binding. Corresponding mutations of intragenic sense sites had less impact on associated gene expression. Surprisingly, mutating intragenic sites on the anti-sense strand commonly reduced expression of genes encoded by the corresponding sense strand.

IMPORTANCE

The alternative sigma factor, RpoN (σ 54), which is widely distributed in eubacteria have been implicated to control gene expression of importance for numerous functions including virulence. Proper responses to host environments are crucial for bacteria to establish infection and regulatory mechanisms involved are therefore of high interest for development of future therapeutics. Little is known about the function of RpoN in the intestinal pathogenY. pseudotuberculosisand we therefore investigated its regulatory role in this pathogen. This regulator was indeed found to be critical for establishment of infection in mice, likely involving its requirement for motility and biofilm formation. The RpoN regulon involved both activating and suppressive effects on gene expression which could be confirmed with mutagenesis of identified binding sites. This is the first of its kind study of RpoN inY. pseudotuberculosisrevealing complex regulation of gene expression involving both productive and silent effects of its binding to DNA providing important information about RpoN regulation in enterobacteria.
Methanotrophic Community Detected by DNA-SIP at Bertioga’s Mangrove Area, Southeast Brazil
Authors: Carmo Linhares Débora do , Saia Flávia Talarico , Delgado Duarte Rubens Tadeu , Nakayama Cristina Rossi , de Melo Itamar Soares , Pellizari Vivian Helena
Published: August 2020

Methanotrophic bacteria can use methane as sole carbon and energy source. Its importance in the environment is related to the mitigation of methane emissions from soil and water to the atmosphere. Brazilian mangroves are highly productive, have potential to methane production, and it is inferred that methanotrophic community is of great importance for this ecosystem. The scope of this study was to investigate the functional and taxonomic diversity of methanotrophic bacteria present in the anthropogenic impacted sediments from Bertioga’s mangrove (SP, Brazil). Sediment sample was cultivated with methane and the microbiota actively involved in methane oxidation was identified by DNA-based stable isotope probing (DNA-SIP) using methane as a labeled substrate. After 4 days of incubation and consumption of 0.7 mmol of methane, the most active microorganisms were related to methanotrophs Methylomonas and Methylobacter as well as to methylotrophic Methylotenera, indicating a possible association of these bacterial groups within a methane derived food chain in the Bertioga mangrove. The abundance of genera Methylomonas, able to couple methane oxidation to nitrate reduction, may indicate that under low dissolved oxygen tensions some aerobic methanotrophs could shift to intraerobic methane oxidation to avoid oxygen starvation.
4β-hydroxycholesterol is a pro-lipogenic factor that promotes SREBP1c expression and activity through Liver X-receptor
Authors: Moldavski Ofer , Zushin Peter-James H. , Berdan Charles A. , Van Eijkeren Robert J. , Jiang Xuntian , Qian Mingxing , Ory Daniel S. , Covey Douglas F. , Nomura Daniel K. , Stahl Andreas , Weiss Ethan J. , Zoncu Roberto
Published: August 2020

Oxysterols are oxidized derivatives of cholesterol that play signaling roles in lipid biosynthesis and homeostasis. Here we show that 4β-hydroxycholesterol (4β-HC), a liver and serum abundant oxysterol of poorly defined function, is a potent and selective inducer of the master lipogenic transcription factor, Sterol Regulatory Element Binding Protein 1c (SREBP1c), but not the related steroidogenic transcription factor SREBP2. Mechanistically, 4β-HC acts as a putative agonist for Liver X receptor (LXR), a sterol sensor and transcriptional regulator previously linked to SREBP1c activation. Unique among the oxysterol agonists of LXR, 4β-HC induced expression of the lipogenic program downstream of SREBP1c, and triggeredde novolipogenesis both in primary hepatocytes and in mouse liver. 4β-HC-acted in parallel to insulin-PI3K-dependent signaling to stimulate triglyceride synthesis and lipid droplet accumulation. Thus, 4β-HC is an endogenous regulator of de novo lipogenesis through the LXR-SREBP1c axis.
The Deubiquitylase Ubp15 Couples Transcription to mRNA Export
Authors: Eyboulet Fanny , Jeronimo Célia , Côté Jacques , Robert François
Published: August 2020

The nuclear export of messenger RNAs (mRNAs) is intimately coupled to their synthesis. pre-mRNAs assemble into dynamic ribonucleoparticles as they are being transcribed, processed and exported. The role of ubiquitylation in this process is increasingly recognized as the ubiquitylation of many key players have been shown to affect mRNA nuclear export. While a few E3 ligases have been shown to regulate nuclear export, evidence for deubiquitylases is currently lacking. Here, we identified the deubiquitylase Ubp15 as a regulator of nuclear export inSaccharomyces cerevisiae. Ubp15 interacts both with RNA polymerase II and with the nuclear pore complex, and its deletion reverts the nuclear export defect of mutants of the E3 ligase Rsp5. The deletion ofUBP15leads to hyper-ubiquitylation of the main nuclear export receptor Mex67 and affects its association with THO, a complex coupling transcription to mRNA processing and involved in the recruitment of mRNA export factors to nascent transcripts. Collectively, our data support a role for Ubp15 in coupling transcription to mRNA export.
Nutrients: trace metals, micronutrients, oestrogen and B-vitamin content of Osun River: A River that runs southwestern Nigeria into the Atlantic Gulf of Guinea
Authors: Afolabi-Balogun N.B. , Oni-Babalola O.A. , Adeleke I.I. , Oseni F.A. , Bello R.H. , Bashir M. , Raji B.A
Published: August 2020

Osun-Osogbo Grove has a long history of healing and therapeutic claims by adherent believers, in spite of advancement in medicine. Scientists made attempts at investigating the biodiversity of the Grove, till date, there has not been convergence point between science and these indigenous beliefs. This study identified the presence of therapeutic agents in the water of Osun-Osogbo River, paying attention to at least six parameters; vitamin, phosphate, nitrate, amino acid, hormone and trace metal. Water samples were taken from two different sites during pre, during and post raining sessions (April 2017 - September 2019) were analysed using High Performance Liquid Chromatography (HPLC), Gas Chromatography Mass Spectroscopy (GC-MS) and Atomic Absorption Spectrometer (AAS). Trace metal analysis revealed an average of 0.009-0.079 mg/Kg Zinc from site one and lower in site two. The mean value of manganese at both sites was virtually the same at 0.018-0.313 mg/kg, aluminum content was 0.045-0.179mg/Kg at site one, 0.050-0.192mg/kg at site two, cobalt was 0.024 mg/kg at site one, 0.026 mg/kg at site two while nickel was 0.006 mg/kg and 0.004 mg/kg for site one and two respectively. HPLC analysis shows mean Methionine content at both sites is higher than the FDA (56.6 ug/mL); site one had 74.41 ug/mL while site two had 57.11 ug/mL The mean values of two water-soluble vitamins; Thiamine (B1) was 3.758 mg/Kg and 2.355 mg/Kg while Pyridoxine (B6) was 0.108 mg/Kg and 0.072 mg/Kg at site one and two. GCMS analysis of steroidal content revealed values below lowest observed effect level (LOEL), testosterone (4.8 ng/L) and estrogen (2.4 ng/L) were still elevated while ethinylestradiol and estriol were ≥1.5 ng/L. Summarily, site one the major part for spiritual activities showed higher essential nutrient contents than site two which support the enrichment and potential therapeutic properties of the Osun river water. However, further scientific research is required to ensure that these therapeutic potentials supersede the toxicological effect.
A molecular timescale for the origin of red algal-derived plastids
Authors: Strassert Jürgen F. H. , Irisarri Iker , Williams Tom A. , Burki Fabien
Published: August 2020

In modern oceans, eukaryotic phytoplankton is dominated by lineages with red algal-derived plastids such as diatoms, dinoflagellates, and coccolithophores. These lineages and countless others representing a huge diversity of forms and lifestyles all belong to four algal groups: cryptophytes, ochrophytes, haptophytes, and myzozoans. Despite the ecological importance of these groups, we still lack a comprehensive understanding of their evolution and how they obtained their plastids. Over the last years, new hypotheses have emerged to explain the acquisition of red algal-derived plastids by serial endosymbiosis, but the chronology of these putative independent plastid acquisitions remains untested. Here, we have established a timeframe for the origin of red algal-derived plastids under scenarios of serial endosymbiosis, using a taxon- and gene-rich phylogenomic dataset combined to Bayesian molecular clock analyses. We find that the hypotheses of serial endosymbiosis are chronologically possible, as the stem lineages of all red plastid-containing groups overlapped in time. This period in the Meso- and Neoproterozoic Eras set the stage for the later expansion to dominance of red algal-derived primary production in the contemporary oceans, which has profoundly altered the global geochemical and ecological conditions of the Earth.
Circuit reorganization in theDrosophilamushroom body calyx accompanies memory consolidation
Authors: Baltruschat Lothar , Ranft Philipp , Prisco Luigi , Lauritzen J. Scott , Fiala André , Bock Davi D. , Tavosanis Gaia
Published: August 2020

The capacity of utilizing past experience to guide future action is a fundamental and conserved function of the nervous system. Associative memory formation initiated by the coincident detection of a conditioned stimulus (CS, e.g. odour) and an unconditioned stimulus (US, e.g. sugar reward) can lead to a short-lived memory trace (STM) within distinct circuits [1-5]. Memories can be consolidated into long-term memories (LTM) through processes that are not fully understood, but depend onde-novoprotein synthesis [6, 7], require structural modifications within the involved neuronal circuits and might lead to the recruitment of additional ones [8-17]. Compared to modulation of existing connections, the reorganization of circuits affords the unique possibility of sampling for potential new partners [18-20]. Nonetheless, only few examples of rewiring associated with learning have been established thus far [14, 21-24]. Here, we report that memory consolidation is associated with the structural and functional reorganization of an identified circuit in the adult fly brain. The formation and retrieval of olfactory associative memories inDrosophilarequires the mushroom body (MB) [25]. We identified the individual synapses of olfactory projection neurons (PNs) that deliver a conditioned odour to the MB and reconstructed the complexity of the microcircuit they form. Combining behavioural experiments with high-resolution microscopy and functional imaging, we demonstrated that the consolidation of appetitive olfactory memories closely correlates with an increase in the number of synaptic complexes formed by the PNs that deliver the conditioned stimulus and their postsynaptic partners. These structural changes result in additional functional synaptic connections.
In Silico Modeling of Virus Particle Propagation and Infectivity along the Respiratory Tract: A Case Study for SARS-COV-2
Authors: Vimalajeewa Dixon , Balasubramaniam Sasitharan , Berry Donagh P. , Barry Gerald
Published: August 2020

Respiratory viruses including Respiratory syncytial virus (RSV), influenza virus and cornaviruses such as Middle Eastern respiratory virus (MERS) and SARS-CoV-2 infect and cause serious and sometimes fatal disease in thousands of people annually. It is critical to understand virus propagation dynamics within the respiratory system because new insights will increase our understanding of virus pathogenesis and enable infection patterns to be more predictablein vivo, which will enhance targeting of vaccines and drug delivery. This study presents a computational model of virus propagation within the respiratory tract network. The model includes the generation network branch structure of the respiratory tract, biophysical and infectivity properties of the virus, as well as air flow models that aid the circulation of the virus particles. The model can also consider the impact of the immune response aim to inhibit virus replication and spread. The model was applied to the SARS-CoV-2 virus by integrating data on its life-cycle, as well as density of Angiotensin Converting Enzyme (ACE2) expressing cells along the respiratory tract network. Using physiological data associated with the respiratory rate and virus load that is inhaled, the model can improve our understanding of the concentration and spatiotemporal dynamics of virus.
Optogenetic activation of nonhuman primate cortical and subcortical brain circuits highlights detection capabilities of MEG source imaging
Authors: Alberto GE , Stapleton-Kotloski JR , Klorig DC , Rogers ER , Constantinidis C , Daunais JB , Godwin DW
Published: August 2020

Magnetoencephalography (MEG) measures neuromagnetic activity with high temporal, and theoretically, high spatial resolution. However, the ability of magnetic source imaging (MSI) to localize deep sources is uncertain. We developed an experimental platform combining MEG-compatible optogenetic techniques in non-human primates (NHPs) to test the ability of MEG/MSI to image deep signals. We demonstrate localization of optogenetically-evoked signals to known sources in the superficial arcuate sulcus of cortex and in CA3 of hippocampus at a resolution of 750 µm3. In response to stimulation of arcuate sulcus and hippocampus, we detected activation in subcortical and thalamic structures, or extended temporal networks, respectively. This is the first demonstration of accurate localization of deep sources within an intact brain using a novel combination of optogenetics with MEG/MSI. This approach is suitable for exploring causal relationships between discrete brain regions through precise optogenetic control and simultaneous whole brain recording.
Dynamics of mechanically coupled hair-cell bundles of the inner ear
Authors: Roongthumskul Y. , Faber J. , Bozovic D.
Published: August 2020

The high sensitivity and effective frequency discrimination of sound detection performed by the auditory system rely on the dynamics of a system of hair cells. In the inner ear, these acoustic receptors are primarily attached to an overlying structure which provides mechanical coupling between the hair bundles. While the dynamics of individual hair bundles have been extensively investigated, the influence of mechanical coupling on the motility of the system of bundles remains underdetermined. We developed a technique of mechanically coupling two active hair bundles, enabling us to probe the dynamics of the coupled system experimentally. We demonstrated that the coupling could enhance the coherence of hair bundles’ spontaneous oscillation as well as their phase-locked response to sinusoidal stimuli, at the calcium concentration in the surrounding fluid near the physiological level. The empirical data were consistent with numerical results from a model of two coupled nonisochronous oscillators, each displaying a supercritical Hopf bifurcation. The model revealed that weak coupling can poise the system of unstable oscillators closer to the bifurcation by a shift in the critical point. In addition, the dynamics of strongly coupled oscillators far from criticality suggested that individual hair bundles may be regarded as nonisochronous oscillators. An optimal degree of nonisochronicity was required for the observed tuning behavior in the coherence of autonomous motion of the coupled system.

STATEMENT OF SIGNIFICANCE

Hair cells of the inner ear transduce acoustic energy into electrical signals via a deflection of hair bundles. Unlike a passive mechanical antenna, a free-standing hair bundle behaves as an active oscillator that can sustain autonomous oscillations, as well as amplify a low-level stimulus. Hair bundles under physiological conditions are elastically coupled to each other via an extracellular matrix. Therefore, the dynamics of coupled nonlinear oscillators underlie the performance of the peripheral auditory system. Despite extensive theoretical investigations, there are limited experimental evidence that support the significance of coupling on hair bundle motility. We develop a technique to mechanically couple hair bundles and demonstrate the benefits of coupling on hair bundle spontaneous motility.
Morphometry of SARS-CoV and SARS-CoV-2 particles in ultrathin plastic sections of infected Vero cell cultures
Authors: Laue Michael , Kauter Anne , Hoffmann Tobias , Möller Lars , Michel Janine , Nitsche Andreas
Published: August 2020

SARS-CoV-2 is the causative of the COVID-19 disease, which has spread pandemically around the globe within a few months. It is therefore necessary to collect fundamental information about the disease, its epidemiology and treatment, as well as about the virus itself. While the virus has been identified rapidly, detailed ultrastructural analysis of virus cell biology and architecture is still in its infancy. We therefore studied the virus morphology and morphometry of SARS-CoV-2 in comparison to SARS-CoV as it appears in Vero cell cultures by using conventional thin section electron microscopy and electron tomography. Both virus isolates, SARS-CoV Frankfurt 1 and SARS-CoV-2 Italy-INMI1, were virtually identical at the ultrastructural level and revealed a very similar particle size distribution with a median of about 100 nm without spikes. Maximal spike length of both viruses was 23 nm. The number of spikes per virus particle was about 30% higher in the SARS-CoV than in the SARS-CoV-2 isolate. This result complements a previous qualitative finding, which was related to a lower productivity of SARS-CoV-2 in cell culture in comparison to SARS-CoV.
Mechanisms of signalling-memory governing progression through the eukaryotic cell cycle
Authors: Novák Béla , Tyson John J
Published: August 2020

As cells pass through each replication-division cycle, they must be able to postpone further progression if they detect any threats to genome integrity, such as DNA damage or misaligned chromosomes. Once a ‘decision’ is made to proceed, the cell unequivocally enters into a qualitatively different biochemical state, which makes the transitions from one cell cycle phase to the next switch-like and irreversible. Each transition is governed by a unique signalling network; nonetheless, they share a common characteristic of bistable behaviour, a hallmark of molecular memory devices. Comparing the cell cycle signalling mechanisms acting at the Restriction Point, G1/S, G2/M and meta-to-anaphase transitions, we deduce a generic network motif of coupled positive and negative feedback loops underlying each transition.
Tumor IsomiR Encyclopedia (TIE): a pan-cancer database of miRNA isoforms
Authors: Bofill-De Ros Xavier , Luke Brian , Guthridge Robert , Mudunuri Uma , Loss Michael , Gu Shuo
Published: August 2020

MicroRNAs (miRNAs) function as master regulators of gene expression in many physiological and pathological conditions including cancer. Sequence variants or isoforms (isomiRs) can account for between 40 to 60% of total miRNA counts, yet despite this overwhelming abundance, their function continues to be debated. Recent studies demonstrate that certain isomiRs can regulate unique sets of target mRNAs by altering their seed sequence or stabilizing 3’ pairing, while others are decay intermediates indicating an active miRNA turnover. Given their short sequence length and high heterogeneity, mapping isomiRs can be challenging; without adequate depth and data aggregation, low frequency events are often disregarded. To address these challenges, we present theTumorIsomiREncyclopedia (TIE): a dynamic database of isomiRs from over 10,000 adult and pediatric tumor samples in The Cancer Genome Atlas (TCGA) and The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) projects. A key novelty of TIE is its ability to annotate heterogeneous isomiR sequences and aggregate the variants obtained across all samples and datasets. The database provides annotation of templated and non-templated nucleotides as well as other advanced analysis. All data can be browsed online or downloaded as simple spreadsheets. Here we show analysis of isomiRs of miR-21 and miR-30a to demonstrate the utility of TIE. TIE search engine and data are hosted athttps://isomir.ccr.cancer.gov/.
Temporal landscape of mutation accumulation in SARS-CoV-2 genomes from Bangladesh: possible implications from the ongoing outbreak in Bangladesh
Authors: Saha Otun , Shatadru Rokaiya Nurani , Rakhi Nadira Naznin , Islam Israt , Hossain Md. Shahadat , Rahaman Md. Mizanur
Published: August 2020

Along with intrinsic evolution, adaptation to selective pressure in new environments might have resulted in the circulatory SARS-CoV-2 strains in response to the geoenvironmental conditions of a country and the demographic profile of its population. Thus the analysis of genomic mutations of these circulatory strains may give an insight into the molecular basis of SARS-CoV-2 pathogenesis and evolution favoring the development of effective treatment and containment strategies. With this target, the current study traced the evolutionary route and mutational frequency of 198 Bangladesh originated SARS-CoV-2 genomic sequences available in the GISAID platform over a period of 13 weeks as of 14 July 2020. The analyses were performed using MEGA 7, Swiss Model Repository, Virus Pathogen Resource and Jalview visualization. Our analysis identified that majority of the circulating strains in the country belong to B and/or L type among cluster A to Z and strikingly differ from both the reference genome and the first sequenced genome from Bangladesh. Mutations in Nonspecific protein 2 (NSP2), NSP3, RNA dependent RNA polymerase (RdRp), Helicase, Spike, ORF3a, and Nucleocapsid (N) protein were common in the circulating strains with varying degrees and the most unique mutations(UM) were found in NSP3 (UM-18). But no or limited changes were observed in NSP9, NSP11, E (Envelope), NSP7a, ORF 6, and ORF 7b suggesting the possible conserved functions of those proteins in SARS-CoV-2 propagation. However, along with D614G mutation, more than 20 different mutations in the Spike protein were detected basically in the S2 domain. Besides, mutations in SR-rich region of N protein and P323L in RDRP were also present. However, the mutation accumulation showed an association with sex and age of the COVID-19 positive cases. So, identification of these mutational accumulation patterns may greatly facilitate drug/ vaccine development deciphering the age and the sex dependent differential susceptibility to COVID-19.
Comparative Transcriptomics of heads and tails betweenSteinernema carpocapsaeandCaenorhabditis elegans
Authors: Rodriguez Isaryhia Maya , Clague Lorrayne Serra , McGill Cassandra Joan , Rodriguez Bryan , Mortazavi Ali
Published: August 2020

Steinernema nematodeshave been widely studied for insect infection and mutualism, but little is known about the patterns of gene expression along the body of these worms or how these compare to the model organismCaenorhabditis elegans. Here we perform the first comparative analysis between the heads and tail regions ofSteinernema carpocapsaeandC. elegansInfective Juveniles (IJs)/dauers and young adults using single-worm RNA-seq. While we find overall agreement in gene expression there were several sets of genes with substantial differences between the two species. Gene expression in theS. carpocapsaefemale compared to theC. eleganshermaphrodite heads and tails revealed differences in metabolism, aging, and determination of lifespan. Young adult male heads and tails showed major differences in developmental related processes such as morphogenesis as well as neuronal development and signaling. We also found head- and tail-specific gene expression differences betweenS. carpocapsaeIJs andC. elegansdauers for genes related to growth and development as well as neuronal signaling and activity. This study is one of the first comparative transcriptomic analyses of body parts between distantly related species of nematodes and provides insight into both the highly conserved and genetically distinctive characteristics of both species.
COVID-19 and Cholinergic Anti-inflammatory Pathway:In silicoIdentification of an Interaction between α7 Nicotinic Acetylcholine Receptor and the Cryptic Epitopes of SARS-CoV and SARS-CoV-2 Spike Glycoproteins
Authors: Lagoumintzis George , Chasapis Christos T. , Alexandris Nikolaos , Tzartos Socrates , Eliopoulos Elias , Farsalinos Konstantinos , Poulas Konstantinos
Published: August 2020

SARS-CoV-2 is the coronavirus that originated in Wuhan in December 2019 and has spread globally. The observation of a low prevalence of smokers among hospitalized COVID-19 patients has led to the development of a hypothesis that nicotine could have protective effects by enhancing the cholinergic anti-inflammatory pathway. Based on clinical data and on modelling and docking experiments we have previously presented the potential interaction between SARS-CoV-2 Spike glycoprotein and nicotinic acetylcholine receptors (nAChRs), due to a “toxin-like” epitope on the Spike Glycoprotein, with homology to a sequence of a snake venom toxin. We here present that this epitope coincides with the well-described cryptic epitope for the human antibody CR3022 and with the epitope for the recently described COVA1-16 antibody. Both antibodies are recognizing neighboring epitopes, are not interfering with the ACE2 protein and are not able to inhibit SARS-CoV and SARS-CoV-2 infections. In this study we present the molecular complexes of both SARS-CoV and SARS-CoV-2 Spike Glycoproteins, at their open or closed conformations, with the molecular model of the human α7 nAChR. We found that the interface of all studied protein complexes involves a large part of the “toxin-like” sequences of SARS-CoV and SARS-CoV-2 Spike glycoproteins and toxin binding site of human α7 nAChR.
Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation
Authors: Lapointe Christopher P. , Grosely Rosslyn , Johnson Alex G. , Wang Jinfan , Fernández Israel S. , Puglisi Joseph D.
Published: August 2020

SARS-CoV-2 recently emerged as a human pathogen and is the causative agent of the COVID-19 pandemic. A molecular framework of how the virus manipulates host cellular machinery to facilitate infection remains unclear. Here, we focus on SARS-CoV-2 NSP1, which is proposed to be a virulence factor that inhibits protein synthesis by directly binding the human ribosome. Using extract-based and reconstitution experiments, we demonstrate that NSP1 inhibits translation initiation on model human and SARS-CoV-2 mRNAs. NSP1 also specifically binds to the small (40S) ribosomal subunit, which is required for translation inhibition. Using single-molecule fluorescence assays to monitor NSP1–40S subunit binding in real time, we demonstrate that eukaryotic translation initiation factors (eIFs) modulate the interaction: NSP1 rapidly and stably associates with most ribosomal pre-initiation complexes in the absence of mRNA, with particular enhancement and inhibition by eIF1 and eIF3j, respectively. Using model mRNAs and an inter-ribosomal-subunit FRET signal, we elucidate that NSP1 competes with RNA segments downstream of the start codon to bind the 40S subunit and that the protein is unable to associate rapidly with 80S ribosomes assembled on an mRNA. Collectively, our findings support a model where NSP1 associates with the open head conformation of the 40S subunit to inhibit an early step of translation, by preventing accommodation of mRNA within the entry channel.

SIGNIFICANCE STATEMENT

SARS-CoV-2 is the causative agent of the COVID-19 pandemic. A molecular framework for how SARS-CoV-2 manipulates host cellular machinery to facilitate infection is needed. Here, we integrate biochemical and single-molecule strategies to reveal molecular insight into how NSP1 from SARS-CoV-2 inhibits translation initiation. NSP1 directly binds to the small (40S) subunit of the human ribosome, which is modulated by human initiation factors. Further, NSP1 and mRNA compete with each other to bind the ribosome. Our findings suggest that the presence of NSP1 on the small ribosomal subunit prevents proper accommodation of the mRNA. How this competition disrupts the many steps of translation initiation is an important target for future studies.
Secondary metabolites of Bacillus subtilis impact soil-derived semi-synthetic bacterial community assembly
Authors: Kiesewalter Heiko T. , Lozano-Andrade Carlos N. , Strube Mikael L. , Kovács Ákos T.
Published: August 2020

Secondary metabolites provide Bacillus subtilis with increased competitiveness towards other microorganisms. In particular nonribosomal peptides (NRPs) have an enormous antimicrobial potential by causing cell lysis, perforation of fungal membranes, enzyme inhibition or disruption of bacterial protein synthesis. This knowledge was primarily acquired in vitro when B. subtilis was competing with other microbial monocultures. However, our understanding of the true ecological role of these small molecules is limited.

In this study, we have established soil-derived semi-synthetic mock communities containing 13 main genera and supplemented them with B. subtilis P5_B1 WT, its NRP deficient strain sfp or single NRP mutants incapable of producing surfactin, plipastatin or bacillaene. 16S amplicon sequencing revealed that the invasion of NRP-producing B. subtilis strains had no major impact on the bacterial communities. Still, the abundances of the two genera Lysinibacillus and Viridibacillus were reduced. Interestingly, this effect was diminished in communities supplemented with the NRPs deficient strain. Growth profiling of Lysinibacillus fusiformis M5 exposed to either spent media of the B. subtilis strains or pure surfactin indicates the sensitivity of this strain towards the biosurfactant surfactin.

Our study provides a more in-depth insight into the influence of B. subtilis NRPs on semi-synthetic bacterial communities and helps to understand their ecological role.
ITS2 Pretrial Gene Identification Related to Seed and Flower Identification for Cyclea barbata
Authors: Pignatti Monica , Jensen William , Henderson Veronica
Published: August 2020

This paper has been withdrawn by bioRxiv because its content, including the author names, was fabricated and fraudulently submitted in what may have been an attempt to game citation statistics or other metrics.
Biocontrol ofAspergillus nigerin 3D-lung cell tissues by oxalotrophic bacteria
Authors: Palmieri Fabio , Palmieri Ilona , Noormamode Nourine , Estoppey Aislinn , Ishak M. Omar , Kelliher Julia M. , Vallat Armelle , Iyer Rashi , Bindschedler Saskia , Davenport Karen , Chain Patrick S. G. , Harris Jennifer Foster , Junier Pilar
Published: August 2020

Aspergillusfungi are opportunistic pathogens that affect a large number of people worldwide. Many aspects ofAspergillusspp. pathogenesis toward humans are known, but their ability to enhance their infectious potential by manipulating the environmental pH of its host has not been considered yet. In this study, we tested the hypothesis that by producing oxalic acid,Aspergillus nigercan manipulate pH during lung infection and thus, interfering with this process could limit pathogenicity. To test this hypothesis, we co-culturedA. nigerwith oxalotrophic bacteria in increasingly complex testing systems (Petri dishes and 3D-cell cultures systems). Inin vitrotests, oxalotrophic bacteria limit oxalic acid production and suppressed the pH shift induced byA. niger. In 3D-cell cultures (Transwells® and Bronchioles-on-a-chip),A. nigeralso modified pH, Ca2+and oxalic acid concentrations. Co-inoculation with as little as 10 cells of the oxalatrophic bacterium strongly inhibited the germination and development ofA. nigerand returned each of the three parameters to the baseline physiological values of uninfected cells. This biocontrol interaction between oxalotrophic bacteria and oxalate-producingA. nigercould represent a paradigm shift in the fight against opportunistic fungal pathogens, where the host environment is rendered less permissive to fungal development.
Phase separation by the Sterile Alpha Motif of Polyhomeotic compartmentalizes Polycomb Group proteins and enhances their activity
Authors: Seif Elias , Kang Jin Joo , Sasseville Charles , Senkovitch Olga , Kaltashov Alexander , Boulier Elodie L. , Kapur Ibani , Kim Chongwoo A. , Francis Nicole J.
Published: August 2020

Polycomb Group (PcG) proteins organize chromatin at multiple scales to regulate gene expression. A conserved Sterile Alpha Motif (SAM) in thePolycombRepressiveComplex 1 (PRC1) subunit Polyhomeotic (Ph) is important for chromatin compaction and large-scale chromatin organization. Like many SAMs, Ph SAM forms helical head to tail polymers, and SAM-SAM interactions between chromatin-bound Ph/PRC1 are believed to compact chromatin and mediate long-range interactions. To understand mechanistically how this occurs, we analyzed the effects of Ph SAM on chromatinin vitro. We find that incubation of chromatin or DNA with a truncated Ph protein containing the SAM results in formation of concentrated, phase-separated condensates. Condensate formation depends on Ph SAM, and is enhanced by but not strictly dependent on, its polymerization activity. Ph SAM-dependent condensates can recruit PRC1 from extracts and enhance PRC1 ubiquitin ligase activity towards histone H2A. Overexpression of Ph with an intact SAM increases ubiquitylated H2A in cells. Thus, phase separation is an activity of the SAM, which, in the context of Ph, can mediate large-scale compaction of chromatin into biochemical compartments that facilitate histone modification.
Mass Spectrometry Imaging of N-Glycans Reveals Racial Discrepancies in Low Grade Prostate Tumors
Authors: Conroy Lindsey R. , Young Lyndsay E.A. , Stanback Alexandra E. , Austin Grant L. , Liu Jinpeng , Liu Jinze , Allison Derek B. , Sun Ramon C.
Published: August 2020

Prostate cancer is the most common cancer in men worldwide. Despite its prevalence, there is a critical knowledge gap regarding the underlining molecular events that result in higher incidence and mortality rate in Black men. Identifying molecular features that separate racial disparities is a critical step in prostate cancer research that could lead to predictive biomarkers and personalized therapy. N-linked glycosylation is a co-translational event during protein folding that modulates a myriad of cellular processes. Recently, aberrant N-linked glycosylation has been reported in prostate cancers. However, the full clinical implications of dysregulated glycosylation in prostate cancer has yet to be explored. Herein, we performed high-throughput matrix-assisted laser desorption ionization mass spectrometry analysis to characterize the N-glycan profile from tissue microarrays of over 100 patient tumors with over 10 years of follow up data. We identified several species of N-glycans that were profoundly different between low grade prostate tumors resected from White and Black patients. Further, these glycans predict opposing overall survival between White and Black patients with prostate cancer. These data suggest differential N-linked glycosylation underline the racial disparity of prostate cancer prognosis. Our study highlights the potential applications of MALDI-MSI for digital pathology and biomarker to study racial disparity of prostate cancer patients.

Graphical Abstract
Maladaptive myelination promotes epileptogenesis in absence epilepsy
Authors: Knowles Juliet K. , Soane Caroline , Frost Eleanor , Tam Lydia T. , Fraga Danielle , Xu Haojun , Batra Ankita , Ni Lijun , Villar Katlin , Saucedo Tristan , Huguenard John , Monje Michelle
Published: August 2020

Neuronal activity can influence the generation of new oligodendrocytes (oligodendrogenesis) and myelination. In health, this is an adaptive process that can increase synchrony within distributed neuronal networks and contribute to cognitive function. We hypothesized that in seizure disorders, aberrant neuronal activity may promote maladaptive myelination that contributes to pathogenesis. Absence epilepsy is a disease defined by increasingly frequent behavioral arrest seizures over time, thought to be due to thalamocortical network hypersynchrony. We tested the hypothesis that activity-dependent myelination resulting from absence seizures promotes epileptogenesis. Using two distinct models of absence epilepsy, Wag/Rij rats andScn8a+/mutmice, we found increased oligodendrogenesis and myelination specifically within the absence seizure network. These changes are evident only after seizure onset in both models and are prevented with pharmacological inhibition of seizures. Genetic blockade of activity-dependent myelination during epileptogenesis markedly decreased seizure frequency in theScn8a+/mutmouse model of absence epilepsy. Taken together, these findings indicate that activity-dependent myelination driven by absence seizures contributes to seizure kindling during epileptogenesis.
Naphthalene monoimide derivative ameliorates amyloid burden and cognitive decline in a transgenic mouse model of Alzheimer’s disease
Authors: Samanta Sourav , Rajasekhar Kolla , Ramesh Madhu , Murugan N. Arul , Alam Shadab , Shah Devanshi , Clement James P , Govindaraju Thimmaiah
Published: August 2020

Alzheimer’s disease (AD) is a major neurodegenerative disorder and the leading cause of dementia worldwide. Predominantly, misfolding and aggregation of amyloid-β (Aβ) peptides associated with multifaceted toxicity is the neuropathological hallmark of AD pathogenesis and thus, primary therapeutic target to ameliorate neuronal toxicity and cognitive deficits. Herein, we report the design, synthesis and evaluation of small molecule inhibitors with naphthalene monoimide scaffold to amelioratein vitroandin vivoamyloid induced neurotoxicity. The detailed studies established TGR63 as the lead candidate to rescue neuronal cells from amyloid toxicity. Thein silicostudies showed disruption of salt bridges and intermolecular hydrogen bonding interactions within Aβ42 fibrils by the interaction of TGR63, causing destabilization of Aβ42 assembly. Remarkably, TGR63 treatment showed a significant reduction in cortical and hippocampal amyloid burden in the progressive stages of APP/PS1 AD mice brain. Various behavioral tests demonstrated rescued cognitive deficits. The excellent biocompatibility, BBB permeability and therapeutic efficacy to reduce amyloid burden make TGR63 a promising candidate for the treatment of AD.