bluuebunny/crossref_metadata_2025_split huggingface dataset:
Historical dispersal and host-switching formed the evolutionary history of a globally distributed multi-host parasite - theLigula intestinalisspecies complex
Authors: Nazarizadeh Masoud , Nováková Milena , Loot Géraldine , Gabagambi Nestory P. , Fatemizadeh Faezeh , Osano Odipo , Presswell Bronwen , Poulin Robert , Vitál Zoltán , Scholz Tomáš , Halajian Ali , Trucchi Emiliano , Kočová Pavlína , Štefka Jan 
Published: October 2022

AbstractStudies on parasite biogeography and host spectrum provide insights into the processes driving parasite diversification. Global geographical distribution and a multi-host spectrum make the tapewormLigula intestinalisa promising model for studying both the vicariant and ecological modes of speciation in parasites. To understand the relative importance of host association and biogeography in the evolutionary history of this tapeworm, we analysed mtDNA and reduced-represented genomic SNP data for a total of 139 specimens collected from 18 fish-host genera across a distribution range representing 21 countries. Our results strongly supported the existence of at least 10 evolutionary lineages and estimated the deepest divergence at approximately 4.99-5.05 Mya, which is much younger than the diversification of the fish host genera and orders. Historical biogeography analyses revealed that the ancestor of the parasite diversified following multiple vicariance events and was widespread throughout the Palearctic, Afrotropical, and Nearctic between the late Miocene and early Pliocene. Cyprinoids were inferred as the ancestral hosts for the parasite. Later, from the late Pliocene to Pleistocene, new lineages emerged following a series of biogeographic dispersal and host-switching events. Although only a few of the currentLigulalineages show narrow host-specificity (to a single host genus), almost no host genera, even those that live in sympatry, overlapped between differentLigulalineages. Our analyses uncovered the impact of historical distribution shifts on host switching and the evolution of host specificity without parallel host-parasite co-speciation. Historical biogeography reconstructions also found that the parasite colonized several areas (Afrotropical and Australasian) much earlier than was suggested by only recent faunistic data.
Multi-level Bayesian analysis of monk parakeet contact calls shows dialects between European cities
Authors: Smeele Simeon Q. , Tyndel Stephen A. , Aplin Lucy M. , McElreath Mary Brooke 
Published: October 2022

AbstractGeographic differences in vocalisations provide strong evidence for animal culture, with patterns likely arising from generations of social learning and transmission. The current knowledge on the evolution of vocal variation has predominantly focused on fixed repertoire, territorial song in passerine birds. The study of vocal communication in open-ended learners and in contexts where vocalisations serve other functions is therefore necessary for a more comprehensive understanding of vocal dialect evolution. Parrots are open-ended vocal production learners that use vocalisations for social contact and coordination. Geographic variation in parrot vocalisations typically take the form of either distinct regional variations known as dialects or graded variation based on geographic distance known as clinal variation. In this study, we recorded monk parakeets (Myiopsitta monachus) across multiple spatial scales (i.e. parks and cities) in their European invasive range. We then compared calls using a multi-level Bayesian model and sensitivity analysis, with this novel approach allowing us to explicitly compare vocalisations at multiple spatial scales. We found support for founder effects and/or cultural drift at the city level, consistent with passive cultural processes leading to large scale dialect differences. We did not find a strong signal for dialect or clinal differences between parks within cities, suggesting that birds did not actively converge on a group level signal, as expected under the group membership hypothesis. We demonstrate the robustness of our findings and offer an explanation that unifies the results of prior monk parakeet vocalisation studies.
VECTRON™ T500, a new broflanilide insecticide for indoor residual spraying, provides prolonged control of pyrethroid-resistant malaria vectors
Authors: Govoetchan Renaud , Fongnikin Augustin , Syme Thomas , Small Graham , Gbegbo Martial , Todjinou Damien , Rowland Mark , Nimmo Derric , Padonou Germain Gil , Ngufor Corine 
Published: October 2022

AbstractBackgroundBroflanilide is a newly discovered insecticide with a novel mode of action targeting insect γ-aminobutyric acid receptors. The efficacy of VECTRON™ T500, a wettable powder formulation of broflanilide, was assessed for IRS against wild pyrethroid-resistant malaria vectors in experimental huts in Benin.MethodsVECTRON™ T500 was evaluated at 100 mg/m² in mud and cement-walled experimental huts against wild pyrethroid-resistantAnopheles gambiae sensu lato(s.l.) in Covè, southern Benin, over 18 months. A direct comparison was made with Actellic® 300CS, a WHO-recommended micro-encapsulated formulation of pirimiphos-methyl, applied at 1000 mg/m². The vector population at Covè was investigated for susceptibility to broflanilide and other classes of insecticides used for vector control. Monthly wall cone bioassays were performed to assess the residual efficacy of VECTRON™ T500 using insecticide susceptibleAn. gambiaeKisumu and pyrethroid-resistantAn. gambiae s.l. Covè strains. The study complied with OECD principles of good laboratory practice.ResultsThe vector population at Covè was resistant to pyrethroids and organochlorines but susceptible to broflanilide and pirimiphos-methyl. A total of 23,171 free-flying wild pyrethroid-resistant femaleAn. gambiae s.l. were collected in the experimental huts over 12 months. VECTRON™ T500 induced 56%-60% mortality in wild vector mosquitoes in both cement and mud-walled huts. Mortality with VECTRON™ T500 was 62%-73% in the first three months and remained >50% for 9 months on both substrate-types. By comparison, mortality with Actellic® 300CS was very high in the first three months (72%-95%) but declined sharply to <40% after 4 months. Using a non-inferiority margin defined by the World Health Organization, overall mortality achieved with VECTRON™ T500 was non-inferior to that observed in huts treated with Actellic® 300CS with both cement and mud wall substrates. Monthlyin situwall cone bioassay mortality with VECTRON™ T500 also remained over 80 % for 18 months but dropped below 80% with Actellic® 300CS at 6-7 months post spraying.ConclusionVECTRON™ T500 shows potential to provide substantial and prolonged control of malaria transmitted by pyrethroid-resistant mosquito vectors when applied for IRS. Its addition to the current list of WHO-approved IRS insecticides will provide a suitable option to facilitate rotation of IRS products with different modes of action.
FC2 stabilizes POR and suppresses ALA formation in the tetrapyrrole biosynthesis pathway
Authors: Fan Tingting , Roling Lena , Hedtke Boris , Grimm Bernhard 
Published: October 2022

SummaryDuring photoperiodic growth, the light-dependent nature of chlorophyll synthesis in angiosperms necessitates robust control of the production of 5-aminolevulinic acid (ALA), the rate-limiting step in the initial stage of tetrapyrrole biosynthesis (TBS). We are interested in dissecting the post-translational control of this process, which suppresses ALA synthesis for chlorophyll synthesis in dark-grown plants.Using biochemical approaches for analysis of wild-type and mutant lines as well as complementation lines, we show that the heme-synthesizing ferrochelatase 2 (FC2) interacts with protochlorophyllide oxidoreductase and the regulator FLU which both promote the feedback-controlled suppression of ALA synthesis by inactivation of glutamyl-tRNA reductase, thus preventing excessive accumulation of potentially deleterious tetrapyrrole intermediates.Thereby FC2 stabilizes POR by physical interaction. When the interaction between FC2 and POR is perturbed, suppression of ALA synthesis is attenuated and photoreactive protochlorophyllide accumulates. FC2 is anchored in the thylakoid membrane via its membrane-spanning CAB (chlorophyll-a-binding) domain.FC2 is one of the two isoforms of ferrochelatase catalyzing the last step of heme synthesis. Although FC2 belongs to the heme-synthesizing branch of TBS, its interaction with POR potentiates the effects of the GluTR-inactivation complex on the chlorophyll-synthesizing branch, and ensures reciprocal control of chlorophyll and heme synthesis.
POU6F2mutation identified in humans with pubertal failure shifts isoform formation and alters GnRH transcript expression
Authors: Cho Hyun-Ju , Gurbuz Fatih , Stamou Maria , Kotan Leman Damla , Farmer Stephen Matthew , Can Sule , Tompkins Miranda Faith , Mammadova Jamala , Altincik S. Ayca , Gokce Cumali , Catli Gonul , Bugrul Fuat , Bartlett Keenan , Turan Ihsan , Balasubramanian Ravikumar , Yuksel Bilgin , Seminara Stephanie B. , Wray Susan , Topaloglu A. Kemal 
Published: October 2022

ABSTRACTIdiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent pubertal development and infertility, often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants inPOU6F2. POU6F2encodes two distinct isoforms. In mouse, pituitary and gonads expressed both isoforms, but only isoform1 was detected in GnRH cells. Although the function of isoform2 is well known, using bioinformatics and cells assays on a human-derived GnRH cell line, we demonstrate isoform1 can also act as a transcriptional regulator, decreasingGNRH1expression. The impact of twoPOU6F2variants (MT1 and MT2) was then examined. MT1, but not MT2, reduced transcriptional activity of either isoform, preventing Hes5 promoter activation by isoform2 and repression of GnRH transcripts by isoform1. GnRH transcription increases as the cells migrate into the brain. Augmentation earlier can disrupt normal GnRH cell migration, consistent with POU6F2 variants contributing to IHH pathogenesis.
Epigenetic and transcriptional plasticity drive inflammation in Cystic Fibrosis
Authors: Dinan Adam M. , Eneje Odiri , Brown Karen P. , Burden Frances , Morse Mary , Prinjha Rab K. , Frontini Mattia , Floto R. Andres 
Published: October 2022

AbstractThe relative contributions of acute and chronic inflammatory mechanisms in diseases characterised by persistent bacterial infection are unclear, despite important consequences for the development of novel anti-inflammatory therapies. Here, we examined longitudinal transcriptional and epigenetic changes in patients with Cystic Fibrosis (CF), a genetic condition characterised by persistent bacterial lung infections that drive progressive inflammatory lung damage. We find that sudden clinical deteriorations in lung health, termed Acute Pulmonary Exacerbations (APEs), are linked to innate immune signalling driven by bacterial components, and accompanied by changes in macrophage function. Treatment of patients with intravenous antibiotics results in rapid modification of myeloid cell gene expression and epigenetic state, towards that of healthy volunteers, suggesting that repeated acute inflammatory episodes play an important role in CF inflammatory lung damage.
wMelreplacement of dengue-competent mosquitoes is robust to near-term climate change
Authors: Vásquez Váleri N. , Kueppers Lara M. , Rašić Gordana , Marshall John M. 
Published: October 2022

AbstractRising temperatures and increasing temperature variability are impacting the range and prevalence of mosquito-borne disease. A promising biocontrol technology replaces wild mosquitoes with those carrying the virus-blockingWolbachiabacterium. Laboratory and field observations show that the most widely used strain,wMel, is adversely affected by heat stress. Here, we examine whether and how climate warming may impactwMel-based replacement. We integrate empirical data on the temperature sensitivity ofwMelbacteria into a mechanistic model of population dynamics for the dengue vectorAedes aegyptiand use CMIP5 climate projections and historical temperature records from Cairns, Australia to simulate vector control interventions. We show that higher mean temperatures are predicted to lowerwMelinfection frequency and that extended heatwaves have the potential to reverse the public health benefits of this intervention. Sensitivity analysis probing the thermal limits ofwMelreplacement reveal that, under existing projections, operational adaptations would be required for heatwaves lasting longer than two weeks. We conclude that this technology is expected to be robust to both the increased mean temperatures and heatwaves associated with near-term climate change in temperate regions. However, more rapid warming or tropical and inland regions that presently feature hotter baselines may challenge these tested limits, requiring further research.
A penultimate classification of canonical antibody CDR conformations
Authors: Kelow Simon , Faezov Bulat , Xu Qifang , Parker Mitchell , Adolf-Bryfogle Jared , Dunbrack Roland L. 
Published: October 2022

AbstractAntibody complementarity determining regions (CDRs) are loops within antibodies responsible for engaging antigens during the immune response and in antibody therapeutics and laboratory reagents. Since the 1980s, the conformations of the hypervariable CDRs have been structurally classified into a number of “canonical conformations” by Chothia, Lesk, Thornton, and others. In 2011 (North et al, J Mol Biol. 2011), we produced a quantitative clustering of approximately 300 structures of each CDR based on their length, a dihedral angle metric, and an affinity propagation algorithm. The data have been made available on our PyIgClassify website since 2015 and have been widely used in assigning conformational labels to antibodies in new structures and in molecular dynamics simulations. In the years since, it is has become apparent that many of the clusters are not “canonical” since they have not grown in size and still contain few sequences. Some clusters represent multiple conformations, given the assignment method we have used since 2015. Electron density calculations indicate that some clusters are due to misfitting of coordinates to electron density. In this work, we have performed a new statistical clustering of antibody CDR conformations. We used Electron Density in Atoms (EDIA, Meyder et al., 2017) to produce data sets with different levels of electron density validation. Clusters were chosen by their presence in high electron density cutoff data sets and with sufficient sequences (≥10) across the entire PDB (no EDIA cutoff). About half of the North et al. clusters have been “retired” and 13 new clusters have been identified. We also include clustering of the H4 and L4 CDRs, otherwise known as the “DE loop” which connects strands D and E of the variable domain. The DE loop sometimes contacts antigens and affects the structure of neighboring CDR1 and CDR2 loops. The current database contains 6,486 PDB antibody entries. The new clustering will be useful in the analysis and development of new antibody structure prediction and design algorithms based on rapidly emerging techniques in deep learning. The new clustering data are available athttp://dunbrack2.fccc.edu/PyIgClassify2.
Aromatic amino acid biosynthesis by aLotusAldolase impacts root hair development and symbiotic associations
Authors: Montiel Jesús , James Euan K. , García-Soto Ivette , Reid Dugald , Napsucialy-Mendivil Selene , Dubrovsky Joseph G. , Cárdenas Luis , Stougaard Jens 
Published: October 2022

SummaryLegume roots can be symbiotically colonized by arbuscular mycorrhizal (AM) fungi and nitrogen-fixing bacteria. InLotus japonicus, the latter occurs intracellularly by the cognate rhizobial partnerMesorhizobium lotior intercellularly with theAgrobacterium pusenseIRBG74 strain. Although these symbiotic programs show distinctive cellular and transcriptome signatures, some molecular components are shared.In this study, we demonstrate thatAldolase1, the first enzyme in the biosynthetic pathway of aromatic amino acids (AAA), plays a critical role in root hair development and for AM and rhizobial symbioses inLotus.Two homozygous mutants affected inAldolase1(ald1-1 andald1-2) show drastic alterations in the root hair morphology, associated with a progressive disruption of the actin cytoskeleton. The altered root hair structure was prevented by chemical and genetic complementation.Bothald1-1 andald1-2 show significant reductions in rhizobial infection (intracellular and intercellular), nodule organogenesis and AM colonization. RNAseq analysis ofald1-2 roots suggested that these phenotypes are associated with downregulation of several cell wall related genes, and with an attenuated symbiotic signalling. This work provides robust evidence that links AAA metabolism to root hair development and successful symbiotic associations.
Root-knot nematodes produce functional mimics of tyrosine-sulfated plant peptides
Authors: Yimer Henok Zemene , Luu Dee Dee , Blundell Alison Coomer , Ercoli Maria Florencia , Vieira Paulo , Williamson Valerie M. , Ronald Pamela C. , Siddique Shahid 
Published: October 2022

AbstractRoot-knot nematodes (Meloidogynespp.) are highly evolved obligate parasites that threaten global food security. These parasites have a remarkable ability to establish elaborate feeding sites in roots, which are their only source of nutrients throughout their life cycle. A wide range of nematode effectors have been implicated in modulation of host pathways for feeding site development. Plants produce a diverse array of peptide hormones including plant peptides containing sulfated tyrosine (PSYs), which promote root growth via cell expansion and proliferation. A sulfated PSY-like peptide RaxX (required for activation of XA21 mediated immunity X) produced by the biotrophic bacterial pathogen (Xanthomonas oryzaepv.oryzae), has been previously shown to contribute to bacterial virulence. Here, we report the identification of genes from root-knot nematodes predicted to encode PSY-like peptides (MigPSYs) with high sequence similarity to both bacterial RaxX and plant PSYs. Sulfated synthetic peptides corresponding to predicted MigPSYs stimulate root growth in Arabidopsis.MigPSYtranscript levels are highest early in the infection cycle. Down-regulation ofMigPSYgene expression reduces root galling and egg production, suggesting that the MigPSYs serve as nematode virulence factors. Together these results indicate that nematodes and bacteria utilize similar sulfated peptides to hijack plant developmental signaling pathways to facilitate parasitism.
Combination of the parent analogue of Remdesivir (GS-441524) and Molnupiravir results in a markedly potent antiviral effect in SARS-CoV-2 infected Syrian hamsters
Authors: Abdelnabi Rana , Maes Piet , de Jonghe Steven , Weynand Birgit , Neyts Johan 
Published: October 2022

AbstractRemdesivir was the first drug to be approved for the treatment of severe COVID-19; followed by molnupiravir (another prodrug of a nucleoside analogue) and the protease inhibitor nirmatrelvir. Combination of antiviral drugs may result in improved potency and help to avoid or delay the development of resistant variants. We set out to explore the combined antiviral potency of GS-441524 (the parent nucleoside of remdesivir) and molnupiravir against SARS-CoV-2. In SARS-CoV-2 (BA.5) infected A549-Dual™ hACE2-TMPRSS2 cells, the combination resulted in an overall additive antiviral effect with a synergism at certain concentrations. Next, the combined effect was explored in Syrian hamsters infected with SARS-CoV-2 (Beta, B.1.351); treatment was started at the time of infection and continued twice daily for four consecutive days. At 4 day 4 post-infection, GS-441524 (50 mg/kg, oral BID) and molnupiravir (150 mg/kg, oral BID) as monotherapy reduced infectious viral loads by 0.5 and 1.6 log10, respectively, compared to the vehicle control. When GS-441524 (50 mg/kg, BID) and molnupiravir (150 mg/kg, BID) were combined, infectious virus was no longer detectable in the lungs of 7 out of 10 of the treated hamsters (4.0 log10reduction) and titers in the other animals were reduced by ~2 log10. The combined antiviral activity of molnupiravir which acts by inducing lethal mutagenesis and GS-441524, which acts as a chain termination appears to be highly effective in reducing SARS-CoV-2 replication/infectivity. The unexpected potent antiviral effect of the combination warrants further exploration as a potential treatment for COVID-19.
Evidence for a compact σ70conformationin vitroandin vivo
Authors: Joron Khalil , Zamel Joanna , Kalisman Nir , Lerner Eitan 
Published: October 2022

AbstractThe initiation of transcription in Escherichia coli (E. coli) is facilitated by promoter specificity factors, also known as σ factors, which may bind a promoter only as part of a complex with RNA polymerase (RNAP). By performingin vitrocross-linking mass spectrometry (CL-MS) of apo-σ70, we reveal structural features suggesting a compact conformation compared to the known RNAP-bound extended conformation. Then, we validate the existence of the compact conformation usingin vivoCL-MS by identifying cross-links similar to those foundin vitro, which deviate from the extended conformation only during the stationary phase of bacterial growth. Conclusively, we provide information in support of a compact conformation of apo-σ70that exists in live cells, which might represent a transcriptionally-inactive form that can be activated upon binding to RNAP.
IMPA1 dependent regulation of plasma membrane phosphatidylinositol 4,5-bisphosphate turnover and calcium signalling by lithium
Authors: Saha Sankhanil , Krishnan Harini , Padinjat Raghu 
Published: October 2022

AbstractLithium (Li) is a widely used as a mood stabilizer in the clinical management of Bipolar Affective Disorder (BPAD). However, the molecular targets of Li in neural cells that underpin its therapeutic effect remain unresolved. Inositol monophosphatase (IMPA1), is an enzyme involved in the resynthesis of phosphatidylinositol 4,5-bisphosphate (PIP2) following receptor-activated phospholipase C (PLC) signalling.In vitro, Li inhibits IMPA1, but the relevance of this inhibition within neural cells remains unknown. Here we report that in human cells, treatment with therapeutically relevant concentrations of Li reduces receptor activated calcium release from intracellular stores and delays the resynthesis of PIP2following receptor activated PLC signalling. Both these effects of Li are abrogated in cells where IMPA1 has been deleted. We also observed that in human forebrain cortical neurons, treatment with Li results in reduced neuronal excitability as well as reduced calcium signals following receptor activated PLC signalling. Following Li treatment of human forebrain cortical neurons, transcriptome analyses reveal downregulation of multiple components of the glutamate receptor signalling system. Glutamate is a key excitatory neurotransmitter in the human brain and thus our findings provide an insight into the mechanisms underlying the dampening of neuronal excitability following Li treatment. Collectively, our findings suggest that Li inhibits receptor activated PLC signalling leading to an altered transcriptional response and reduced neuronal excitability.