bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modelling to infer the role of animals in gambiense human African trypanosomiasis transmission and elimination in DRC
Authors: Crump Ronald E , Huang Ching-I , Spencer Simon E F , Brown Paul E , Shampa Chansy , Miaka Erick Mwamba , Rock Kat S 
Published: December 2021

AbstractGambiense human African trypanosomiasis (gHAT) has been targeted for elimination of transmission (EoT) to humans by 2030. Whilst this ambitious goal is rapidly approaching, there remain fundamental questions about the presence of non-human animal transmission cycles and their potential role in slowing progress towards, or even preventing, EoT. In this study we focus on the country with the most gHAT disease burden, the Democratic Republic of Congo (DRC), and use mathematical modelling to assess whether animals may contribute to transmission in specific regions, and if so, how their presence could impact the likelihood and timing of EoT.By fitting two model variants – one with, and one without animal transmission – to the human case data from 2000–2016 we estimate model parameters for 158 endemic health zones of DRC. We evaluate the statistical support for each model variant in each health zone and infer the contribution of animals to overall transmission and how this could impact predicted time to EoT.We conclude that there are 24/158 health zones where there is moderate or high statistical support for some animal transmission. However, – even in these regions – we estimate that animals would be extremely unlikely to maintain transmission on their own. Animal transmission could hamper progress towards EoT in some settings, with projections under continuing interventions indicating that the number of health zones expected to achieve EoT by 2030 reduces from 68 to 61 if animals are included in the model. With supplementary vector control (at a modest 60% tsetse reduction) added to medical screening and treatment interventions, the predicted number of health zones meeting the goal increases to 147/158 for the model including animals. This is due to the impact of vector reduction on transmission to and from all hosts.Author summaryElimination of African sleeping sickness by 2030 is an ambitious goal, not least because of the unclear role that animals might play in transmission. We use mathematical models, fitted to case data from DRC to assess and quantify the contribution of animals to the human case burden.We found that 24/158 geographic regions included in this study had statistical evidence of animal transmission, although it appears extremely unlikely that animals could maintain transmission on their own. Animals could, however, delay elimination; using our model without animal transmission we predicted that 68 regions are expected to achieve elimination by 2030, whereas this reduces to 61 with animals. If vector control to reduce fly populations (which transmit the disease to and from hosts) are controlled in addition to medical interventions, then 147 regions are predicted to reach elimination by 2030 even with animal transmission.
A world of viruses nested within parasites: Unraveling viral diversity within parasitic flatworms (Platyhelminthes)
Authors: Dheilly Nolwenn M , Lucas Pierrick , Blanchard Yannick , Rosario Karyna 
Published: December 2021

AbstractBecause parasites have an inextricable relationship with their host, they have the potential to serve as viral reservoirs or facilitate virus host-shifts. Yet, little is known about viruses infecting parasitic hosts except for blood-feeding arthropods that are well-known vectors of zoonotic viruses. Herein we uncover viruses of flatworms (Phylum Platyhelminthes, group Neodermata) that specialize in parasitizing vertebrates and their ancestral free-living relatives. We discovered 115 novel viral sequences, including 1 in Macrostomorpha, 5 in Polycladida, 44 in Tricladida, 1 in Monogenea, 15 in Cestoda and 49 in Trematoda, through data mining. The majority of newly identified viruses constitute novel families or genera. Phylogenetic analyses show that the virome of flatworms changed dramatically during the transition of Neodermatans to a parasitic lifestyle. Most Neodermatan viruses seem to co-diversify with their host, with the exception of rhabdoviruses which may switch host more often, based on phylogenetic relationships. Neodermatan rhabodviruses also have an ancestral position to vertebrate-associated viruses, including Lyssaviruses, suggesting that vertebrate rhabdoviruses emerged from a flatworm rhabdovirus in a parasitized host. This study reveals an extensive diversity of viruses in Platyhelminthes and highlights the need to evaluate the role of viral infection in flatworm-associated diseases.
TRPM4 is required for calcium oscillations downstream from the stretch-activated TRPV4 channel
Authors: Yarishkin Oleg , Phuong Tam T. T. , Vazquez-Chona Felix , Bertrand Jacques , Redmon Sarah N. , Lakk Monika , Rudzitis Christopher N. , Baumann Jackson M. , Hwang Eun Mi , Overby Darryl , Križaj David 
Published: December 2021

AbstractTransduction of mechanical information is influenced by physical, chemical and thermal cues but the molecular mechanisms through which transducer activation shapes temporal signaling remain underexplored. In the present study, electrophysiology, histochemistry and functional imaging were combined with gene silencing and heterologous expression to gain insight into calcium signaling downstream from TRPV4 (Transient Receptor Potential Vanilloid 4), a stretch-activated nonselective cation channel. We show that trabecular meshwork (TM) cells, which employ mechanotransduction to actively regulate intraocular pressure, respond to the TRPV4 agonist GSK1016790A with fluctuations in intracellular Ca2+ concentration ([Ca2+]i) and an increase in [Na+]i. ([Ca2+]i oscillations coincided with a monovalent cation current that was suppressed by BAPTA, Ruthenium Red and 9-phenanthrol, an inhibitor of TRPM4 (Transient Receptor Potential Melastatin 4) channels. Accordingly, TM cells expressed TRPM4 mRNA, protein at the expected 130-150 kDa and showed punctate TRPM4 immunoreactivity at the membrane surface. Genetic silencing of TRPM4 antagonized TRPV4-evoked oscillatory signaling whereas TRPV4 and TRPM4 co-expression in HEK-293 cells reconstituted the oscillations. Membrane potential recordings indicated that TRPM4-dependent oscillations required release of Ca2+ from internal stores. 9-phenanthrol did not affect the outflow facility in mouse eyes. Collectively, our results show that TRPV4 activity initiates dynamic calcium signaling in TM cells by stimulating TRPM4 channels and intracellular Ca2+ release. These findings provide insight into the complexity of membrane-cytosolic interactions during TRPV4 signaling and may foster strategies to promote homeostatic regulation and counter pathological remodeling within the conventional outflow pathway of the mammalian eye.
Differing Associations between Optic Nerve Head Strains and Visual Field Loss in Normal- and High-Tension Glaucoma Subjects
Authors: Chuangsuwanich Thanadet , Tun Tin A. , Braeu Fabian A. , Wang Xiaofei , Chin Zhi Yun , Panda Satish Kumar , Buist Martin , Strouthidis Nicholas , Perera Shamira , Nongpiur Monisha , Aung Tin , Girard Michael JA 
Published: December 2021

AbstractPurposeTo study the associations between optic nerve head (ONH) strains under intraocular pressure (IOP) elevation with retinal sensitivity in glaucoma subjects.DesignClinic based cross-sectional study.Participants229 subjects with primary open angle glaucoma (subdivided into 115 high tension glaucoma (HTG) subjects and 114 normal tension glaucoma (NTG) subjects).MethodsFor one eye of each subject, we imaged the ONH using spectral-domain optical coherence tomography (OCT) under the following conditions: (1) primary gaze and (2) primary gaze with acute IOP elevation (to approximately 33 mmHg) achieved through ophthalmodynamometry. A 3-dimensional (3D) strain-mapping algorithm was applied to quantify IOP-induced ONH tissue strain (i.e. deformation) in each ONH. Strains in the pre-lamina tissue (PLT)and the retina, the choroid, the sclera and the lamina cribrosa (LC) were associated (using linear regression) with measures of retinal sensitivity from the 24-2 Humphrey visual field test (Carl Zeiss Meditec, Dublin, CA, USA). This was done globally, then locally according to the regionalization scheme of Garway-Heath et al.Main Outcome MeasuresAssociations between ONH strains and values of retinal sensitivity from visual field testing.ResultsFor HTG subjects, we found that (1) there were significant negative linear associations between ONH strains and retinal sensitivity (p<0.001) (on average, a 1% increase in ONH strains corresponded to a decrease in retinal sensitivity of 1.1 dB), (2) high strain regions co-localized with anatomically-mapped regions of high visual field loss, (3) the strongest negative associations were observed in the superior region and in the PLT. In contrast, for NTG subjects, no significant associations between strains and retinal sensitivity were observed except in the supero-temporal region of the LC.ConclusionWe found significant negative associations between IOP-induced ONH strains and retinal sensitivity in a relatively large glaucoma cohort. Specifically, HTG subjects who experienced higher ONH strains were more likely to exhibit lower retinal sensitivities. Interestingly, this trend was in general less pronounced in NTG subjects, which could suggest a distinct pathophysiology between the two glaucoma subtypes.
Nest aggregations of wild bees and apoid wasps in urban pavements: a “street life” to be promoted in urban planning
Authors: Noël Grégoire , Van Keymeulen Violette , Barbier Yvan , Smets Sylvie , Van Damme Olivier , Colinet Gilles , Ruelle Julien , Francis Frédéric 
Published: December 2021

AbstractIn the last 10 years, knowledges of wild bees and apoid wasps’ community dynamics have gained interest in urban ecology focusing on the availability of floral resources in cities. Although understudied, the urban environment impacts the conditions of their nesting sites. Recent observations in the Brussels-Capital Region (Belgium) showed that urban pavements can be a novel nesting opportunity for Hymenoptera ground-nesting species such as wild bees and apoid wasps. Here, using citizen science, we investigated the richness of ground-nesting species living under urban pavements, the preferences of the sidewalk joint size related to ground-nesting species size and for sidewalk type or for soils texture under the pavements on the nesting site selection. A total of 22 species belonging to 10 Hymenoptera families of wild bees and digger wasps with their associated kleptoparasites were identified on 89 sites in Brussels. Sandstone setts or concrete slabs with an unbound joint size around 1 cm were found to be best suitable urban pavements for the ground-nesting species. The soil texture under the pavement was highly sandy among our samples. Finally, we also suggest engineering management guidelines to support bee and wasp species nesting under urban pavement in highly urbanized areas. Such observations pave the way for much research in the field of urban ecology to conceive multifunctional pavement promoting biodiversity.
Plexins Promote Hedgehog Signaling Through Their Cytoplasmic GAP Activity
Authors: Pinskey Justine M. , Hoard Tyler M. , Zhao Xiao-Feng , Franks Nicole E. , Frank Zoë C. , McMellen Alexandra N. , Giger Roman J. , Allen Benjamin L. 
Published: December 2021

AbstractHedgehog signaling controls tissue patterning during embryonic and postnatal development and continues to play important roles throughout life. Characterizing the full complement of Hedgehog pathway components is essential to understanding its wide- ranging functions. Previous work has identified Neuropilins, established Semaphorin receptors, as positive regulators of Hedgehog signaling. Neuropilins require Plexin co- receptors to mediate Semaphorin signaling, but a role for Plexins in Hedgehog signaling has not yet been explored. Here, we provide evidence that multiple Plexins promote Hedgehog signaling in NIH/3T3 fibroblasts and that Plexin loss-of-function in these cells results in significantly reduced Hedgehog pathway activity. Catalytic activity of the Plexin GTPase activating protein (GAP) domain is required for Hedgehog signal promotion, and constitutive activation of the GAP domain further amplifies Hedgehog signaling. Additionally, we demonstrate that Plexins promote Hedgehog signaling at the level of GLI transcription factors and that this promotion requires intact primary cilia.Finally, we find that Plexin loss-of-function significantly reduces the response to Hedgehogα pathway activation in the mouse dentate gyrus. Together, these data identify Plexins as novel components of the Hedgehog pathway and provide insight into their mechanism of action.
Bacterial origin of thymidylate and folate metabolism in Asgard Archaea
Authors: Filée Jonathan , Becker Hubert F. , Mellottee Lucille , Li Zhihui , Lambry Jean-Christophe , Liebl Ursula , Myllykallio Hannu 
Published: December 2021

AbstractLittle is known about the evolution and biosynthetic function of DNA precursor and the folate metabolism in the Asgard group of archaea. As Asgard occupy a key position in the archaeal and eukaryotic phylogenetic trees, we have exploited very recently emerged genome and metagenome sequence information to investigate these central metabolic pathways. Our genome-wide analyses revealed that the recently cultured Asgard archaeon Candidatus Prometheoarchaeum syntrophicum strain MK-D1 (Psyn) contains a complete folate-dependent network for the biosynthesis of DNA/RNA precursors, amino acids and syntrophic amino acid utilization. Altogether our experimental and computational data suggest that phylogenetic incongruences of functional folate-dependent enzymes from Asgard archaea reflect their persistent horizontal transmission from various bacterial groups, which has rewired the key metabolic reactions in an important and recently identified archaeal phylogenetic group. We also experimentally validated the functionality of the lateral gene transfer of Psyn thymidylate synthase ThyX. This enzyme uses bacterial-like folates efficiently and is inhibited by mycobacterial ThyX inhibitors. Our data raise the possibility that the thymidylate metabolism, required for de novo DNA synthesis, originated in bacteria and has been independently transferred to archaea and eukaryotes. In conclusion, our study has revealed that recent prevalent lateral gene transfer has markedly shaped the evolution of Asgard archaea by allowing them to adapt to specific ecological niches.
Dynamic epistasis analysis reveals how chromatin remodeling regulates transcriptional bursting
Authors: Brouwer Ineke , Kerklingh Emma , van Leeuwen Fred , Lenstra Tineke Laura 
Published: December 2021

SummaryTranscriptional bursting has been linked to the stochastic positioning of nucleosomes. However, how bursting is regulated by remodeling of promoter nucleosomes is unknown. Here, we use single-molecule live-cell imaging of GAL10 transcription in budding yeast to measure how transcriptional bursting changes upon single and double perturbations of chromatin remodeling factors, the transcription factor Gal4 and preinitiation complex (PIC) components. Using dynamic epistasis analysis, we reveal how remodeling of different nucleosomes regulates individual transcriptional bursting parameters. At the nucleosome covering the Gal4 binding sites, RSC acts synergistically with Gal4 binding to facilitate each burst. Conversely, nucleosome remodeling at the TATA box controls only the first burst upon galactose induction. In the absence of remodelers, nucleosomes at canonical TATA boxes are displaced by TBP binding to allow for transcription activation. Overall, our results reveal how promoter nucleosome remodeling, together with transcription factor and PIC binding regulates the kinetics of transcriptional bursting.
Period Doubling Bifurcations in a Forced Cell-Free Genetic Oscillator
Authors: Aufinger Lukas , Brenner Johann , Simmel Friedrich C. 
Published: December 2021

AbstractComplex non-linear dynamics such as period doubling and chaos have been previously found in computational models of the oscillatory gene networks of biological circadian clocks, but their experimental study is difficult. Here, we present experimental evidence of period doubling in a forced synthetic genetic oscillator operated in a cell-free gene expression system. To this end, an oscillatory negative feedback gene circuit is established in a microfluidic reactor, which allows continuous operation of the system over extended periods of time. We first thoroughly characterize the unperturbed oscillator and find good agreement with a four-species ODE model of the system. Guided by simulations, microfluidics is then used to periodically perturb the system by modulating the concentration of one of the oscillator components with a given amplitude and frequency. When the ratio of the external ‘zeitgeber’ period and the intrinisic period is close to 1, we experimentally find period doubling and quadrupling in the oscillator dynamics, whereas for longer zeitgeber periods, we find stable entrainment. Our theoretical model suggests favorable conditions for which the oscillator can be utilized as an externally synchronized clock, but also demonstrates that related systems could, in principle, display chaotic dynamics.
A putative cap binding protein and the methyl phosphate capping enzyme Bin3/MePCE function in telomerase biogenesis
Authors: Páez-Moscoso Diego J. , Ho David V. , Pan Lili , Hildebrand Katie , Jensen Kristi L. , Levy Michaella J. , Florens Laurence , Baumann Peter 
Published: December 2021

AbstractTelomerase reverse transcriptase (TERT) and the noncoding telomerase RNA (TR) subunit constitute the core of telomerase. Additional subunits are required for ribonucleoprotein complex assembly and in some cases remain stably associated with the active holoenzyme. Pof8, a member of the LARP7 protein family is such a constitutive component of telomerase in fission yeast. Using affinity purification of Pof8, we have identified two previously uncharacterized proteins that form a complex with Pof8 and participate in telomerase biogenesis. Both proteins participate in ribonucleoprotein complex assembly and are required for wildtype telomerase activity and telomere length maintenance. One factor we named Thc1 (Telomerase Holoenzyme Component 1) shares structural similarity with the nuclear cap binding complex and the poly-adenosine ribonuclease (PARN), the other is the ortholog of the methyl phosphate capping enzyme (Bin3/MePCE) in metazoans and was named Bmc1 (Bin3/MePCE 1) to reflect its evolutionary roots. Thc1 and Bmc1 function together with Pof8 in recognizing correctly folded telomerase RNA and promoting the recruitment of the Lsm2-8 complex and the catalytic subunit to assemble functional telomerase.
Rostral and caudal BLA engage distinct circuits in the prelimbic and infralimbic PFC
Authors: Manoocheri Kasra , Carter Adam G. 
Published: December 2021

ABSTRACTConnections from the basolateral amygdala (BLA) to medial prefrontal cortex (PFC) regulate memory and emotion and become disrupted in neuropsychiatric disorders. We hypothesized that the diverse roles attributed to interactions between the BLA and PFC reflect multiple circuits nested within a wider network. To assess these circuits, we first used anatomy to show that the rostral BLA (rBLA) and caudal BLA (cBLA) differentially project to prelimbic (PL) and infralimbic (IL) subregions of the PFC, respectively. We then combined in vivo silicon probe recordings and optogenetics to show that rBLA primarily engages PL, whereas cBLA mainly influences IL. Using ex vivo whole-cell recordings and optogenetics, we then assessed which neuronal subtypes are targeted, showing that rBLA preferentially drives layer 2 (L2) cortico-amygdalar (CA) neurons in PL, whereas cBLA drives layer 5 (L5) pyramidal tract (PT) cells in IL. Lastly, we used soma-tagged optogenetics to explore the local circuits linking superficial and deep layers of PL, showing how rBLA can also impact L5 PT cells. Together, our findings delineate how subregions of the BLA target distinct networks within the PFC to have different influence on prefrontal output.
The phospho-docking protein 14-3-3 regulates microtubule-associated proteins in oocytes including the chromosomal passenger Borealin
Authors: Repton Charlotte , Cullen C. Fiona , Costa Mariana F. A. , Spanos Christos , Rappsilber Juri , Ohkura Hiroyuki 
Published: December 2021

AbstractGlobal regulation of spindle-associated proteins is crucial in oocytes due to the absence of centrosomes and their very large cytoplasmic volume, but little is known about how this is achieved beyond involvement of the Ran-importin pathway. We previously uncovered a novel regulatory mechanism in Drosophila oocytes, in which the phospho-docking protein 14-3-3 suppresses microtubule binding of Kinesin-14/Ncd away from chromosomes. Here we report systematic identification of microtubule-associated proteins regulated by 14-3-3 from Drosophila oocytes. Proteins from ovary extract were co-sedimented with microtubules in the presence or absence of a 14-3-3 inhibitor. Through quantitative mass-spectrometry, we identified proteins or complexes whose ability to binding microtubules is suppressed by 14-3-3, including the chromosomal passenger complex (CPC), the centralspindlin complex and Kinesin-14/Ncd. We showed that 14-3-3 binds to the disordered region of Borealin, and this binding is regulated differentially by two phosphorylations on Borealin. Mutations at these two phospho-sites compromised normal Borealin localisation and centromere bi-orientation in oocytes, showing that phospho-regulation of 14-3-3 binding is important for Borealin localisation and function. The mass spectrometry data are available from ProteomeXchange, identifier <ID to be provided when available, PXD000xxx>.Author SummaryAccurate segregation of chromosomes during cell division is fundamental for genome stability. Chromosome segregation is mediated by the spindle, which is made of dynamic microtubules and associated proteins that regulate microtubule behaviour. How these microtubule-associated proteins are regulated is not well understood. Furthermore, as oocytes have an exceptionally large volume of cytoplasm and lack centrosomes, regulation of microtubule-associated proteins is especially crucial for organisation and function of the meiotic spindle. In this study, we showed that 14-3-3, a protein that binds to phosphorylated proteins, plays an important role to regulate multiple microtubule-associated proteins in fly oocytes. The regulated proteins include subunits of the conserved kinase complex called the chromosomal passenger complex. We further found that interaction of one of the subunits with 14-3-3 is regulated by two phosphorylations, and that these phosphorylations are important for localisation and function of this subunit. As these proteins are widely conserved including humans, this study may provide an insight into chromosome mis-segregation in human oocytes, which is very frequent and a major cause of human infertility, miscarriages and congenital birth conditions.