bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global genome diversity of theLeishmania donovanicomplex
Authors: Franssen Susanne U. , Durrant Caroline , Stark Olivia , Moser Bettina , Downing Tim , Imamura Hideo , Dujardin Jean-Claude , Sanders Mandy , Mauricio Isabel , Miles Michael A. , Schnur Lionel F. , Jaffe Charles L. , Nasereddin Abdelmajeed , Schallig Henk , Yeo Matthew , Bhattacharyya Tapan , Alam Mohammad Z. , Berriman Matthew , Wirth Thierry , Schönian Gabriele , Cotton James A. 
Published: July 2019

AbstractProtozoan parasites of theLeishmania donovanicomplex –L. donovaniandL. infantum– cause the fatal disease visceral leishmaniasis. We present the first comprehensive genome-wide global study, with 151 cultured field isolates representing most of the geographical distribution.L. donovaniisolates separated into five groups that largely coincide with geographical origin but vary greatly in diversity. In contrast, the majority ofL. infantumsamples fell into one globally-distributed group with little diversity. This picture is complicated by several hybrid lineages. Identified genetic groups vary in heterozygosity and levels of linkage, suggesting different recombination histories. We characterise chromosome-specific patterns of aneuploidy and identified extensive structural variation, including known and suspected drug resistance loci. This study reveals greater genetic diversity than suggested by geographically-focused studies, provides a resource of genomic variation for future work and sets the scene for a new understanding of the evolution and genetics of theLeishmania donovanicomplex.
Progressive shifts in the gut microbiome reflect prediabetes and diabetes development in a treatment-naive Mexican cohort
Authors: Diener Christian , Reyes Lourdes , Jimenez Lilia , Matus Mariana , Gomez Claudia , Chu Nathaniel D. , Zhong Vivian , Tejero Elizabeth , Alm Eric , Resendis-Antonio Osbaldo , Guardado-Mendoza Rodolfo 
Published: July 2019

AbstractType 2 diabetes (T2D) is a global epidemic that affects more than 8% of the world’s population and is a leading cause of death in Mexico. Diet and lifestyle are known to contribute to the onset of T2D. However, the role of the gut microbiome in T2D progression remains uncertain. Associations between microbiome composition and diabetes are confounded by medication use, diet, and obesity. Here we present data on a treatment-naive cohort of 405 Mexican individuals across varying stages of T2D severity. Associations between gut bacteria and more than 200 clinical variables revealed a defined set of bacterial genera that were consistent biomarkers of T2D prevalence and risk. Specifically, gradual increases in blood glucose levels, beta cell dysfunction, and the accumulation of measured T2D risk factors was correlated with the relative abundances of four bacterial genera. In a cohort of 25 individuals, T2D treatment - predominantly metformin - reliably returned the microbiome to the normoglycemic community state. Deep clinical characterization allowed us to broadly control for confounding variables, indicating that these microbiome patterns were independent of common T2D comorbidities, like obesity or cardiovascular disease. Thus, our work provides the first solid evidence for a direct link between the gut microbiome and T2D in a critically high-risk population. Whether or not these T2D-associated changes in the gut contribute to the etiology of T2D or its comorbidities remains to be seen.
Mismatch repair hierarchy of Pseudomonas putida revealed by mutagenic ssDNA recombineering of the pyrF gene
Authors: Aparicio Tomas , Nyerges Akos , Nagy István , Pal Csaba , Martínez-García Esteban , de Lorenzo Víctor 
Published: July 2019

SUMMARYThe mismatch repair (MMR) system is one of the key molecular devices that prokaryotic cells have for ensuring fidelity of DNA replication. While the canonical MMR of E. coli involves 3 proteins (encoded by mutS, mutL and mutH), the soil bacterium Pseudomonads putida has only 2 bona fide homologues (mutS and mutL) and the sensitivity of this abridged system to different types of mismatches is unknown. On this background, sensitivity to MMR of this bacterium was inspected through single stranded (ss) DNA recombineering of the pyrF gene (the prokaryotic equivalent to yeast’s URA3) with mutagenic oligos representative of every possible mispairing under either wild-type conditions, permanent deletion of mutS or transient loss of mutL activity (brought about by the thermoinducible dominant negative allele mutLE36K). Analysis of single nucleotide mutations borne by clones resistant to fluoroorotic acid (5FOA, the target of wild type PyrF) pinpointed prohibited and tolerated single-nucleotide replacements and exposed a clear grading of mismatch recognition. The resulting data unequivocally established the hierarchy A:G< C:C< G:A< C:A, A:A, G:G, T:T, T:G, A:C, C:T< G:T, T:C as the one prevalent in Pseudomonas putida. This information was vital for enabling recombineering strategies aimed at single-nucleotide changes in this biotechnologically important species.Originality-Significance StatementSingle-stranded DNA (ssDNA) recombineering has emerged in recent years as one of the most powerful technologies of genome editing in E. coli and other Enterobacteria. However, the efforts to expand the concept and the methods towards environmental microorganisms such as Pseudomonas putida have been limited thus far by several gaps in our fundamental knowledge of how nucleotide mismatch repair (MMR) operates in such non-model species. One critical bottleneck is the hierarchy of recognition of different types of base mispairings as well as the need of setting up strategies for counteracting MMR and thus enabling tolerance to all types of changes. The work presented here tackles both issues and makes P. putida amenable to sophisticated genetic manipulations that were impossible before.
In Vivo Large Scale Mapping Of Protein Turnover In The Human Cerebrospinal Fluid
Authors: Lehmann Sylvain , Hirtz Christophe , Vialaret Jérôme , Ory Maxence , Combes Guillaume Gras , Le Corre Marine , Badiou Stéphanie , Cristol Jean-Paul , Hanon Olivier , Cornillot Emmanuel , Bauchet Luc , Gabelle Audrey , Colinge Jacques 
Published: July 2019

SummaryThe extraction of accurate physiological parameters from clinical samples provides a unique perspective to understand disease etiology and evolution, including under therapy. We introduce a new proteomics framework to map patient proteome dynamics in vivo, either proteome wide or in large targeted panels. We applied it to ventricular cerebrospinal fluid (CSF) and could determine the turnover parameters of almost 200 proteins, whereas a handful were known previously. We covered a large number of neuron biology- and immune system-related proteins including many biomarkers and drug targets. This first large data set unraveled a significant relationship between turnover and protein origin that relates to our ability to investigate the central nervous system physiology precisely in future studies. Our data constitute a reference in CSF biology as well as a repertoire of peptides for the community to design new proteome dynamics analyses. The disclosed methods apply to other fluids or tissues provided sequential sample collection can be performed.
Altered stomatal patterning accompanies a trichome dimorphism in a natural population ofArabidopsis
Authors: Simon Noriane M. L. , Sugisaka Jiro , Honjo Mie N. , Tunstad Sverre Aarseth , Tunna George , Kudoh Hiroshi , Dodd Antony N. 
Published: July 2019

AbstractTrichomes are large epidermal cells on the surface of leaves that are thought to deter herbivores, yet the presence of trichomes can also negatively impact plant growth and reproduction. Stomatal guard cells and trichomes have shared developmental origins, and experimental manipulation of trichome formation can lead to changes in stomatal density. The influence of trichome formation upon stomatal development in natural populations of plants is currently unknown. Here, we show that a natural population ofArabidopsis hallerithat includes hairy (trichome-bearing) and glabrous (no trichomes) morphs has differences in stomatal density that are associated with this trichome dimorphism. We found that glabrous morphs had significantly greater stomatal density and stomatal index than hairy morphs. One interpretation is that this arises from a trade-off between the proportions of cells that have trichome and guard cell fates during leaf development. The differences in stomatal density between the two morphs might have impacts upon environmental adaptation, in addition to herbivory deterrence caused by trichome development.
Application of high-resolution landmark-free morphometrics to a mouse model of Down Syndrome reveals a tightly localised cranial phenotype
Authors: Toussaint Nicolas , Redhead Yushi , Liu Wei , Fisher Elizabeth M. C. , Hallgrimsson Benedikt , Tybulewicz Victor L.J. , Schnabel Julia A. , Green Jeremy B.A. 
Published: July 2019

AbstractCharacterising phenotypes often requires quantification of anatomical shapes. Quantitative shape comparison (morphometrics) traditionally uses anatomical landmarks and is therefore limited by the number of landmarks and operator accuracy when landmarks are located manually. Here we apply a landmark-free method to characterise the craniofacial skeletal phenotype of the Dp1Tyb mouse model of Down syndrome (DS), validating it against a landmark-based approach. We identify cranial dysmorphologies in Dp1Tyb mice, especially smaller size and brachycephaly (front-back shortening) homologous to the human phenotype. The landmark-free phenotyping was less labour-intensive and required less user training than the landmark-based method. It also enabled mapping of local differences as planar expansion or shrinkage. This higher resolution and local mapping pinpointed reductions in interior mid-snout structures and occipital bones in this DS model that were not as apparent using a traditional landmark-based method. This approach could make morphometrics widely-accessible beyond traditional niches in zoology and palaeontology, especially in characterising mutant phenotypes.
The apical annuli ofToxoplasma gondiiare composed of coiled-coil and signaling proteins embedded in the IMC sutures
Authors: Engelberg Klemens , Chen Chun-Ti , Bechtel Tyler , Guzmán Victoria Sánchez , Drozda Allison A. , Chavan Suyog , Weerapana Eranthie , Gubbels Marc-Jan 
Published: July 2019

AbstractThe apical annuli are among the most intriguing and understudied structures in the cytoskeleton of the apicomplexan parasiteToxoplasma gondii. We mapped the proteome of the annuli inToxoplasmaby reciprocal proximity biotinylation (BioID), and validated five apical annuli proteins (AAP1-5), Centrin2 and a methyltransferase (AAMT). Moreover, Inner Membrane Complex (IMC) suture proteins connecting the alveolar vesicles were also detected and support annuli residence within the sutures. Super-resolution microscopy (SR-SIM) identified a concentric organization comprising four rings with diameters ranging from 200-400 nm. The high prevalence of domain signatures shared with centrosomal proteins in the AAPs together with Centrin2 suggest that the annuli are related and/or derived from the centrosomes. Phylogenetic analysis revealed the AAPs are conserved narrowly in Coccidian, apicomplexan parasites that multiply by an internal budding mechanism. This suggests a role in replication, for example, to provide pores in the mother IMC permitting exchange of building blocks and waste products. However, presence of multiple signaling domains and proteins are suggestive of additional functions. Knockout of AAP4, the most conserved compound forming the largest ring-like structure, modestly decreased parasite fitnessin vitrobut had no significant impact on acute virulencein vivo. In conclusion, the apical annuli are composed of coiled-coil and signaling proteins assembled in a pore-like structure crossing the IMC barrier maintained during internal budding.
A comparison of resting state EEG and structural MRI for classifying Alzheimer’s disease and mild cognitive impairment
Authors: Farina FR , Emek-Savaş DD , Rueda-Delgado L , Boyle R , Kiiski H , Yener G , Whelan R 
Published: July 2019

AbstractAlzheimer’s disease (AD) is a neurodegenerative disorder characterised by severe cognitive decline and loss of autonomy. AD is the leading cause of dementia. AD is preceded by mild cognitive impairment (MCI). By 2050, 68% of new dementia cases will occur in low- and middle-income countries. In the absence of objective biomarkers, psychological assessments are typically used to diagnose MCI and AD. However, these require specialist training and rely on subjective judgements. The need for low-cost, accessible and objective tools to aid AD and MCI diagnosis is therefore crucial. Electroencephalography (EEG) has potential as one such tool: it is relatively inexpensive (cf. magnetic resonance imaging; MRI) and is portable. In this study, we collected resting state EEG, structural MRI and rich neuropsychological data from older adults (55+ years) with AD, with MCI and from healthy controls (n~60 per group). Our goal was to evaluate the utility of EEG, relative to MRI, for the classification of MCI and AD. We also assessed the performance of combined EEG and behavioural (Mini-Mental State Examination; MMSE) and structural MRI classification models. Resting state EEG classified AD and HC participants with moderate accuracy (AROC=0.76), with lower accuracy when distinguishing MCI from HC participants (AROC=0.67). The addition of EEG data to MMSE scores had no additional value compared to MMSE alone. Structural MRI out-performed EEG (AD vs HC, AD vs MCI: AROCs=1.00; HC vs MCI: AROC=0.73). Resting state EEG does not appear to be a suitable tool for classifying AD. However, EEG classification accuracy was comparable to structural MRI when distinguishing MCI from healthy aging, although neither were sufficiently accurate to have clinical utility. This is the first direct comparison of EEG and MRI as classification tools in AD and MCI participants.
DEET and other repellents are inhibitors of mosquito odorant receptors for oviposition attractants
Authors: Xu Pingxi , Zeng Fangfang , Bedoukian Robert H. , Leal Walter S. 
Published: July 2019

AbstractIn addition to its primary function as an insect repellent, DEET has many “off-label” properties, including a deterrent effect on attraction of gravid female mosquitoes. DEET negatively affects oviposition sites. While deorphanizing odorant receptors (ORs) using the Xenopus oocyte recording system, we have previously observed that DEET generated outward (inhibitory) currents on ORs sensitive to oviposition attractants. Here, we systematically investigated these inhibitory currents. We recorded dose-dependent outward currents elicited by DEET and other repellents on ORs from Culex quinquefasciatus, Aedes aegypti, and Anopheles gambiae. Similar responses were observed with other plant-derived and plant-inspired compounds, including methyl jasmonate and methyl dihydrojasmolate. Inward (regular) currents elicited by skatole upon activation of CquiOR21 were modulated when this oviposition attractant was coapplied with a repellent. Compounds that generate outward currents in ORs sensitive to oviposition attractants elicited inward currents in a DEET-sensitive receptor, CquiOR136. The best ligand for this receptor, methyl dihydrojasmolate, showed repellency activity, but was not as strong as DEET in our test protocol.
The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance and neuronal survival in mice
Authors: Minis Adi , Rodriguez Jose , Levin Avi , Liu Kai , Govek Eve-Ellen , Hatten Mary E. , Steller Hermann 
Published: July 2019

AbstractProteasome-mediated degradation of intracellular proteins is essential for cell function and survival. The proteasome-binding protein PI31 (Proteasomal Inhibitor of 31kD) promotes 26S assembly and functions as an adapter for proteasome transport in axons. As localized protein synthesis and degradation is especially critical in neurons, we generated a conditional loss of PI31 in spinal motor neurons (MNs) and cerebellar Purkinje cells (PCs). A cKO of PI31 in these neurons caused axon degeneration, neuronal loss and progressive spinal and cerebellar neurological dysfunction. For both MNs and PCs, markers of proteotoxic stress preceded axonal degeneration and motor dysfunction, indicating a critical role for PI31 in neuronal homeostasis. The time course of the loss of MN and PC function in developing mouse CNS suggests a key role for PI31 in human developmental neurological disorders.Statement of SignificanceThe conserved proteasome-binding protein PI31 serves as an adapter to couple proteasomes with cellular motors to mediate their transport to distal tips of neurons where protein breakdown occurs. We generated global and conditional PI31 knockout mouse strains and show that this protein is required for protein homeostasis, and that its conditional inactivation in neurons disrupts synaptic structures and long-term survival. This work establishes a critical role for PI31 and local protein degradation in the maintenance of neuronal architecture, circuitry and function. Because mutations that impair PI31 function cause neurodegenerative diseases in humans, reduced PI31 activity may contribute to age-related neurodegenerative diseases.
Diverse temporal dynamics of repetition suppression revealed by intracranial recordings in human ventral temporal cortex
Authors: Rangarajan Vinitha , Jacques Corentin , Knight Robert T. , Weiner Kevin S. , Grill-Spector Kalanit 
Published: July 2019

AbstractRepeated stimulus presentations commonly produce decreased neural responses - a phenomenon known as repetition suppression (RS) or adaptation – in ventral temporal cortex (VTC) in humans and nonhuman primates. However, the temporal features of RS in human VTC are not well understood. To fill this gap in knowledge, we utilized the precise spatial localization and high temporal resolution of electrocorticography (ECoG) from 9 human subjects implanted with intracranial electrodes in VTC. Subjects viewed non-repeated and repeated images of faces with long-lagged intervals and many intervening stimuli between repeats. We report three main findings: (i) robust RS occurs in VTC for activity in high-frequency broadband (HFB), but not lower frequency bands, (ii) RS of the HFB signal is associated with lower peak magnitude, lower total responses, and earlier peak responses, and (iii) RS effects occur early within initial stages of stimulus processing and persist for the entire stimulus duration. We discuss these findings in the context of early and late components of visual perception, as well as theoretical models of repetition suppression.
Rational Design of a Bifunctional AND-Gate Ligand to Modulate Cell-Cell Interactions
Authors: Lee Jungmin , Vernet Andyna , Redfield Katherine , Lu Shulin , Ghiran Ionita C. , Way Jeffrey C. , Silver Pamela A. 
Published: July 2019

ABSTRACTProtein “AND-gate” systems, in which a ligand acts only on cells with two different receptors, direct signaling activity to a particular cell type and avoid action on other cells. In a bifunctional AND-Gate protein, the molecular geometry of the protein domains is crucial. Here we constructed a tissue-targeted erythropoietin (EPO) that stimulates red blood cell (RBC) production without triggering thrombosis. EPO was directed to RBC precursors and mature RBCs by fusion to an anti-glycophorin A antibody V region. Many such constructs activated EPO receptorsin vitroand stimulated RBC and not platelet production in mice but nonetheless enhanced thrombosis in mice and caused adhesion between RBCs and EPO receptor-bearing cells. Based on a protein-structural model of the RBC surface, we rationally designed an anti-glycophorin/EPO fusion that does not induce cell adhesionin vitroor enhance thrombosisin vivo. Thus, meso-scale geometry can inform design of synthetic-biological systems.
Tropomyosin Tpm3.1 is required to maintain the structure and function of the axon initial segment
Authors: Abouelezz Amr , Stefen Holly , Segerstråle Mikael , Micinski David , Minkeviciene Rimante , Hardeman Edna C. , Gunning Peter W. , Hoogenraad Casper C. , Taira Tomi , Fath Thomas , Hotulainen Pirta 
Published: July 2019

ABSTRACTThe axon initial segment (AIS) is the site of action potential initiation and serves as a vesicular filter and diffusion barrier that help maintain neuronal polarity. Recent studies have revealed details about a specialized structural complex in the AIS. While an intact actin cytoskeleton is required for AIS formation, pharmacological disruption of actin polymerization compromises the AIS vesicle filter but does not affect overall AIS structure. In this study, we found that the tropomyosin isoform Tpm3.1 decorates a population of relatively stable actin filaments in the AIS. Inhibiting Tpm3.1 in cultured hippocampal neurons led to the loss of AIS structure, the AIS vesicle filter, the clustering of sodium ion channels, and reduced firing frequency. We propose that Tpm3.1-decorated actin filaments form a stable actin filament network under the AIS membrane which provides a scaffold for membrane organization and AIS proteins.
A genetic toolkit for the analysis of metabolic changes in Drosophila provides new insights into metabolic responses to stress and malignant transformation
Authors: Gándara L , Durrieu L , Behrensen C , Wappner P 
Published: July 2019

AbstractRegulation of the energetic metabolism occurs fundamentally at the cellular level, so analytical strategies must aim to attain single cell resolution to fully embrace its inherent complexity. We have developed methods to utilize a toolset of metabolic FRET sensors for assessing lactate, pyruvate and 2-oxoglutarate levels of Drosophila tissues in vivo by imaging techniques. We show here how the energetic metabolism is altered by hypoxia: While larval tissues that contribute directly to adult organs respond to low oxygen levels by executing a metabolic switch towards lactic fermentation, polytene tissues that are degraded during metamorphosis do not alter their energetic metabolism. Analysis of tumor metabolism revealed that depending on the genetic background, some tumors undergo a lactogenic switch typical of the Warburg effect, while other tumors don’t. This toolset allows for developmental and physiologic studies in genetically manipulated Drosophila individuals in vivo.