bluuebunny/crossref_metadata_2025_split huggingface dataset:
Restructured mitochondrial-nuclear interaction inPlasmodium falciparumdormancy and persister survival after artemisinin exposure
Authors: Connelly Sean V. , Manzella-Lapeira Javier , Levine Zoë C. , Brzostowski Joseph , Krymskaya Ludmila , Rahman Rifat S. , Ellis Angela C. , Amin Shuchi N. , Sá Juliana M. , Wellems Thomas E. 
Published: September 2020

ABSTRACTArtemisinin and its semi-synthetic derivatives (ART) are fast acting, potent antimalarials; however, their use in malaria treatment is frequently confounded by recrudescences from bloodstreamPlasmodiumparasites that enter into and later reactivate from a dormant persister state. Here we provide evidence that the mitochondria of dihydroartemisinin (DHA)-exposed persisters are dramatically altered and enlarged relative to the mitochondria of young, actively replicating ring forms. Restructured mitochondrial-nuclear associations and an altered metabolic state are consistent with stress from reactive oxygen species. New contacts between the mitochondria and nuclei may support communication pathways of mitochondrial retrograde signaling, resulting in transcriptional changes in the nucleus as a survival response. Further characterization of the organelle communication and metabolic dependencies of persisters may suggest strategies to combat recrudescences of malaria after treatment.IMPORTANCEThe major first-line treatment for malaria, especially the deadliest form caused byPlasmodium falciparum, is combination therapy with an artemisinin-based drug (ART) plus a partner drug to assure complete cure. Without an effective partner drug, ART administration alone can fail because of the ability of small populations of blood-stage malaria parasites to enter into a dormant state and survive repeated treatments for a week or more. Understanding the nature of parasites in dormancy (persisters), and their ability to wake and reestablish actively-propagating parasitemias (recrudesce) after ART exposure, may suggest strategies to improve treatment outcomes and counter the threats posed by parasites that develop resistance to partner drugs. Here we show that persisters have dramatically altered mitochondria and mitochondrial-nuclear interactions associated with features of metabolic quiescence. Restructured associations between the mitochondria and nuclei may support signaling pathways that enable the ART survival responses of dormancy.
Inoculation by mosquito induces durable differences in serological profile in non-human primates infected with DENV1
Authors: Rajan Jayant V. , McCracken Michael , Mandel-Brehm Caleigh , Gromowski Greg , Pollett Simon , Jarman Richard , DeRisi Joseph L. 
Published: September 2020

ABSTRACTNatural dengue virus (DENV) infections are delivered by mosquito bite but how the route of inoculation route could shape the humoral immune response is not well understood. Here, we serologically profiled 20 non-human primates (NHP) from a prior study of DENV1 infection in which the animals were inoculated by mosquito (N=10) or subcutaneous injection (N=10). Using a comprehensive, densely tiled and highly redundant pan-flavivirus programmable phage library containing 91,562 overlapping 62 amino acid peptides, we produced a high-resolution map of linear peptide sequences enriched during DENV seroconversion. We found that serological profiles in mosquito-inoculated and subcutaneously-inoculated animals were similar up to 90 days after primary infection, but diverged at 1 year. We found differences in sero-reactivity, as indicated by the median area under the curve (AUC) in the Envelope (E; residues 215-406; p < 0.08), and Nonstructural-3 (NS3; residues 549-615; p < 0.05) proteins in mosquito-inoculated versus subcutaneously-inoculated animals. Within the E protein, residues 339-384 in domain III accounted for >99% of the total AUC difference across residues 215-406. Antibody breadth did not vary by mode of inoculation. The differential reactivity to E domain III (EDIII) seen by phage display validated orthogonally by ELISA, but did not correlate with late neutralization titers. Serological profiling of humoral immune responses to DENV infection in NHP by programmable phage display demonstrated durable differences in sero-reactivity by route of inoculation. These findings could have implications for DENV diagnostics and evaluation of vaccines.IMPORTANCEDengue virus (DENV) infections are transmitted by mosquito bite, but how being infected by mosquito bite affects the immune response is not known. In this study, we analyzed antibodies produced by rhesus macaques infected with DENV using programmable phage display, a high-throughput method for characterizing what viral protein derived peptides serum antibodies bind to. We found that while there was no difference in antibody binding profiles at early timepoints post-infection, at one year post-infection, there were substantial differences in the antibody binding profiles of macaques who were infected by mosquito bite versus those that were infected by injection. In general, antibodies in the macaques inoculated by mosquito maintained higher levels of sero-reactivity, with a strong signal still present one year post-infection. The findings we report could have implications for DENV diagnostics and evaluation of DENV vaccines.
Zinc-binding motif acts as an oxidative stress sensor to regulate TRPM7 channel activity
Authors: Inoue Hana , Murayama Takashi , Kobayashi Takuya , Konishi Masato , Yokoyama Utako 
Published: September 2020

AbstractTRPM7 channel activity is negatively regulated by intracellular Mg2+. We previously reported that TRPM7 was inhibited by oxidative stress due to an enhancement of the inhibition by intracellular Mg2+. In the present study, we aimed to clarify the precise mechanism underlying the TRPM7 inhibition by oxidative stress induced by hydrogen peroxide (H2O2). Site-directed mutagenesis on full-length TRPM7 revealed that none of the cysteines other than C1809 and C1813 within the zinc-binding motif of the TRPM7 kinase domain were involved in the H2O2-induced TRPM7 inhibition. When C1809 or C1813 was mutated, full-length TRPM7 was not expressed on the plasma membrane. We, therefore, developed a novel approach in which the full-length TRPM7 is functionally reconstituted by co-expressing the TRPM7 channel domain (M7cd) and the TRPM7 kinase domain (M7kd) as separate individual proteins in HEK293 cells. When M7cd was expressed alone, the current was inhibited by intracellular Mg2+more strongly than in full-length TRPM7. Co-expression of M7cd and M7kd attenuated the current inhibition by intracellular Mg2+, and the current was sensitive to oxidative stress, indicating successful reconstitution of a full-length TRPM7-like current. A similar current reconstitution was observed when M7cd was co-expressed with the kinase inactive mutant M7kd-K1645R. Thus, it is suggested that the kinase activity is not essential for the reconstitution. Co-expression of M7cd and M7kd carrying a mutation at C1809 or C1813 failed to restore the full-length TRPM7-like current. No reconstitution was also observed with M7kd carrying a mutation at H1750 and H1807, which are involved in the zinc-binding motif formation together with C1809 and C1813. These data suggest that the zinc-binding motif is essential for the intracellular Mg2+-dependent regulation of the TRPM7 channel activity by M7kd, and the cysteines in the zinc-binding motif might play a role in the oxidative stress response of TRPM7.
Pinching the cortex of live cells reveals thickness instabilities caused by Myosin II motors
Authors: Laplaud V. , Levernier N. , Pineau J. , Roman M. San , Barbier L. , Saez P. J. , Lennon A. M. , Vargas P. , Kruse K. , du Roure O. , Piel M. , Heuvingh J. 
Published: September 2020

AbstractThe cell cortex is a contractile actin meshwork, which determines cell shape and is essential for cell mechanics, migration and division. Because the cortical thickness is below optical resolution, it has been generally considered as a thin uniform two-dimensional layer. Using two mutually attracted magnetic beads, one inside the cell and the other in the extracellular medium, we pinch the cortex of dendritic cells and provide an accurate and time resolved measure of its thickness. Our observations draw a new picture of the cell cortex as a highly dynamic layer, harboring large fluctuations in its third dimension due to actomyosin contractility. We propose that the cortex dynamics might be responsible for the fast shape changing capacity of highly contractile cells that use amoeboid-like migration.
Phenology and function in lycopod-Mucoromycotina symbiosis
Authors: Hoysted Grace A. , Bidartondo Martin I. , Duckett Jeffrey G. , Pressel Silvia , Field Katie J. 
Published: September 2020

AbstractLycopodiella inundatais a lycophyte with a complex life cycle. The gametophytes and the juvenile, mature and retreating sporophytes form associations with Mucoromycotina fine root endophyte (MFRE) fungi, being mycoheterotrophic as gametophytes and mutualistic as mature sporophytes. However, the function of the symbiosis across juvenile and retreating sporophyte life stages remains unknown. We measured carbon-for-nutrient exchanges betweenL. inundataand MFRE across the transition from newly emerging sporophytes to mature sporophytes and in retreating adult sporophytes. We show MFRE fungi play distinct functional roles at each plant life stage, with evidence of bidirectional exchange of plant C for fungal acquired nutrients (N and P) between mature adult and retreating adult sporophytes and fungi, but no transfer of plant C to fungi and little fungal-acquired nutrient gain in juvenile sporophytes. Furthermore, we show that these functional stages correspond with different cytologies of colonisation. Our results show that MFRE have considerable plasticity in their interactions with the host plant which is related to the developmental stage of the host. This highlights the need for further research into symbiotic fungal function across plant life histories.
Combining computational controls with natural text reveals new aspects of meaning composition
Authors: Toneva Mariya , Mitchell Tom M. , Wehbe Leila 
Published: September 2020

AbstractTo study a core component of human intelligence—our ability to combine the meaning of words—neuroscientists have looked to theories from linguistics. However, linguistic theories are insufficient to account for all brain responses that reflect linguistic composition. In contrast, we adopt a data-driven computational approach to study the combined meaning of words beyond their individual meaning. We term this product “supra-word meaning” and investigate its neural bases by devising a computational representation for it and using it to predict brain recordings from two imaging modalities with complementary spatial and temporal resolutions. Using functional magnetic resonance imaging, we reveal that hubs that are thought to process lexical-level meaning also maintain supra-word meaning, suggesting a common substrate for lexical and combinatorial semantics. Surprisingly, we cannot detect supra-word meaning in magnetoencephalography, which suggests the hypothesis that composed meaning might be maintained through a different neural mechanism than the synchronized firing of pyramidal cells. This sensitivity difference has implications for past neuroimaging results and future wearable neurotechnology.
Luxotonic signals in human prefrontal cortex as a possible substrate for effects of light on mood and cognition
Authors: Sabbah Shai , Worden Michael S. , Laniado Dimitrios D. , Berson David M. , Sanes Jerome N. 
Published: September 2020

SummaryAnimal studies revealed a mood-regulating neural pathway linking intrinsically photosensitive retinal ganglion cells (ipRGCs) and the prefrontal cortex (PFC), involved in the pathophysiology of mood disorders. As humans too have luminance-encoding ipRGCs, we asked whether a similar pathway exist in humans. Here, fMRI was used to identify PFC regions and other areas exhibiting luminance-dependent signals. We report 29 human brain regions where activation either monotonically decreased or increased with luminance. Luxotonic activity was identified across the cerebral cortex, in diverse subcortical structures, and in the cerebellum, regions that have functions related to visual image formation, motor control, cognition, emotion, and reward processing. Light suppressed PFC activation level, the activation monotonically decreasing with increasing luminance. The sustained time course of light-evoked PFC responses, and their susceptibility to prior light exposure, most closely resembled those of ipRGCs. These findings offer a functional link between light exposure and PFC-mediated cognitive and affective phenomena.
Metabolomic signature of the maternal microbiota in the fetus
Authors: Pessa-Morikawa Tiina , Husso Aleksi , Kärkkäinen Olli , Koistinen Ville , Hanhineva Kati , Iivanainen Antti , Niku Mikael 
Published: September 2020

AbstractThe maternal microbiota affects the development of the offspring by microbial metabolites translocating to the fetus. We investigated samples of placenta, fetal intestine and brain from germ-free (GF) and specific pathogen free (SPF) mouse dams by non-targeted metabolic profiling. One hundred one annotated metabolites and altogether 3680 molecular features were present in significantly different amounts in the placenta and/or fetal organs of GF and SPF mice. The concentrations of more than half of the annotated and differentially expressed metabolites were lower in the GF organs, suggesting their microbial origin or a metabolic response of the host to the presence of gut microbiota. The clearest separation was observed in the placenta. Metabolites that were detected in lower amounts in the fetal organs in the GF mice included 5-aminovaleric acid betaine, trimethylamine N-oxide, catechol-O-sulphate, hippuric and pipecolic acid. Derivatives of the amino acid tryptophan, such as kynurenine, 3-indolepropionic acid and hydroxyindoleacetic acid, were also decreased in the absence of microbiota. Several metabolites had higher levels in the GF mice. These could be precursors of microbial metabolites or indicators of host metabolic response to the absence of gut microbiota. Ninety-nine molecular features were only detected in the SPF mice, suggesting the existence of yet unidentified microbially modified metabolites that potentially influence fetal development.
Predicting age and clinical risk from the neonatal connectome
Authors: Taoudi-Benchekroun Yassine , Christiaens Daan , Grigorescu Irina , Gale-Grant Oliver , Schuh Andreas , Pietsch Maximilian , Chew Andrew , Harper Nicholas , Falconer Shona , Poppe Tanya , Hughes Emer , Hutter Jana , Price Anthony N , Tournier J-Donald , Cordero-Grande Lucilio , Counsell Serena J , Rueckert Daniel , Arichi Tomoki , Hajnal Joseph V , Edwards A David , Deprez Maria , Batalle Dafnis 
Published: September 2020

AbstractThe development of perinatal brain connectivity underpins motor, cognitive and behavioural abilities in later life. Diffusion MRI allows the characterisation of subtle inter-individual differences in structural brain connectivity. Individual brain connectivity maps (connectomes) are by nature high in dimensionality and are complex to interpret. Machine learning methods are a powerful tool to uncover properties of the connectome which are not readily visible, and can give us clues as to how and why individual developmental trajectories differ.In this manuscript we used Deep Neural Networks and Random Forests to predict demographic and neurodevelopmental characteristics from neonatal structural connectomes in a large sample of babies (n = 524) from the developing Human Connectome Project. We achieved an accurate prediction of post menstrual age (PMA) at scan in term-born infants (Mean absolute error (MAE) = 0.72 weeks, r = 0.83 and p<0.001). We also achieved good accuracy when predicting gestational age at birth in a cohort of term and preterm babies scanned at term equivalent age (MAE = 2.21 weeks, r = 0.82, p<0.001). We subsequently used sensitivity analysis to obtain feature relevance from our prediction models, with the most important connections for prediction of PMA and GA found to be predominantly thalamocortical. From our models of PMA at scan for infants born at term, we computed a brain maturation index (predicted age minus actual age) of individual preterm neonates and found a significant correlation between this index and motor outcome at 18 months corrected age. Our results demonstrate the applicability of machine learning techniques in analyses of the neonatal connectome, and suggest that a neural substrate for later developmental outcome is detectable at term equivalent age.
A Probabilistic and Anisotropic Failure Metric for Ascending Thoracic Aortic Aneurysm Risk Stratification
Authors: Liu Minliang , Liang Liang , Zou Qing , Ismail Yasmeen , Lou Xiaoying , Iannucci Glen , Chen Edward P. , Leshnower Bradley G. , Elefteriades John A. , Sun Wei 
Published: September 2020

AbstractExperimental studies have shown that aortic wall tensile strengths in circumferential and longitudinal directions are different (i.e., anisotropic), and vary significantly among patients with aortic aneurysm. To assess aneurysm rupture and dissection risk, material failure metric of the aortic wall needs to be accurately defined and determined. Previously such risk assessment methods have largely relied on deterministic or isotropic failure metric. In this study, we develop a novel probabilistic and anisotropic failure metric for risk stratification of ascending thoracic aortic aneurysm (ATAA). To this end, uniaxial tensile tests were performed using aortic tissue samples of 84 ATAA patients, from which a joint probability distribution of the anisotropic wall strengths was obtained. Next, the anisotropic failure probability (FP) based on the Tsai−Hill (TH) failure criterion was derived. The novel FP metric, which incorporates uncertainty in the anisotropic failure properties, can be evaluated after the aortic wall stresses are computed from patient-specific biomechanical analysis. For method validation, “ground-truth” risks of additional 41 ATAA patients were numerically-reconstructed using corresponding CT images and tissue testing data. Performance of different risk stratification methods (e.g., with and without patient-specific hyperelastic properties) was compared using p-value and receiver operating characteristic (ROC) curve. The results show that: (1) the probabilistic FP metric outperforms the deterministic TH metric; and (2) patient-specific hyperelastic properties can help to improve the performance of probabilistic FP metric in ATAA risk stratification.
Interconversion of unexpected thiol states affects stability, structure and dynamics in engineered antibody for site-specific conjugation
Authors: Orozco C. T. , Edgeworth M. J. , Devine P. W. A. , Hines A. R. , Cornwell O. , Wang X. , Phillips J. J. , Ravn P. , Jackson S. E. , Bond N. J. 
Published: September 2020

AbstractAntibody drug conjugates have become one of the most actively developed classes of drugs in recent years. Their great potential comes from combining the strengths of large and small molecule therapeutics: the exquisite specificity of antibodies and the highly potent nature of cytotoxic compounds. More recently, the approach of engineering antibody drug conjugate scaffolds to achieve highly controlled drug to antibody ratios has focused on substituting or inserting cysteines to facilitate site-specific conjugation. Herein, we characterise an antibody scaffold engineered with an inserted cysteine that formed an unexpected disulfide bridge. A combination of mass spectrometry and biophysical techniques have been used to understand how the additional disulfide bridge forms, interconverts and changes the stability and structural dynamics of the antibody. Insight is gained into the local and global destabilisation associated with the engineering and subsequent disulfide bonded variant that will inform future engineering strategies.
A deep learning algorithm to translate and classify cardiac electrophysiology: From induced pluripotent stem cell-derived cardiomyocytes to adult cardiac cells
Authors: Aghasafari Parya , Yang Pei-Chi , Kernik Divya C. , Sakamoto Kauho , Kanda Yasunari , Kurokawa Junko , Vorobyov Igor , Clancy Colleen E. 
Published: September 2020

AbstractThe development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has been a critical in vitro advance in the study of patient-specific physiology, pathophysiology and pharmacology. We designed a new deep learning multitask network approach intended to address the low throughput, high variability and immature phenotype of the iPSC-CM platform. It was trained using simulated action potential (AP) data and applied to classify cells into the drug-free and drugged categories and to predict the impact of electrophysiological perturbation across the continuum of aging from the immature iPSC-CMs to the adult ventricular myocytes. The phase of the AP extremely sensitive to perturbation due to a steep rise of the membrane resistance was found to contain the key information required for successful network multitasking. We also demonstrated successful translation of both experimental and simulated iPSC-CM AP data validating our network by prediction of experimental drug-induced effects on adult cardiomyocyte APs by the latter.
Identification of a unique ZIP transporter involved in zinc uptake via the arbuscular mycorrhizal fungal pathway
Authors: Watts-Williams Stephanie J , Wege Stefanie , Ramesh Sunita A , Berkowitz Oliver , Gilliham Matthew , Whelan James , Tyerman Stephen D 
Published: September 2020

AbstractLow soil zinc (Zn) availability is a limiting factor for crop yield, and increasing Zn content is a major target for the biofortification of major crops. Arbuscular mycorrhizal (AM) fungi associate with the roots of most terrestrial plant species and improve the host plant’s growth and nutrition through the mycorrhizal pathway of nutrient uptake. Although the physiology of Zn uptake through the mycorrhizal pathway is well established, the identity of the molecular components responsible for Zn transport in the mycorrhizal pathway are unknown.RNA-seq analysis identified the putative Zn transporter geneMtZIP14by its marked up-regulation inMedicago truncatularoots when colonised by the AM fungusRhizophagus irregularisunder varying soil Zn supply. Expression of GFP-tagged MtZIP14 in roots revealed that it is exclusively localised to the site of plant-fungal nutrient exchange in cortical cells, the peri-arbuscular membrane. Expression of MtZIP14 in a yeast mutant lacking Zn transport function restored growth under low Zn availability.M. truncatula MtZIP14loss-of-function mutants had reduced shoot biomass compared to the wild-type when colonised by AM fungi and grown under low Zn. Vesicular and arbuscular colonisation, but not hyphal colonisation, were also lower inmtzip14mutant plants.Based on these results we propose that MtZIP14 plays a key role in the transport of Zn from AM fungus to plant across the peri-arbuscular membrane, andMtZIP14function is crucial to plant competitiveness in a low Zn soil.Significance statementMajority of crop plant species associate with arbuscular mycorrhizal fungi, which can increase plant nutrient uptake. Improving our knowledge of how Zn is taken up in mycorrhizal plants will lead to improved plant and human Zn nutrition outcomes. Here, we report a novel plant transporter with a major role in Zn nutrition of mycorrhizal plants. MtZIP14 is involved in Zn transport, is exclusively localised to the specialised plant-fungal interface in roots, and impairment ofMtZIP14gene function results in negative impacts on both plant growth and Zn nutrition.