Helminth parasites secrete extracellular vesicles (EVs) that can be internalised by host immune cells resulting in modulation of host immunity. While the molecular cargo of EVs have been ...characterised in many parasites, little is known about the surface-exposed molecules that participate in ligand-receptor interactions with the host cell surface to initiate vesicle docking and subsequent internalisation. Using a membrane-impermeable biotin reagent to capture proteins displayed on the outer membrane surface of two EV sub-populations (termed 15k and 120k EVs) released by adult F. hepatica, we describe 380 surface proteins including an array of virulence factors, membrane transport proteins and molecules involved in EV biogenesis/trafficking. Proteomics and immunohistochemical analysis show that the 120k EVs have an endosomal origin and may be released from the parasite via the protonephridial (excretory) system whilst the larger 15k EVs are released from the gastrodermal epithelial cells that line the fluke gut. A parallel lectin microarray strategy was used to profile the topology of major surface oligosaccharides of intact fluorogenically-labelled EVs as they would be displayed to the host. Lectin profiles corresponding to glycoconjugates exposed on the surface of the 15 K and 120K EV sub-populations are practically identical but are distinct from those of the parasite surface tegument, although all are predominated by high mannose sugars. We found that while the F. hepatica EVs were resistant to exo- and endo-glycosidases, the glyco-amidase PNGase F drastically remodelled the surface oligosaccharides and blocked the uptake of EVs by host macrophages. In contrast, pre-treatment with antibodies obtained from infected hosts, or purified antibodies raised against the extracellular domains of specific EV surface proteins (DM9-containing protein, CD63 receptor and myoferlin), significantly enhanced their cellular internalisation. This work highlights the diversity of EV biogenesis and trafficking pathways used by F. hepatica and sheds light on the molecular interaction between parasite EVs and host cells.
Studies have shown that the remnants of destroyed planets and debris-disk planetesimals can survive the volatile evolution of their host stars into white dwarfs, but few intact planetary bodies ...around white dwarfs have been detected. Simulations predict that planets in Jupiter-like orbits around stars of ≲8 Mꙩ (solar mass) avoid being destroyed by the strong tidal forces of their stellar host, but as yet, there has been no observational confirmation of such a survivor. Here we report the non-detection of a main-sequence lens star in the microlensing event MOA-2010-BLG-477Lb using near-infrared observations from the Keck Observatory. We determine that this system contains a 0.53 ± 0.11 Mꙩ white-dwarf host orbited by a 1.4 ± 0.3 Jupiter-mass planet with a separation on the plane of the sky of 2.8 ± 0.5 astronomical units, which implies a semi-major axis larger than this. This system is evidence that planets around white dwarfs can survive the giant and asymptotic giant phases of their host’s evolution, and supports the prediction that more than half of white dwarfs have Jovian planetary companions. Located at approximately 2.0 kiloparsecs towards the center of our Galaxy, it is likely to represent an analogue to the end stages of the Sun and Jupiter in our own Solar System.
A critical issue for geologic carbon sequestration is the ability to detect CO2 in the vadose zone. Here we present a new process‐based approach to identify CO2 that has leaked from deep geologic ...storage reservoirs into the shallow subsurface. Whereas current CO2concentration‐based methods require years of background measurements to quantify variability of natural vadose zone CO2, this new approach examines chemical relationships between vadose zone N2, O2, CO2, and CH4 to promptly distinguish a leakage signal from natural vadose zone CO2. The method uses sequential inspection of the following gas concentration relationships: 1) O2 versus CO2to distinguish in‐situ vadose zone background processes (biologic respiration, methane oxidation, and CO2 dissolution) from exogenous deep leakage input, 2) CO2 versus N2 to further distinguish dissolution of CO2 from exogenous deep leakage input, and 3) CO2 versus N2/O2 to assess the degree of respiration, CH4 oxidation and atmospheric mixing/dilution occurring in the system. The approach was developed at a natural CO2‐rich control site and successfully applied at an engineered site where deep gases migrated into the vadose zone. The ability to identify gas leakage into the vadose zone without the need for background measurements could decrease uncertainty in leakage detection and expedite implementation of future geologic CO2 storage projects.
Key Points
Gas relationships show carbon cycling processes
Method is an innovative new way to distinguish CO2 leakage from depth
The method has broad implications for geoscience
Progranulin is a secreted growth factor that is active in tumorigenesis, wound repair, and inflammation. Haploinsufficiency of the human progranulin gene, GRN, causes frontotemporal dementia. ...Progranulins are composed of chains of cysteine-rich granulin modules. Modules may be released from progranulin by proteolysis as 6kDa granulin polypeptides. Both intact progranulin and some of the granulin polypeptides are biologically active. The granulin module occurs in certain plant proteases and progranulins are present in early diverging metazoan clades such as the sponges, indicating their ancient evolutionary origin. There is only one Grn gene in mammalian genomes. More gene-rich Grn families occur in teleost fish with between 3 and 6 members per species including short-form Grns that have no tetrapod counterparts. Our goals are to elucidate progranulin and granulin module evolution by investigating (i): the origins of metazoan progranulins (ii): the evolutionary relationships between the single Grn of tetrapods and the multiple Grn genes of fish (iii): the evolution of granulin module architectures of vertebrate progranulins (iv): the conservation of mammalian granulin polypeptide sequences and how the conserved granulin amino acid sequences map to the known three dimensional structures of granulin modules. We report that progranulin-like proteins are present in unicellular eukaryotes that are closely related to metazoa suggesting that progranulin is among the earliest extracellular regulatory proteins still employed by multicellular animals. From the genomes of the elephant shark and coelacanth we identified contemporary representatives of a precursor for short-from Grn genes of ray-finned fish that is lost in tetrapods. In vertebrate Grns pathways of exon duplication resulted in a conserved module architecture at the amino-terminus that is frequently accompanied by an unusual pattern of tandem nearly identical module repeats near the carboxyl-terminus. Polypeptide sequence conservation of mammalian granulin modules identified potential structure-activity relationships that may be informative in designing progranulin based therapeutics.
ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful ...therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned >50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG's). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network "hub" gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF's involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients.
Lysyl-tRNA synthetase (LysRS), a component of the translation apparatus, is released from the cytoplasmic multi-tRNA synthetase complex (MSC) to activate the transcription factor MITF in stimulated ...mast cells through undefined mechanisms. Here we show that Ser207 phosphorylation provokes a new conformer of LysRS that inactivates its translational function but activates its transcriptional function. The crystal structure of an MSC subcomplex established that LysRS is held in the MSC by binding to the N terminus of the scaffold protein p38/AIMP2. Phosphorylation-created steric clashes at the LysRS domain interface disrupt its binding grooves for p38/AIMP2, releasing LysRS and provoking its nuclear translocation. This alteration also exposes the C-terminal domain of LysRS to bind to MITF and triggers LysRS-directed production of the second messenger Ap4A that activates MITF. Thus our results establish that a single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription.
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► Phosphorylation of Ser207 triggers a structural opening of LysRS in mast cell ► The open conformer releases LysRS from the multi-tRNA-synthetase complex ► It traps tRNA in an inactive state and switches off the canonical function of LysRS ► It drives Ap4A production and LysRS-MITF interaction for gene transcription in cell
ABSTRACT We report the results of the statistical analysis of planetary signals discovered in MOA-II microlensing survey alert system events from 2007 to 2012. We determine the survey sensitivity as ...a function of planet-star mass ratio, q, and projected planet-star separation, s, in Einstein radius units. We find that the mass-ratio function is not a single power law, but has a change in slope at q ∼ 10−4, corresponding to ∼20 M⊕ for the median host-star mass of ∼0.6 . We find significant planetary signals in 23 of the 1474 alert events that are well-characterized by the MOA-II survey data alone. Data from other groups are used only to characterize planetary signals that have been identified in the MOA data alone. The distribution of mass ratios and separations of the planets found in our sample are well fit by a broken power-law model of the form for q > qbr and for q < qbr, where qbr is the mass ratio of the break. We also combine this analysis with the previous analyses of Gould et al. and Cassan et al., bringing the total sample to 30 planets. This combined analysis yields , n = −0.93 0.13, , and for qbr 1.7 × 10−4. The unbroken power-law model is disfavored with a p-value of 0.0022, which corresponds to a Bayes factor of 27 favoring the broken power-law model. These results imply that cold Neptunes are likely to be the most common type of planets beyond the snow line.
Mutation of human
GRN
, the gene encoding the secreted glycoprotein progranulin, results in a form of frontotemporal lobar degeneration that is characterized by the presence of ubiquitinated ...inclusions containing phosphorylated and cleaved fragments of the transactivation response element DNA-binding protein-43. This has stimulated interest in understanding the role of progranulin in the central nervous system, and in particular, how this relates to neurodegeneration. Progranulin has many roles outside the brain, including regulation of cellular proliferation, survival, and migration, in cancer, including cancers of the brain, in wound repair, and inflammation. It often acts through the extracellular signal-regulated kinase and phopshatidylinositol-3-kinases pathways. The neurobiology of progranulin has followed a similar pattern with proposed roles for progranulin (PGRN) in the central nervous system as a neuroprotective agent and in neuroinflammation. Here we review the structure, biology, and mechanism of progranulin action. By understanding PGRN in a wider context, we may be better able to delineate its roles in the normal brain and in neurodegenerative disease.
Objective
To investigate the relation between vaginal microbiota composition and outcome of rescue cervical cerclage.
Design
Prospective observational study.
Setting
Queen Charlotte's and Chelsea ...Hospital, London.
Population
Twenty singleton pregnancies undergoing a rescue cervical cerclage.
Methods
Vaginal microbiota composition was analysed in women presenting with a dilated cervix and exposed fetal membranes before and 10 days following rescue cervical cerclage and was correlated with clinical outcomes.
Main outcome measures
Composition of vaginal bacteria was characterised by culture‐independent next generation sequencing. Successful cerclage was defined as that resulting in the birth of a neonate discharged from hospital without morbidity. Unsuccessful cerclage was defined as procedures culminating in miscarriage, intrauterine death, neonatal death or significant neonatal morbidity.
Results
Reduced Lactobacillus spp. relative abundance was observed in 40% of cases prior to rescue cerclage compared with 10% of gestation age‐matched controls (8/20, 40% versus 3/30, 10%, P = 0.017). Gardnerella vaginalis was over‐represented in women presenting with symptoms (3/7, 43% versus 0/13, 0%, P = 0.03, linear discriminant analysis, LDA (log 10) and cases culminating in miscarriage (3/6, 50% versus 0/14, 0%, P = 0.017). In the majority of cases (10/14, 71%) bacterial composition was unchanged following cerclage insertion and perioperative interventions.
Conclusions
Reduced relative abundance of Lactobacillus spp. is associated with premature cervical dilation, whereas high levels of G. vaginalis are associated with unsuccessful rescue cerclage cases. The insertion of a rescue cerclage does not affect the underlying bacterial composition in the majority of cases.
Tweetable
Preterm cervical dilatation associates with reduced Lactobacillus spp. Presence of Gardnerella vaginalis predicts rescue cerclage failure.
Tweetable
Preterm cervical dilatation associates with reduced Lactobacillus spp. Presence of Gardnerella vaginalis predicts rescue cerclage failure.
Abstract
The PRime-focus Infrared Microlensing Experiment (PRIME) will be the first to conduct a dedicated near-infrared microlensing survey by using a 1.8 m telescope with a wide field of view of ...1.45 deg
2
at the South African Astronomical Observatory. The major goals of the PRIME microlensing survey are to measure the microlensing event rate in the inner Galactic bulge to help design the observing strategy for the exoplanet microlensing survey by the Nancy Grace Roman Space Telescope and to make a first statistical measurement of exoplanet demographics in the central bulge fields where optical observations are very difficult owing to the high extinction in these fields. Here we conduct a simulation of the PRIME microlensing survey to estimate its planet yields and determine the optimal survey strategy, using a Galactic model optimized for the inner Galactic bulge. In order to maximize the number of planet detections and the range of planet mass, we compare the planet yields among four observation strategies. Assuming the Cassan et al. mass function as modified by Penny et al., we predict that PRIME will detect planetary signals for 42–52 planets (1–2 planets with
M
p
≤ 1
M
⊕
, 22−25 planets with mass 1
M
⊕
<
M
p
≤ 100
M
⊕
, 19–25 planets 100
M
⊕
<
M
p
≤ 10, 000
M
⊕
), per year depending on the chosen observation strategy.
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