Wildlife disease surveillance and pathogen detection are fundamental for conservation, population sustainability, and public health. Detection of pathogens in snakes is often overlooked despite their ...essential roles as both predators and prey within their communities. Ophidiomycosis (formerly referred to as Snake Fungal Disease, SFD), an emergent disease on the North American landscape caused by the fungus Ophidiomyces ophiodiicola, poses a threat to snake population health and stability. We tested 657 individual snakes representing 58 species in 31 states from 56 military bases in the continental US and Puerto Rico for O. ophiodiicola. Ophidiomyces ophiodiicola DNA was detected in samples from 113 snakes for a prevalence of 17.2% (95% CI: 14.4-20.3%), representing 25 species from 19 states/territories, including the first reports of the pathogen in snakes in Idaho, Oklahoma, and Puerto Rico. Most animals were ophidiomycosis negative (n = 462), with Ophidiomyces detected by qPCR (n = 64), possible ophidiomycosis (n = 82), and apparent ophidiomycosis (n = 49) occurring less frequently. Adults had 2.38 times greater odds than juveniles of being diagnosed with ophidiomycosis. Snakes from Georgia, Massachusetts, Pennsylvania, and Virginia all had greater odds of ophidiomycosis diagnosis, while snakes from Idaho were less likely to be diagnosed with ophidiomycosis. The results of this survey indicate that this pathogen is endemic in the eastern US and identified new sites that could represent emergence or improved detection of endemic sites. The direct mortality of snakes with ophidiomycosis is unknown from this study, but the presence of numerous individuals with clinical disease warrants further investigation and possible conservation action.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Virus-like particles (VLPs) of bacteriophage MS2 possess numerous features that make them well-suited for use in targeted delivery of therapeutic and imaging agents. MS2 VLPs can be rapidly produced ...in large quantities using in vivo or in vitro synthesis techniques. Their capsids can be modified in precise locations via genetic insertion or chemical conjugation, facilitating the multivalent display of targeting ligands. MS2 VLPs also self-assemble in the presence of nucleic acids to specifically encapsidate siRNA and RNA-modified cargos. Here we report the use of MS2 VLPs to selectively deliver nanoparticles, chemotherapeutic drugs, siRNA cocktails, and protein toxins to human hepatocellular carcinoma (HCC). MS2 VLPs modified with a peptide (SP94) that binds HCC exhibit a 104-fold higher avidity for HCC than for hepatocytes, endothelial cells, monocytes, or lymphocytes and can deliver high concentrations of encapsidated cargo to the cytosol of HCC cells. SP94-targeted VLPs loaded with doxorubicin, cisplatin, and 5-fluorouracil selectively kill the HCC cell line, Hep3B, at drug concentrations <1 nM, while SP94-targeted VLPs that encapsidate a siRNA cocktail, which silences expression of cyclin family members, induce growth arrest and apoptosis of Hep3B at siRNA concentrations <150 pM. Impressively, MS2 VLPs, when loaded with ricin toxin A-chain (RTA) and modified to codisplay the SP94 targeting peptide and a histidine-rich fusogenic peptide (H5WYG) that promotes endosomal escape, kill virtually the entire population of Hep3B cells at an RTA concentration of 100 fM without affecting the viability of control cells. Our results demonstrate that MS2 VLPs, because of their tolerance of multivalent peptide display and their ability to specifically encapsidate a variety of chemically disparate cargos, induce selective cytotoxicity of cancer in vitro and represent a significant improvement in the characteristics of VLP-based delivery systems.
The northern North Sea rift evolved through multiple rift phases within a highly heterogeneous crystalline basement. The geometry and evolution of syn‐rift depocenters during this multiphase ...evolution and the mechanisms and extent to which they were influenced by preexisting structural heterogeneities remain elusive, particularly at the regional scale. Using an extensive database of borehole‐constrained 2D seismic reflection data, we examine how the physiography of the northern North Sea rift evolved throughout late Permian‐Early Triassic (RP1) and Late Jurassic‐Early Cretaceous (RP2) rift phases, and assess the influence of basement structures related to the Caledonian orogeny and subsequent Devonian extension. During RP1, the location of major depocenters, the Stord and East Shetland basins, was controlled by favorably oriented Devonian shear zones. RP2 shows a diminished influence from structural heterogeneities, activity localizes along the Viking‐Sogn graben system and the East Shetland Basin, with negligible activity in the Stord Basin and Horda Platform. The Utsira High and the Devonian Lomre Shear Zone form the eastern barrier to rift activity during RP2. Toward the end of RP2, rift activity migrated northward as extension related to opening of the proto‐North Atlantic becomes the dominant regional stress as rift activity in the northern North Sea decreases. Through documenting the evolving syn‐rift depocenters of the northern North Sea rift, we show how structural heterogeneities and prior rift phases influence regional rift physiography and kinematics, controlling the segmentation of depocenters, as well as the locations, styles, and magnitude of fault activity and reactivation during subsequent events.
Key Points
The regional evolution of the northern North Sea rift is documented throughout late Permian‐early Triassic and Late Jurassic‐Early Cretaceous rift phases
Preexisting structural heterogeneities may control the initial geometry of rift‐related faults and associated syn‐rift depocenters when favorably oriented, and may also segment faults and depocenters
Rift activity migrates throughout the evolution of the rift, showing a decreased influence from structural inheritance and increased localization of activity during subsequent phases
Pre-existing structures within crystalline basement may exert a significant influence over the evolution of rifts. However, the exact manner in which these structures reactivate and thus their degree ...of influence over the overlying rift is poorly understood. Using borehole-constrained 2D and 3D seismic reflection data from offshore southern Norway we identify and constrain the three-dimensional geometry of a series of enigmatic intrabasement reflections. Through 1D waveform modelling and 3D mapping of these reflection packages, we correlate them to the onshore Caledonian thrust belt and Devonian shear zones. Based on the seismic-stratigraphic architecture of the post-basement succession, we identify several phases of reactivation of the intrabasement structures associated with multiple tectonic events. Reactivation preferentially occurs along relatively thick (c. 1 km), relatively steeply dipping (c. 30°) structures, with three main styles of interactions observed between them and overlying faults: i) faults exploiting intrabasement weaknesses represented by intra-shear zone mylonites; ii) faults that initiate within the hangingwall of the shear zones, inheriting their orientation and merging with said structure at depth; or iii) faults that initiate independently from and cross-cut intrabasement structures. We demonstrate that large-scale discrete shear zones act as a long-lived structural template for fault initiation during multiple phases of rifting.
•2D and 3D seismic reflection data used to constrain the 3D geometry of structures within crystalline basement.•Mapped structures linked to onshore mylonitic layers within the onshore Caledonian thrust belt and Devonian shear zones.•Brittle reactivation of selected intrabasement structures during multiple phases of continental rifting.•Multiple styles of interaction observed between the intrabasement structure and rift-related faults.•Devonian shear zones act as a long-lived structural template for the initiation of later rift-related faults.
Snake fungal disease (SFD) is a clinical syndrome associated with dermatitis, myositis, osteomyelitis, and pneumonia in several species of free-ranging snakes in the US. The causative agent has been ...suggested as Ophidiomyces ophiodiicola, but other agents may contribute to the syndrome and the pathogenesis is not understood. To understand the role of O. ophiodiicola in SFD, a cottonmouth snake model of SFD was designed. Five cottonmouths (Agkistrodon piscivorous) were experimentally challenged by nasolabial pit inoculation with a pure culture of O. ophiodiicola. Development of skin lesions or facial swelling at the site of inoculation was observed in all snakes. Twice weekly swabs of the inoculation site revealed variable presence of O. ophiodiicola DNA by qPCR in all five inoculated snakes for 3 to 58 days post-inoculation; nasolabial flushes were not a useful sampling method for detection. Inoculated snakes had a 40% mortality rate. All inoculated snakes had microscopic lesions unilaterally on the side of the swabbed nasolabial pit, including erosions to ulcerations and heterophilic dermatitis. All signs were consistent with SFD; however, the severity of lesions varied in individual snakes, and fungal hyphae were only observed in 3 of 5 inoculated snakes. These three snakes correlated with post-mortem tissue qPCR evidence of O. ophiodiicola. The findings of this study conclude that O. ophiodiicola inoculation in a cottonmouth snake model leads to disease similar to SFD, although lesion severity and the fungal load are quite variable within the model. Future studies may utilize this model to further understand the pathogenesis of this disease and develop management strategies that mitigate disease effects, but investigation of other models with less variability may be warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. Maternal GBS colonization is associated with early-onset neonatal sepsis and extensive efforts are directed to preventing this complication. Less is known about maternal risks of GBS ...colonization. We seek to provide a modern estimate of the incidence and impact of maternal GBS colonization and invasive GBS disease. Methods. A single center historical cohort study of all births between 2003 and 2015 was performed. Data was collected via electronic health record abstraction using an institutional specific tool. Descriptive statistics were performed regarding GBS status. Inferential statistics were performed comparing risk of adverse pregnancy outcomes in cohorts with and without GBS colonization as well as cohorts with GBS colonization and invasive GBS disease. Results. A total of 60,029 deliveries were included for analysis. Overall, 21.6% of the population was GBS colonized and 0.1% had invasive GBS disease. GBS colonization was associated with younger maternal age, Black race, non-Hispanic ethnicity, chronic hypertension, preexisting diabetes, and tobacco use (p<0.01). In the adjusted analyses, there was an increased risk of gestational diabetes (aRR 1.21, 95% CI 1.11-1.32) in colonized pregnancies and a decreased incidence of short cervix (aRR 0.64, 95% CI 0.52-0.79), chorioamnionitis (aRR 0.76, 95% CI 0.66-0.87), wound infection (aRR 0.75, 95% CI 0.64-0.88), and operative delivery (aRR 0.85, 95% CI 0.83-0.88). Conclusions. This modern-day large cohort of all births over a 12-year period demonstrates a GBS colonization rate of 21.6%. This data reflects a need to assess maternal and perinatal outcomes in addition to neonatal GBS sepsis rates to inform decisions regarding the utility of maternal vaccination.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules ...governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
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•A scRNA-seq study reveals shared and distinct features of human MMRd and MMRp CRC•Co-variation of single-cell transcriptional programs across specimens predicts immune hubs•A myeloid-rich inflammatory hub is identified below the colonic lumen in human CRC•CXCR3-ligand+ cells form foci with activated T cells in human MMRd CRC
Single-cell transcriptomics-based co-variation analysis of human colorectal cancer identifies a spatially resolved myeloid-rich inflammatory hub that is shared by mismatch repair-deficient (MMRd) and mismatch repair-proficient (MMRp) tumors and CXCR3-ligand+ multicellular foci distinct for MMRd tumors.
Abstract
Exoplanet detection with precise radial velocity (RV) observations is currently limited by spurious RV signals introduced by stellar activity. We show that machine-learning techniques such ...as linear regression and neural networks can effectively remove the activity signals (due to starspots/faculae) from RV observations. Previous efforts focused on carefully filtering out activity signals in time using modeling techniques like Gaussian process regression. Instead, we systematically remove activity signals using only changes to the average shape of spectral lines, and use no timing information. We trained our machine-learning models on both simulated data (generated with the SOAP 2.0 software) and observations of the Sun from the HARPS-N Solar Telescope. We find that these techniques can predict and remove stellar activity both from simulated data (improving RV scatter from 82 to 3 cm s
−1
) and from more than 600 real observations taken nearly daily over 3 yr with the HARPS-N Solar Telescope (improving the RV scatter from 1.753 to 1.039 m s
−1
, a factor of ∼1.7 improvement). In the future, these or similar techniques could remove activity signals from observations of stars outside our solar system and eventually help detect habitable-zone Earth-mass exoplanets around Sun-like stars.
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