Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and ...Drug Administration (FDA) for another indication is a more rapid and less expensive option. We present DRIAD (Drug Repurposing In AD), a machine learning framework that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD is applied to lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs are inspected for common trends among their targets. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be readily evaluated in a clinical trial.
Freshwater fauna are particularly sensitive to environmental change and disturbance. Management agencies frequently use fish and amphibian biodiversity as indicators of ecosystem health and a way to ...prioritize and assess management strategies. Traditional aquatic bioassessment that relies on capture of organisms via nets, traps and electrofishing gear typically has low detection probabilities for rare species and can injure individuals of protected species. Our objective was to determine whether environmental DNA (eDNA) sampling and metabarcoding analysis can be used to accurately measure species diversity in aquatic assemblages with differing structures. We manipulated the density and relative abundance of eight fish and one amphibian species in replicated 206‐L mesocosms. Environmental DNA was filtered from water samples, and six mitochondrial gene fragments were Illumina‐sequenced to measure species diversity in each mesocosm. Metabarcoding detected all nine species in all treatment replicates. Additionally, we found a modest, but positive relationship between species abundance and sequencing read abundance. Our results illustrate the potential for eDNA sampling and metabarcoding approaches to improve quantification of aquatic species diversity in natural environments and point the way towards using eDNA metabarcoding as an index of macrofaunal species abundance.
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Despite its widespread clinical use in load-bearing orthopedic implants, polyether-ether-ketone (PEEK) is often associated with poor osseointegration. In this study, a surface-porous ...PEEK material (PEEK-SP) was created using a melt extrusion technique. The porous layer was 399.6±63.3μm thick and possessed a mean pore size of 279.9±31.6μm, strut spacing of 186.8±55.5μm, porosity of 67.3±3.1% and interconnectivity of 99.9±0.1%. Monotonic tensile tests showed that PEEK-SP preserved 73.9% of the strength (71.06±2.17MPa) and 73.4% of the elastic modulus (2.45±0.31GPa) of as-received, injection-molded PEEK. PEEK-SP further demonstrated a fatigue strength of 60.0MPa at one million cycles, preserving 73.4% of the fatigue resistance of injection-molded PEEK. Interfacial shear testing showed the pore layer shear strength to be 23.96±2.26MPa. An osseointegration model in the rat revealed substantial bone formation within the pore layer at 6 and 12weeks via microcomputed tomography and histological evaluation. Ingrown bone was more closely apposed to the pore wall and fibrous tissue growth was reduced in PEEK-SP when compared to non-porous PEEK controls. These results indicate that PEEK-SP could provide improved osseointegration while maintaining the structural integrity necessary for load-bearing orthopedic applications.
Species richness is a metric of biodiversity that represents the number of species present in a community. Traditional fisheries assessments that rely on capture of organisms often underestimate true ...species richness. Environmental DNA (eDNA) metabarcoding is an alternative tool that infers species richness by collecting and sequencing DNA present in the ecosystem. Our objective was to determine how spatial distribution of samples and “bioinformatic stringency” affected eDNA-metabarcoding estimates of species richness compared with capture-based estimates in a 2.2 ha reservoir. When bioinformatic criteria required species to be detected only in a single sample, eDNA metabarcoding detected all species captured with traditional methods plus an additional 11 noncaptured species. However, when we required species to be detected with multiple markers and in multiple samples, eDNA metabarcoding detected only seven of the captured species. Our analysis of the spatial patterns of species detection indicated that eDNA was distributed relatively homogeneously throughout the reservoir, except near the inflowing stream. We suggest that interpretation of eDNA metabarcoding data must consider the potential effects of water body type, spatial resolution, and bioinformatic stringency.
The foundation for any ecological study and for the effective management of biodiversity in natural systems requires knowing what species are present in an ecosystem. We assessed fish communities in ...a stream using two methods, depletion‐based electrofishing and environmental DNA metabarcoding (eDNA) from water samples, to test the hypothesis that eDNA provides an alternative means of determining species richness and species identities for a natural ecosystem. In a northern Indiana stream, electrofishing yielded a direct estimate of 12 species and a mean estimated richness (Chao II estimator) of 16.6 species with a 95% confidence interval from 12.8 to 42.2. eDNA sampling detected an additional four species, congruent with the mean Chao II estimate from electrofishing. This increased detection rate for fish species between methods suggests that eDNA sampling can enhance estimation of fish fauna in flowing waters while having minimal sampling impacts on fish and their habitat. Modern genetic approaches therefore have the potential to transform our ability to build a more complete list of species for ecological investigations and inform management of aquatic ecosystems.
The foundation for any ecological study and the effective management of biodiversity in natural systems requires knowing what species are present in an ecosystem. Using environmental DNA and metabarcoding techniques to assess the fish species present in a stream environment, we demonstrate molecular techniques can identify all 12 species captured by traditional means along with four additional species not captured. This increased detection rate for fish species between methods suggests that eDNA sampling can enhance estimation of fish fauna in flowing waters while having minimal sampling impacts on fish and their habitat.
Background
Despite its widespread use in orthopaedic implants such as soft tissue fasteners and spinal intervertebral implants, polyetheretherketone (PEEK) often suffers from poor osseointegration. ...Introducing porosity can overcome this limitation by encouraging bone ingrowth; however, the corresponding decrease in implant strength can potentially reduce the implant’s ability to bear physiologic loads. We have previously shown, using a single pore size, that limiting porosity to the surface of PEEK implants preserves strength while supporting in vivo osseointegration. However, additional work is needed to investigate the effect of pore size on both the mechanical properties and cellular response to PEEK.
Questions/purposes
(1) Can surface porous PEEK (PEEK-SP) microstructure be reliably controlled? (2) What is the effect of pore size on the mechanical properties of PEEK-SP? (3) Do surface porosity and pore size influence the cellular response to PEEK?
Methods
PEEK-SP was created by extruding PEEK through NaCl crystals of three controlled ranges: 200 to 312, 312 to 425, and 425 to 508 µm. Micro-CT was used to characterize the microstructure of PEEK-SP. Tensile, fatigue, and interfacial shear tests were performed to compare the mechanical properties of PEEK-SP with injection-molded PEEK (PEEK-IM). The cellular response to PEEK-SP, assessed by proliferation, alkaline phosphatase activity, vascular endothelial growth factor production, and calcium content of osteoblast, mesenchymal stem cell, and preosteoblast (MC3T3-E1) cultures, was compared with that of machined smooth PEEK and Ti6Al4V.
Results
Micro-CT analysis showed that PEEK-SP layers possessed pores that were 284 ± 35 µm, 341 ± 49 µm, and 416 ± 54 µm for each pore size group. Porosity and pore layer depth ranged from 61% to 69% and 303 to 391 µm, respectively. Mechanical testing revealed tensile strengths > 67 MPa and interfacial shear strengths > 20 MPa for all three pore size groups. All PEEK-SP groups exhibited > 50% decrease in ductility compared with PEEK-IM and demonstrated fatigue strength > 38 MPa at one million cycles. All PEEK-SP groups also supported greater proliferation and cell-mediated mineralization compared with smooth PEEK and Ti6Al4V.
Conclusions
The PEEK-SP formulations evaluated in this study maintained favorable mechanical properties that merit further investigation into their use in load-bearing orthopaedic applications and supported greater in vitro osteogenic differentiation compared with smooth PEEK and Ti6Al4V. These results are independent of pore sizes ranging 200 µm to 508 µm.
Clinical Relevance
PEEK-SP may provide enhanced osseointegration compared with current implants while maintaining the structural integrity to be considered for several load-bearing orthopaedic applications such as spinal fusion or soft tissue repair.
The ability to control the surface topography of orthopedic implant materials is desired to improve osseointegration but is often at the expense of mechanical performance in load bearing ...environments. Here we investigate the effects of surface modifications, roughness and porosity, on the mechanical properties of a set of polymers with diverse chemistry and structure. Both roughness and surface porosity resulted in samples with lower strength, failure strain and fatigue life due to stress concentrations at the surface; however, the decrease in ductility and fatigue strength were greater than the decrease in monotonic strength. The fatigue properties of the injection molded polymers did not correlate with yield strength as would be traditionally observed in metals. Rather, the fatigue properties and the capacity to maintain properties with the introduction of surface porosity correlated with the fracture toughness of the polymers. Polymer structure impacted the materials relative capacity to maintain monotonic and cyclic properties in the face of surface texture and porosity. Generally, amorphous polymers with large ratios of upper to lower yield points demonstrated a more significant drop in ductility and fatigue strength with the introduction of porosity compared to crystalline polymers with smaller ratios in their upper to lower yield strength. The latter materials have more effective dissipation mechanisms to minimize the impact of surface porosity on both monotonic and cyclic damage.
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•Surface roughness and porosity significantly decrease the toughness of polymers.•Greatest effect of surface defects is significant decrease in ductility.•Fracture toughness correlates with and predicts notched polymer properties.•Crystalline polymers are more resistant to defects due to two-phase structure.•Shape of the stress–strain curve important in determining the sensitivity to notches.
We herein discuss the use of 1,1-diphosphineamide ligands for the synthesis of mono- and heterobimetallic complexes of Rh(I) and Ti(IV) metal centers. A small library of monometallic species was ...synthesized and isolated: Ti was used to complex to the amide moiety, whereas Rh was used to bind to the diphosphine. The sequential synthesis of the heterobimetallic species started from isolation of the Ti(amidate) complex followed by addition of Rh precursors in solution. Meticulous analysis of the complexes by NMR spectroscopy allowed stereometric and spatial recognition of these challenging to synthesize and isolate heterobimetallic complexes.
The ability to properly identify species present in a landscape is foundational to ecology and essential for natural resource management and conservation. However, many species are often unaccounted ...for due to ineffective direct capture and visual surveys, especially in aquatic environments. Environmental DNA metabarcoding is an approach that overcomes low detection probabilities and should consequently enhance estimates of biodiversity and its proxy, species richness. Here, we synthesize 37 studies in natural aquatic systems to compare species richness estimates for bony fish between eDNA metabarcoding and conventional methods, such as nets, visual census, and electrofishing. In freshwater systems with fewer than 100 species, we found eDNA metabarcoding detected more species than conventional methods. Using multiple genetic markers further increased species richness estimates with eDNA metabarcoding. For more diverse freshwater systems and across marine systems, eDNA metabarcoding reported similar values of species richness to conventional methods; however, more studies are needed in these environments to better evaluate relative performance. In systems with greater biodiversity, eDNA metabarcoding will require more populated reference databases, increased sampling effort, and multi-marker assays to ensure robust species richness estimates to further validate the approach. eDNA metabarcoding is reliable and provides a path for broader biodiversity assessments that can outperform conventional methods for estimating species richness.
Surface porous polyether-ether-ketone has the ability to maintain the tensile monotonic and cyclic strength necessary for many load bearing orthopedic applications while providing a surface that ...facilitates bone ingrowth; however, the relevant deformation behavior of the pore architecture in response to various loading conditions is not yet fully characterized or understood. The focus of this study was to examine the compressive and wear behavior of the surface porous architecture using micro Computed Tomography (micro CT). Pore architectures of various depths (~0.5–2.5mm) and pore sizes (212–508µm) were manufactured using a melt extrusion and porogen leaching process. Compression testing revealed that the pore architecture deforms in the typical three staged linear elastic, plastic, and densification stages characteristic of porous materials. The experimental moduli and yield strengths decreased as the porosity increased but there was no difference in properties between pore sizes. The porous architecture maintained a high degree of porosity available for bone-ingrowth at all strains. Surface porous samples showed no increase in wear rate compared to injection molded samples, with slight pore densification accompanying wear.
•Porous compressive response occurs in three stages as predicted by foam theory.•At 50% strain, porous regions still offer high porosity for bone ingrowth.•No increase in mass loss occurs in abrasion of surface porous samples.
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