Neuronal subpopulations display differential vulnerabilities to disease, but the factors that determine their susceptibility are poorly understood. Toxic increases in intracellular calcium are a key ...factor in several neurodegenerative processes, with calcium-binding proteins providing an important first line of defense through their ability to buffer incoming calcium, allowing the neuron to quickly achieve homeostasis. Since neurons expressing different calcium-binding proteins have been reported to be differentially susceptible to degeneration, it can be hypothesized that rather than just serving as markers of different neuronal subpopulations, they might actually be a key determinant of survival. In this review, we will summarize some of the evidence that expression of the EF-hand calcium-binding proteins, calbindin, calretinin and parvalbumin, may influence the susceptibility of distinct neuronal subpopulations to disease processes.
Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of ...patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
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•Efficient generation of a biobank of patient-derived bladder cancer organoids•Organoids recapitulate the histological and molecular spectrum of human bladder cancer•Bladder tumor organoids display clonal evolution in culture and as xenografts•Drug response of organoids can be validated in xenografts
A biobank of patient-derived bladder tumor organoids faithfully recapitulates features of human cancer and enables analysis of clonal evolution and drug responses.
Microbial interactions occur in habitats much smaller than those generally captured in homogenized soil cores sampled across a plot or field. This study uses soil aggregates to examine soil microbial ...community composition and structure of both bacteria and fungi at a microbially-relevant scale. Aggregates were isolated from three land management systems in central Iowa, USA to test if aggregate-level microbial responses were sensitive to large-scale shifts in plant community and management practices. Bacteria and fungi exhibited similar patterns of community structure and diversity among soil aggregates, regardless of land management. Microaggregates supported more diverse microbial communities, and Fimbriimonadales, Acidimicrobiales, Actinomycetales, Alteromonodales, Burkholderiales, Gemmatimonadales, Rhodobacterales, Soligubrobacterales, Sphingobacteriales, Sphingomonodales, Spirobacillaes, Onygenales, Chaetosphaeriales, and Trichosporanales were indicator taxa for microaggregate communities. Large macroaggregates contained greater abundance of Pedosphaerales, Planctomycetales, Syntrophobacterales, and Glomeromycota (arbuscular mycorrhizal fungi). To demonstrate the potential for additional insights into soil microbial diversity, we calculated of a weighted proportional whole soil diversity, which accounted for microbes found in aggregate fractions and resulted in 65% greater bacterial richness and 100% greater fungal richness over independently sampled whole soil (i.e. bulk soil). Our results show microaggregates support highly diverse microbial communities, including several unidentified genera. Isolating aggregates with a microbially sensitive approach provides new opportunities to explore soil microbial communities and the factors shaping them at relevant spatial scales.
•Microbial communities differed between aggregates, regardless of land management.•Microaggregates supported more diverse microbial communities.•Traditional whole soil measures underestimated bacterial and fungal richness.•Community differences in land management systems were observed at aggregate-level.
The Global Burden of Disease (GBD) Study 2010 estimated the GBD attributable to 15 categories of skin disease from 1990 to 2010 for 187 countries. For each of the following diseases, we performed ...systematic literature reviews and analyzed resulting data: eczema, psoriasis, acne vulgaris, pruritus, alopecia areata, decubitus ulcer, urticaria, scabies, fungal skin diseases, impetigo, abscess, and other bacterial skin diseases, cellulitis, viral warts, molluscum contagiosum, and non-melanoma skin cancer. We used disability estimates to determine nonfatal burden. Three skin conditions, fungal skin diseases, other skin and subcutaneous diseases, and acne were in the top 10 most prevalent diseases worldwide in 2010, and eight fell into the top 50; these additional five skin problems were pruritus, eczema, impetigo, scabies, and molluscum contagiosum. Collectively, skin conditions ranged from the 2nd to 11th leading cause of years lived with disability at the country level. At the global level, skin conditions were the fourth leading cause of nonfatal disease burden. Using more data than has been used previously, the burden due to these diseases is enormous in both high- and low-income countries. These results argue strongly to include skin disease prevention and treatment in future global health strategies as a matter of urgency.
Abstract
Background
Children’s Hospital Colorado created a unique method of antimicrobial stewardship, called handshake stewardship, that effectively decreased hospital anti-infective use and costs ...in its pilot year (2013). Handshake stewardship is distinguished by: (1) the lack of prior authorization; (2) a review of all prescribed anti-infectives; (3) a shared review by the physician and the pharmacist; and (4) a daily, rounding-based, in-person approach to supporting providers. We sought to reevaluate the outcomes of the program after 5 years of experience, totaling 8 years of data.
Methods
We retrospectively measured anti-infective (antibiotic, antiviral, antifungal) use hospital-wide by unit and by drug for an 8-year period spanning October 2010 to October 2018. Aggregated monthly use was measured in days of therapy per thousand patient days (DOT/1000 PD). The percentage of children admitted ever receiving an anti-infective was also measured, as well as severity-adjusted mortality, readmissions, and lengths of stay.
Results
Hospital-wide mean anti-infective use significantly decreased, from 891 (95% confidence interval CI 859–923) in the pre-implementation phase to 655 (95% CI 637–694) DOT/1000 PD in post-implementation Year 5; in a segmented regression time series analysis, this was a rate of -2.6 DOT/1000 PD (95% CI -4.8 to -0.4). This is largely attributable to decreased antibacterial use, from 704 (95% CI 686–722) to 544 (95% CI 525 –562) DOT/1000 PD. The percentage of children ever receiving an anti-infective during admission likewise declined, from 65% to 52% (95% CI 49–54). There were no detrimental effects on severity adjusted mortality, readmissions, or lengths of stay.
Conclusions
The handshake method is an effective and sustainable approach to stewardship.
Handshake stewardship is an in-person approach to stewardship that is considered a leading practice by the Joint Commission. An 8-year assessment of this method at a large, quaternary-care pediatric hospital confirms it is highly effective in decreasing anti-infective use.
Neural micro-electrode arrays that are transparent over a broad wavelength spectrum from ultraviolet to infrared could allow for simultaneous electrophysiology and optical imaging, as well as ...optogenetic modulation of the underlying brain tissue. The long-term biocompatibility and reliability of neural micro-electrodes also require their mechanical flexibility and compliance with soft tissues. Here we present a graphene-based, carbon-layered electrode array (CLEAR) device, which can be implanted on the brain surface in rodents for high-resolution neurophysiological recording. We characterize optical transparency of the device at >90% transmission over the ultraviolet to infrared spectrum and demonstrate its utility through optical interface experiments that use this broad spectrum transparency. These include optogenetic activation of focal cortical areas directly beneath electrodes, in vivo imaging of the cortical vasculature via fluorescence microscopy and 3D optical coherence tomography. This study demonstrates an array of interfacing abilities of the CLEAR device and its utility for neural applications.
White-nose syndrome (WNS) is an infectious disease that disrupts hibernation in bats, leading to premature exhaustion of fat stores. Though we know WNS does impact reproduction in hibernating female ...bats, we are unsure how these impacts are exacerbated by local climate factors. We compiled data from four southeastern U.S. states and used generalized linear mixed effects models to compare effects of WNS, pre-hibernation climate variables, and winter duration on the number of reproductive females in species across the range of WNS susceptibility. We predicted we would see a decline in the number of reproductive females in WNS-susceptible species, with the effect exaggerated by longer winter durations and pre-hibernation climate variables that lead to reductions in foraging. We found that the number of reproductive females in WNS-susceptible species was positively correlated with pre-hibernation local climate conditions conducive to foraging; however, WNS-susceptible species experienced an overall decline with the presence of WNS and as winter duration increased. Our long-term dataset provides evidence that pre-hibernation climate, specifically favorable summer weather conditions for foraging, greatly influences the reproduction, regardless of WNS status.
T cell responses are essential for appropriate protection against pathogens. T cell immunity is achieved through the ability to discriminate between foreign and self-molecules, and this relies ...heavily on stringent T cell receptor (TCR) specificity. Recently, bystander activated T lymphocytes, that are specific for unrelated epitopes during an antigen-specific response, have been implicated in diverse diseases. Numerous infection models have challenged the classic dogma of T cell activation as being solely dependent on TCR and major histocompatibility complex (MHC) interactions, indicating an unappreciated role for pathogen-associated receptors on T cells. We discuss here the specific roles of bystander activated T cells in pathogenesis, shedding light on the ability of these cells to modulate disease severity independently from TCR recognition.
T cell activation independent of TCR signaling (bystander activation) can be beneficial but also detrimental to the host, as in certain microbial infections. It is driven by T cell-intrinsic expression of pattern-recognition receptors and other costimulatory signals.
Bystander activation of T cells has been associated with the exacerbation of disease symptoms for several infections including Borrelia burgdorferi (Lyme disease), Leishmania major (Leishmaniasis), HIV, hepatitis A virus, and Epstein–Barr virus, and others.
TCR-independent activation may be beneficial in the context of cancer immunotherapy, where bystander T cells might promote antitumor responses. Present studies aim to better elucidate these pathways.
Plant and soil properties cooperatively structure soil microbial communities, with implications for ecosystem functioning. However, the extent to which each factor contributes to community ...structuring is not fully understood. To quantify the influence of plants and soil properties on microbial diversity and composition in an agricultural context, we conducted an experiment within a corn-based annual cropping system and a perennial switchgrass cropping system across three topographic positions. We sequenced barcoded 16S ribosomal RNA genes from whole soil three times throughout a single growing season and across two years in July. To target the belowground effects of plants, we also sampled rhizosphere soil in July. We hypothesized that microbial community α-diversity and composition (β-diversity) would be more sensitive to cropping system effects (annual vs. perennial inputs) than edaphic differences among topographic positions, with greater differences occurring in the rhizosphere compared to whole soil. We found that microbial community composition consistently varied with topographic position, and cropping system and the rhizosphere influenced α-diversity. In July, cropping system and rhizosphere structured a small but specific group of microbes implying a subset of microbial taxa, rather than broad shifts in community composition, may explain previously observed differences in resource cycling between treatments. Using rank abundance analysis, we detected enrichment of Saprospirales and Actinomycetales, including cellulose and chitin degraders, in the rhizosphere soil and enrichment of Nitrospirales, Syntrophobacterales, and MND1 in the whole soil. Overall, these findings support environmental filtering for the soil microbial community first by soil and second by the rhizosphere. Across cropping systems, plants selected for a general rhizosphere community with evidence for plant-specific effects related to time of sampling.
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