To document the nociceptive innervation of the normal and osteoarthritic murine knee.
Knees were collected from naïve male C57BL/6 NaV1.8-tdTomato reporter mice aged 10, 26, and 52 weeks ...(n = 5/group). Destabilization of the medial meniscus (DMM) or sham surgeries (n = 5/group) were performed in the right knee of 10-week old male NaV1.8-tdTomato mice, and knees were harvested 16 weeks later. Twenty 20-μm frozen sections from a 400-μm mid-joint region were collected for confocal microscopy. Integrated density of the tdTomato signal was calculated using Image J by two independent observers blinded to the groups. Consecutive sections were stained with hematoxylin & eosin. C57BL/6-Pirt-GCaMP3 mice (n = 5/group) and protein gene product 9.5 (PGP9.5) immunostaining of C57BL/6 wild type (WT) mice (n = 5/group) were used to confirm innervation patterns.
In naive 10-week old mice, nociceptive innervation was most dense in bone marrow cavities, lateral synovium and at the insertions of the cruciate ligaments. By age 26 weeks, unoperated knees showed a marked decline in nociceptors in the lateral synovium and cruciate ligament insertions. No further decline was observed by age 1 year. Sixteen weeks after DMM, the medial compartment of OA knees exhibited striking changes in NaV1.8+ innervation, including increased innervation of the medial synovium and meniscus, and nociceptors in subchondral bone channels. All results were confirmed through quantification, also in Pirt-GCaMP3 and PGP9.5-immunostained WT mice.
Nociceptive innervation of the mouse knee markedly declines by age 26 weeks, before onset of spontaneous OA. Late-stage surgically induced OA is associated with striking plasticity of joint afferents in the medial compartment of the knee.
In this narrative review, we discuss the emerging role of innate immunity in osteoarthritis (OA) joint pain. First, we give a brief description of the pain pathway in the context of OA. Then we ...consider how neuro-immune signaling pathways may promote OA pain. First, activation of neuronal Pattern Recognition Receptors by mediators released in a damaged joint can result in direct excitation of nociceptors, as well as in production of chemokines and cytokines. Secondly, indirect neuro-immune signaling may occur when innate immune cells produce algogenic factors, including chemokines and cytokines, that act on the pain pathway. Neuro-immune crosstalk occurs at different levels of the pathway, starting in the joint but also in the innervating dorsal root ganglia and in the dorsal horn. Synovitis is characterized by recruitment of immune cells, including macrophages, mast cells, and CD4+ lymphocytes, which may contribute to nociceptor sensitization and OA pain through production of algogenic factors that amplify the activation of sensory neurons. We discuss examples where this scenario has been suggested by findings in human OA and in animal models. Overall, increasing evidence suggests that innate immune pathways play an initiating as well as facilitating role in pain, but information on how these pathways operate in OA remains limited. Since these innate pathways are eminently targetable, future studies in this area may provide fruitful leads towards a better management of symptomatic OA.
Rapidly rotating neutron stars are promising sources of continuous gravitational wave radiation for the LIGO and Virgo interferometers. The majority of neutron stars in our galaxy have not been ...identified with electromagnetic observations. All-sky searches for isolated neutron stars offer the potential to detect gravitational waves from these unidentified sources. The parameter space of these blind all-sky searches, which also cover a large range of frequencies and frequency derivatives, presents a significant computational challenge. Different methods have been designed to perform these searches within acceptable computational limits. Here we describe the first benchmark in a project to compare the search methods currently available for the detection of unknown isolated neutron stars. The five methods compared here are individually referred to as the PowerFlux, sky Hough, frequency Hough, Einstein@Home, and time domain F-statistic methods. We employ a mock data challenge to compare the ability of each search method to recover signals simulated assuming a standard signal model. We find similar performance among the four quick-look search methods, while the more computationally intensive search method, Einstein@Home, achieves up to a factor of two higher sensitivity. We find that the absence of a second derivative frequency in the search parameter space does not degrade search sensitivity for signals with physically plausible second derivative frequencies. We also report on the parameter estimation accuracy of each search method, and the stability of the sensitivity in frequency and frequency derivative and in the presence of detector noise.
Sea otters in California are commonly infected with
Toxoplasma gondii. A unique Type X strain is responsible for 72% of otter infections, but its prevalence in terrestrial animals and marine ...invertebrates inhabiting the same area was unknown. Between 2000 and 2005, 45 terrestrial carnivores (lions, bobcats, domestic cats and foxes) and 1396 invertebrates (mussels, clams and worms) were screened for
T. gondii using PCR and DNA sequencing to determine the phylogeographic distribution of
T. gondii archetypal I, II, III and Type X genotypes. Marine bivalves have been shown to concentrate
T. gondii oocysts in the laboratory, but a comprehensive survey of wild invertebrates has not been reported. A California mussel from an estuary draining into Monterey Bay was confirmed positive for Type X
T. gondii by multilocus PCR and DNA sequencing at the
B1 and
SAG1 loci. This mussel was collected from nearshore marine waters just after the first significant rainfall event in the fall of 2002. Of 45 carnivores tested at the
B1,
SAG1, and
GRA6 typing loci, 15 had PCR-confirmed
T. gondii infection; 11 possessed alleles consistent with infection by archetypal Type I, II or III strains and 4 possessed alleles consistent with Type X
T. gondii infection. No non-canonical alleles were identified. The four
T. gondii strains with Type X alleles were identified from two mountain lions, a bobcat and a fox residing in coastal watersheds adjacent to sea otter habitat near Monterey Bay and Estero Bay. Confirmation of Type X
T. gondii in coastal-dwelling felids, canids, a marine bivalve and nearshore-dwelling sea otters supports the hypotheses that feline faecal contamination is flowing from land to sea through surface runoff, and that otters can be infected with
T. gondii via consumption of filter-feeding marine invertebrates.
Abstract
We use very long baseline interferometry to measure the proper motions of three black hole X-ray binaries (BHXBs). Using these results together with data from the literature and Gaia DR2 to ...collate the best available constraints on proper motion, parallax, distance, and systemic radial velocity of 16 BHXBs, we determined their three-dimensional Galactocentric orbits. We extended this analysis to estimate the probability distribution for the potential kick velocity (PKV) a BHXB system could have received on formation. Constraining the kicks imparted to BHXBs provides insight into the birth mechanism of black holes (BHs). Kicks also have a significant effect on BH–BH merger rates, merger sites, and binary evolution, and can be responsible for spin–orbit misalignment in BH binary systems. 75 per cent of our systems have potential kicks $\gt 70\, \rm {km\,s^{-1}}$. This suggests that strong kicks and hence spin–orbit misalignment might be common among BHXBs, in agreement with the observed quasi-periodic X-ray variability in their power density spectra. We used a Bayesian hierarchical methodology to analyse the PKV distribution of the BHXB population, and suggest that a unimodal Gaussian model with a mean of 107 $\pm \,\,16\, \rm {km\,s^{-1}}$ is a statistically favourable fit. Such relatively high PKVs would also reduce the number of BHs likely to be retained in globular clusters. We found no significant correlation between the BH mass and PKV, suggesting a lack of correlation between BH mass and the BH birth mechanism. Our python code allows the estimation of the PKV for any system with sufficient observational constraints.
OPTN/SRTR 2019 Annual Data Report: Kidney Hart, A.; Lentine, K. L.; Smith, J. M. ...
American journal of transplantation,
February 2021, 2021-02-00, 20210201, Letnik:
21, Številka:
S2
Journal Article
Recenzirano
Odprti dostop
Despite the ongoing severe shortage of available kidney grafts relative to candidates in need, data from 2019 reveal some promising trends. After remaining relatively stagnant for many years, the ...number of kidney transplants has increased each year since 2015, reaching the highest annual count to date of 24,273 in 2019. The number of patients waiting for a kidney transplant in the United States was relatively stable, despite an increase in the number of new candidates added in 2019 and a decrease in patients removed from the waiting list owing to death or deteriorating medical condition. However, these encouraging trends are tempered by ongoing challenges. Nationwide, only a quarter of waitlisted patients receive a deceased‐donor kidney transplant within 5 years, and this proportion varies dramatically by donation service area, from 15.5% to 67.8%. The non‐utilization (discard) rate of recovered organs remains at 20.1%, despite adramatic decline in the discard of organs from hepatitis C‐positive donors. Non‐utilization rates remain particularly high for Kidney Donor Profile Index ≥85% kidneys and kidneys from which a biopsy specimen was obtained. While the number of living‐donor transplants increased again in 2019, only a small proportion of the waiting list receives living‐donor transplants each year, and racial disparities in living‐donor transplant access persist. As both graft and patient survival continue to improve incrementally, the total number of living kidney transplant recipients with a functioning graft is anticipated to exceed 250,000 in the next 1‐2 years. Over the past decade, the total number of pediatric kidney transplants performed has remained stable. Despite numerous efforts, living donor kidney transplant remains low among pediatric recipients with continued racial disparities among recipients. Congenital anomalies of the kidney and urinary tract remain the leading cause of kidney disease. While most deceased donor recipients receive a kidney from a donor with KDPI less than 35%, the majority of pediatric recipients had four or more HLA mismatches. Graft survival continues to improve with superior outcomes for living donor recipients.
Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results ...from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.
Gaps in our understanding of genetic susceptibility to malignant hyperthermia (MH) limit the application and interpretation of genetic diagnosis of the condition. Our aim was to define the prevalence ...and role of variants in the three genes implicated in MH susceptibility in the largest comprehensively phenotyped MH cohort worldwide.
We initially included one individual from each positive family tested in the UK MH Unit since 1971 to detect variants in RYR1, CACNA1S, or STAC3. Screening for genetic variants has been ongoing since 1991 and has involved a range of techniques, most recently next generation sequencing. We assessed the pathogenicity of variants using standard guidelines, including family segregation studies. The prevalence of recurrent variants of unknown significance was compared with the prevalence reported in a large database of sequence variants in low-risk populations.
We have confirmed MH susceptibility in 795 independent families, for 722 of which we have a DNA sample. Potentially pathogenic variants were found in 555 families, with 25 RYR1 and one CACNA1S variants previously unclassified recurrent variants significantly over-represented (P<1×10−7) in our cohort compared with the Exome Aggregation Consortium database. There was genotype–phenotype discordance in 86 of 328 families suitable for segregation analysis. We estimate non-RYR1/CACNA1S/STAC3 susceptibility occurs in 14–23% of MH families.
Our data provide current estimates of the role of variants in RYR1, CACNA1S, and STAC3 in susceptibility to MH in a predominantly white European population.
The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome ...inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique β-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.
For halide perovskite solar cells (PSCs) to fulfill their vast potential for combining low-cost, high efficiency, and high throughput production they must be scaled using a truly transformative ...method, such as roll-to-roll processing. Bringing this reality closer to fruition, the present work demonstrates flexible perovskite solar cells with 18.1% power conversion efficiency on flexible Willow Glass substrates. We highlight the importance of the transparent conductive oxide (TCO) layers on device performance by studying various TCOs. While tin-doped indium oxide (ITO) and indium zinc oxide (IZO) based PSC devices demonstrate high photovoltaic performances, aluminum-doped zinc oxide (AZO) based devices underperformed in all device parameters. Analysis of X-ray photoemission spectroscopy data shows that the stoichiometry of the perovskite film surface changes dramatically when it is fabricated on AZO, demonstrating the importance of the substrate in perovskite film formation.
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