Our previous studies showed that salicylate ototoxicity is associated with decreased levels of vasodilating prostaglandins (PGs) and increased vasoconstricting leukotrienes (LTs) in the perilymph and ...reduced cochlear blood flow (CoBF). The purpose of this study was to test the hypothesis that leukotriene inhibitor prevents salicylate ototoxicity by preventing abnormal elevation of LT levels in the inner ear, thus averting a decrease in CoBF resulting from abnormal levels of arachidonic acid metabolites in the inner ear. Ototoxicity was induced in chinchillas by either local round window membrane (RWM) application or systemic treatment with salicylate both with and without pretreatment with leukotriene inhibitor (Sch 37224). A moderate reduction in CoBF was documented with both local RWM and systemic treatment with salicylate. Salicylate induced hearing loss and reduction in CoBF were prevented by pretreatment with a leukotriene inhibitor. This study suggests that leukotriene inhibitor prevents salicylate ototoxicity by averting a decrease in CoBF mediated by abnormal levels of arachidonic acid metabolites in the inner ear.
Implicated in persistence and stress response pathways in bacteria, RelE shuts down protein synthesis by cleaving mRNA within the ribosomal A site. Structural and biochemical studies have shown that ...RelE cuts with some sequence specificity, which we further characterize here, and that it shows no activity outside the context of the ribosome. We obtained a global view of the effect of RelE on translation by ribosome profiling, observing that ribosomes accumulate on the 5'-end of genes through dynamic cycles of mRNA cleavage, ribosome rescue and initiation. Moreover, the addition of purified RelE to cell lysates shows promise as a method for generating ribosome footprints. In bacteria, profiling studies have suffered from relatively low resolution and have yielded no information on reading frame due to problems inherent to MNase digestion, the method used to degrade unprotected regions of mRNA. In contrast, we find that RelE yields precise 3'-ends that for the first time reveal reading frame in bacteria. Given that RelE has been shown to function in all three domains of life, RelE has potential to improve reading frame and shed light on A-site occupancy in ribosome profiling experiments more broadly.
Shallow hydrothermal vent environments are typically very warm and acidic due to the mixing of ambient seawater with volcanic gasses (> 92% CO
) released through the seafloor making them potential ...'natural laboratories' to study long-term adaptations to extreme hypercapnic conditions. Xenograpsus testudinatus, the shallow hydrothermal vent crab, is the sole metazoan inhabitant endemic to vents surrounding Kueishantao Island, Taiwan, where it inhabits waters that are generally pH 6.50 with maximum acidities reported as pH 5.50. This study assessed the acid-base regulatory capacity and the compensatory response of X. testudinatus to investigate its remarkable physiological adaptations. Hemolymph parameters (pH, HCO
, Formula: see text, NH
, and major ion compositions) and the whole animal's rates of oxygen consumption and ammonia excretion were measured throughout a 14-day acclimation to pH 6.5 and 5.5. Data revealed that vent crabs are exceptionally strong acid-base regulators capable of maintaining homeostatic pH against extreme hypercapnia (pH 5.50, 24.6 kPa Formula: see text) via HCO
/Cl
exchange, retention and utilization of extracellular ammonia. Intact crabs as well as their isolated perfused gills maintained Formula: see texttensions below environmental levels suggesting the gills can excrete CO
against a hemolymph-directed Formula: see text gradient. These specialized physiological mechanisms may be amongst the adaptations required by vent-endemic animals surviving in extreme conditions.
The dynamic nature of the COVID-19 pandemic has demanded a public health response that is constantly evolving due to the novelty of the virus. Many jurisdictions in the USA, Canada, and across the ...world have adopted social distancing and recommended the use of face masks. Considering these measures, it is prudent to understand the contributions of subpopulations—such as “silent spreaders”—to disease transmission dynamics in order to inform public health strategies in a jurisdiction-dependent manner. Additionally, we and others have shown that demographic and environmental stochasticity in transmission rates can play an important role in shaping disease dynamics. Here, we create a model for the COVID-19 pandemic by including two classes of individuals: silent spreaders, who either never experience a symptomatic phase or remain undetected throughout their disease course; and symptomatic spreaders, who experience symptoms and are detected. We fit the model to real-time COVID-19 confirmed cases and deaths to derive the transmission rates, death rates, and other relevant parameters for multiple phases of outbreaks in British Columbia (BC), Canada. We determine the extent to which SilS contributed to BC’s early wave of disease transmission as well as the impact of public health interventions on reducing transmission from both SilS and SymS. To do this, we validate our model against an existing COVID-19 parameterized framework and then fit our model to clinical data to estimate key parameter values for different stages of BC’s disease dynamics. We then use these parameters to construct a hybrid stochastic model that leverages the strengths of both a time-nonhomogeneous discrete process and a stochastic differential equation model. By combining these previously established approaches, we explore the impact of demographic and environmental variability on disease dynamics by simulating various scenarios in which a COVID-19 outbreak is initiated. Our results demonstrate that variability in disease transmission rate impacts the probability and severity of COVID-19 outbreaks differently in high- versus low-transmission scenarios.
Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features transdifferentiation of tissue-resident ...pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin-LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth
. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration. SIGNIFICANCE: Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration.
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This paper reports on Magnetospheric Multiscale observations of whistler mode chorus and higher‐frequency electrostatic waves near and within a reconnection diffusion region on 23 November 2016. The ...diffusion region is bounded by crescent‐shaped electron distributions and associated dissipation just upstream of the X‐line and by magnetic field‐aligned currents and electric fields leading to dissipation near the electron stagnation point. Measurements were made southward of the X‐line as determined by southward directed ion and electron jets. We show that electrostatic wave generation is due to magnetosheath electron beams formed by the electron jets as they interact with a cold background plasma and more energetic population of magnetospheric electrons. On the magnetosphere side of the X‐line the electron beams are accompanied by a strong perpendicular electron temperature anisotropy, which is shown to be the source of an observed rising‐tone whistler mode chorus event. We show that the apex of the chorus event and the onset of electrostatic waves coincide with the opening of magnetic field lines at the electron stagnation point.
Key Points
Whistler mode chorus and higher‐frequency electrostatic waves were observed in the vicinity of a reconnection diffusion region at the dayside magnetopause
The location of the Earthward boundary of chorus and electrostatic waves coincides with the opening of magnetic field lines via reconnection
The causes of whistler mode chorus and electrostatic waves are shown to be electron temperature anisotropy and beam‐plasma interactions, respectively
TAR DNA-binding protein 43 (TDP-43) aggregation is the most common pathological hallmark in frontotemporal dementia (FTD) and characterizes nearly all patients with motor neuron disease (MND). The ...earliest stages of TDP-43 pathobiology are not well-characterized, and whether neurodegeneration results from TDP-43 loss-of-function or aggregation remains unclear. In the behavioral variant of FTD (bvFTD), patients undergo selective dropout of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices. Here, we examined TDP-43 pathobiology within these vulnerable neurons in the FI across a clinical spectrum including 17 patients with sporadic bvFTD, MND, or both. In an exploratory analysis based on our initial observations, we further assessed ten patients with
C9orf72
-associated bvFTD/MND. VENs and fork cells showed early, disproportionate TDP-43 aggregation that correlated with anatomical and clinical severity, including loss of emotional empathy. The presence of a TDP-43 inclusion was associated with striking nuclear and somatodendritic atrophy. An intriguing minority of neurons lacked detectable nuclear TDP-43 despite the apparent absence of a cytoplasmic TDP-43 inclusion. These cells showed neuronal atrophy comparable to inclusion-bearing neurons, suggesting that the loss of nuclear TDP-43 function promotes neurodegeneration, even when TDP-43 aggregation is inconspicuous or absent.
A variety of immunohistochemical (IHC) stains have been proposed to mark either benign or malignant mesothelial proliferations. Loss of the p16 tumor suppressor (CDKN2A), through homozygous deletions ...of 9p21, is a good marker of mesotheliomas but lacks sensitivity. Recent reports indicate that some mesotheliomas are associated with loss of BRCA-associated protein 1 (BAP1) expression. Here we investigate BAP1 and p16 as potential markers of malignancy and compare test characteristics with previously proposed markers using a well-characterized tissue microarray. BAP1 protein expression was interrogated by IHC. The p16 locus was examined by fluorescence in situ hybridization (FISH) directed toward chromosome 9p21. Loss of BAP1 was identified in 7/26 mesotheliomas and 0/49 benign proliferations. Loss of p16 was identified in 14/27 mesotheliomas and 0/40 benign proliferations, yielding 100% specificity and positive predictive value for each marker. Together, BAP1 IHC and p16 FISH were 58% sensitive for detecting malignancy. Various combinations of p53, EMA, IMP3, and GLUT1 showed reasonably high specificity (96% to 98%) but poor to extremely poor sensitivity. Combined BAP1 IHC/p16 FISH testing is a highly specific method of diagnosing malignant mesotheliomas when the question is whether a mesothelial proliferation is benign or malignant and is particularly useful when tissue invasion by mesothelial cells cannot be demonstrated. However, combined BAP1/p16 FISH testing is not highly sensitive, and negative results do not rule out a mesothelioma. The test characteristics of previously proposed markers EMA, p53, GLUT1, IMP3 suggest that, even in combination, these markers are not useful tools in this clinical setting.
Alterations in DNA damage response (DDR) genes are common in advanced prostate tumors and are associated with unique genomic and clinical features. ATM is a DDR kinase that has a central role in ...coordinating DNA repair and cell-cycle response following DNA damage, and
alterations are present in approximately 5% of advanced prostate tumors. Recently, inhibitors of PARP have demonstrated activity in advanced prostate tumors harboring DDR gene alterations, particularly in tumors with
alterations. However, the role of alterations in DDR genes beyond
in mediating PARP inhibitor sensitivity is poorly understood. To define the role of
loss in prostate tumor DDR function and sensitivity to DDR-directed agents, we created a series of
-deficient preclinical prostate cancer models and tested the impact of
loss on DNA repair function and therapeutic sensitivities.
loss altered DDR signaling, but did not directly impact homologous recombination function. Furthermore,
loss did not significantly impact sensitivity to PARP inhibition but robustly sensitized to inhibitors of the related DDR kinase ATR. These results have important implications for planned and ongoing prostate cancer clinical trials and suggest that patients with tumor
alterations may be more likely to benefit from ATR inhibitor than PARP inhibitor therapy. SIGNIFICANCE: ATM loss occurs in a subset of prostate tumors. This study shows that deleting ATM in prostate cancer models does not significantly increase sensitivity to PARP inhibition but does sensitize to ATR inhibition.
The diagnosis of malignant mesothelioma in effusion cytology specimens is controversial. BAP1 immunohistochemistry and p16 fluorescence in situ hybridization (FISH) have recently been reported as ...reliable markers of malignancy in biopsies of mesothelioma. To determine whether these markers, singly or in combination, might also be useful in effusion cytology specimens, we examined 15 biopsies of epithelial mesotheliomas and 3 benign mesothelial reactions and corresponding effusion cytology paraffin-embedded cell blocks. Four cytology specimens were too scanty for p16 FISH analysis but were interpretable for BAP1 immunohistochemistry. Overall, loss of BAP1 and/or deletion of p16 was seen in 11/11 (100%) of matched cytology and tissue biopsy specimens. BAP1 loss alone was seen in 10/15 (67%) biopsies and 10/15 (67%) cytology specimens. Homozygous deletion of p16 by FISH was found in 12/15 (80%) biopsy specimens and 8/11 (73%) evaluable cytology specimens. Seven of 15 (47%) biopsies and 5/11 (42%) cytology specimens showed loss of both markers. All mesothelioma biopsy/cytology pairs showed exactly the same pattern of BAP1 or p16 retention or loss in the biopsy and cytology specimens. The 2 peritoneal mesothelioma cases demonstrated loss of BAP1 but not p16. None of the benign mesothelial reactions or corresponding cytology specimens showed loss of either marker. We conclude that both BAP1 immunohistochemistry and p16 FISH analysis provide reliable markers of mesothelial malignancy in effusion cytology specimens, especially where the atypical mesothelial proliferation is well sampled. BAP1 is easier to interpret with scanty specimens. On the basis of small numbers of cases, use of both markers appears to increase sensitivity.
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