Core components of cytokinesis are conserved from yeast to human, but how these components are assembled into a robust machine that drives cytokinesis remains poorly understood. In this paper, we ...show by fluorescence recovery after photobleaching analysis that Myo1, the sole myosin-II in budding yeast, was mobile at the division site before anaphase and became immobilized shortly before cytokinesis. This immobility was independent of actin filaments or the motor domain of Myo1 but required a small region in the Myo1 tail that is thought to be involved in higher-order assembly. As expected, proteins involved in actin ring assembly (tropomyosin and formin) and membrane trafficking (myosin-V and exocyst) were dynamic during cytokinesis. Strikingly, proteins involved in septum formation (the chitin synthase Chs2) and/or its coordination with the actomyosin ring (essential light chain, IQGAP, F-BAR, etc.) displayed Myo1-dependent immobility during cytokinesis, suggesting that Myo1 plays a scaffolding role in the assembly of a cytokinesis machine.
Atopic dermatitis (AD) is a chronic itch and inflammatory disorder of the skin that affects one in ten people. Patients suffering from severe AD eventually progress to develop asthma and allergic ...rhinitis, in a process known as the “atopic march.” Signaling between epithelial cells and innate immune cells via the cytokine thymic stromal lymphopoietin (TSLP) is thought to drive AD and the atopic march. Here, we report that epithelial cells directly communicate to cutaneous sensory neurons via TSLP to promote itch. We identify the ORAI1/NFAT calcium signaling pathway as an essential regulator of TSLP release from keratinocytes, the primary epithelial cells of the skin. TSLP then acts directly on a subset of TRPA1-positive sensory neurons to trigger robust itch behaviors. Our results support a model whereby calcium-dependent TSLP release by keratinocytes activates both primary afferent neurons and immune cells to promote inflammatory responses in the skin and airways.
Display omitted
•Epithelial cells communicate to sensory neurons via TSLP to promote itch•ORAI1/NFAT calcium signaling regulates release of TSLP from keratinocytes•TSLP is a robust pruritogen that promotes itch-evoked scratching•TSLP-evoked itch behaviors require TRPA1 ion channels that promote inflammation
The proinflammatory cytokine TSLP is a potent driver of dermatitis and is primarily thought to act through modulation of immune cells. TSLP is now found to directly activate sensory neurons via signaling involving ORAI1 and TRPA1 channels to trigger itch behaviors.
Although the neurobiology of rodent facial whiskers has been studied intensively, little is known about sensing in other vibrissae. Here we describe the under-investigated submandibular "whisker ...trident" on the rat's chin. In this three-whisker array, a unique unpaired midline whisker is laterally flanked by two slightly shorter whiskers. All three whiskers point to the ground and are curved backwards. Unlike other whiskers, the trident is not located on an exposed body part. Trident vibrissae are not whisked and do not touch anything over long stretches of time. However, trident whiskers engage in sustained ground contact during head-down running while the animal is exploring or foraging. In biomechanical experiments, trident whiskers follow caudal ground movement more smoothly than facial whiskers. Remarkably, deflection angles decrease with increasing ground velocity. We identified one putative trident barrel in the left somatosensory cortex and two barrels in the right somatosensory cortex. The elongated putative trident-midline barrel is the longest and largest whisker barrel, suggesting that the midline trident whisker is of great functional significance. Cortical postsynaptic air-puff responses in the trident representation show much less temporal precision than facial whisker responses. Trident whiskers do not provide as much high-resolution information about object contacts as facial whiskers. Instead, our observations suggest an idiothetic function: their biomechanics allow trident whiskers to derive continuous measurements about ego motion from ground contacts. The midline position offers unique advantages in sensing heading direction in a laterally symmetric manner. The changes in trident deflection angle with velocity suggest that trident whiskers might function as a tactile speedometer.
There is accumulating evidence suggesting that keratinocytes, the predominant cell type in the skin, may play a key role in the transduction of several somatosensory modalities, including itch. ...Keratinocytes are activated by a number of itch compounds and release a variety of molecules associated with itch. Additionally, itch-transducing neurons terminate as free nerve endings in the keratinocyte layer of the skin, which would permit rapid keratinocyte-neuron signaling. Our work has focused on two areas: 1) defining the molecular mechanisms by which the atopic dermatitis cytokine TSLP is released from keratinocytes and act on neurons to cause itch and 2) identifying the distinct mechanisms by which histamine and protease signaling in keratinocytes triggers itch. Previous studies have shown that activation of the Protease-Activated Receptor 2 (PAR2) leads to upregulation of TSLP in keratinocytes and that TSLP overexpression in keratinocytes induces chronic itch in mice. We characterized the mechanisms by which PAR2 activation leads to TSLP expression and secretion, and elucidated the mechanisms by which secreted TSLP in the skin leads to itch. Understanding the molecular mechanisms underlying atopic dermatitis may identify targets that could lead to the development of drugs that specifically block atopic dermatitis itch while leaving other somatosensations intact. Previous studies have linked histamine and protease signaling to distinct clinical itch phenotypes; histamine signaling is associated with allergic itch, while protease signaling is associated with atopic dermatitis. Histamine and PAR2 agonists activate the same population of keratinocytes, thus how these pruritogens trigger distinct itch pathologies was unknown. We now demonstrate that histamine and protease signaling in keratinocytes induce distinct calcium signals that lead to divergent downstream transcriptional outputs.
Fibroblast Growth Factor 23 and Inflammation in CKD Munoz Mendoza, Jair; Isakova, Tamara; Ricardo, Ana C ...
Clinical journal of the American Society of Nephrology,
07/2012, Volume:
7, Issue:
7
Journal Article
Peer reviewed
Open access
Levels of fibroblast growth factor 23 (FGF23) and inflammatory markers are commonly elevated in CKD, and each is associated with adverse clinical outcomes. This study tested the hypothesis that FGF23 ...is independently associated with inflammation in CKD.
The association between levels of FGF23 and the inflammatory markers IL-6, C-reactive protein (CRP), TNF-α, and fibrinogen was assessed in a cross-sectional analysis of 3879 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study between June 2003 and September 2008.
FGF23 correlated directly with IL-6 (r=0.4), CRP (r=0.2), TNF-α (r=0.4), and fibrinogen (r=0.3; P<0.001 for each). In univariate and multivariable-adjusted linear regression analyses, natural log (ln) transformed FGF23 was significantly associated with lnIL-6, lnCRP, lnTNF-α, and fibrinogen (P<0.001 for each). Each unit higher lnFGF23 was associated with severe inflammation, defined as levels of all inflammatory markers in the highest 25th percentile, in univariate (odds ratio OR, 2.4 95% confidence interval (CI), 2.0-2.9) and multivariable-adjusted (OR, 2.0 95% CI, 1.6-2.5) logistic regression analyses. Ascending FGF23 quartiles were independently associated with severe inflammation (OR, 5.6 for the highest versus lowest FGF23 quartile 95% CI, 2.3-13.9; P for trend < 0.001).
Higher FGF23 levels are independently associated with higher levels of inflammatory markers in patients with CKD and with significantly greater odds of severe inflammation. Future studies should evaluate whether inflammation modifies the association between FGF23 and adverse outcomes in CKD.
Mineral springs in Massif Central, France can be characterized by higher levels of natural radioactivity in comparison to the background. The biota in these waters is constantly under radiation ...exposure mainly from the alpha-emitters of the natural decay chains, with .sup.226 Ra in sediments ranging from 21 Bq/g to 43 Bq/g and .sup.222 Rn activity concentrations in water up to 4600 Bq/L. This study couples for the first time micro- and nanodosimetric approaches to radioecology by combining GATE and Geant4-DNA to assess the dose rates and DNA damages to microorganisms living in these naturally radioactive ecosystems. It focuses on unicellular eukaryotic microalgae (diatoms) which display an exceptional abundance of teratological forms in the most radioactive mineral springs in Auvergne. Using spherical geometries for the microorganisms and based on gamma-spectrometric analyses, we evaluate the impact of the external exposure to 1000 Bq/L .sup.222 Rn dissolved in the water and 30 Bq/g .sup.226 Ra in the sediments. Our results show that the external dose rates for diatoms are significant (9.7 muGy/h) and comparable to the threshold (10 muGy/h) for the protection of the ecosystems suggested by the literature. In a first attempt of simulating the radiation induced DNA damage on this species, the rate of DNA Double Strand Breaks per day is estimated to 1.11E-04. Our study confirms the significant mutational pressure from natural radioactivity to which microbial biodiversity has been exposed since Earth origin in hydrothermal springs.
Obesity and unhealthy eating habits have been associated with sleep disturbances (SD). The Mediterranean diet (MD) is a healthy nutritional pattern that has been reported to be associated with better ...health and sleep quality. Thus, the aim of the study was to investigate whether adherence to the MD is associated with sleep quality in a population of middle-aged Italian adults. This cross-sectional study included 172 middle-aged adults (71.5% females; 51.8 ± 15.7 years) that were consecutively enrolled in a campaign to prevent obesity called the OPERA (Obesity, Programs of Nutrition, Education, Research and Assessment of the best treatment) prevention project that was held in Naples on 11-13 October 2019. Anthropometric parameters, adherence to the MD and sleep quality were studied. Overall, 50.6% of the subjects were good sleepers (the Pittsburgh Sleep Quality Index (PSQI) < 5) while 49.4% were poor sleepers (PSQI ≥ 5). Our results demonstrated that good sleepers, when compared to poor sleepers (
< 0.001) had significantly higher adherence to the MD as assessed by PREDIMED (Prevención con Dieta Mediterránea) score, lower BMI (body mass index) and waist circumference (WC). The higher PSQI, the higher the BMI (
< 0.001) and WC values (
< 0.001), thus suggesting that poor sleep was more common in subjects with obesity. In addition, a negative correlation between PSQI and the PREDIMED score (
< 0.001) was found. to the intake of the cluster of foods enclosed in the MD, rather than the intake of the single food, predicted PSQI. By performing a receiver operator characteristic (ROC) curve analysis, we determined a cut-off value at a PREDIMED score < 9 as the threshold for screening poor sleepers. In conclusion, good sleepers had lower BMI and WC and higher adherence to the MD than poor sleepers. PSQI was positively associated to BMI and WC while it was negatively associated to adherence to the MD. The consumption of the MD dietary pattern rather than the intake of a single nutrient has a beneficial effect on sleep quality. Hence, the assessment of sleep should be taken into account in the management of obesity and promoting adherence to the MD could be a tool to improve SD.
PDF
