The transformation of mechanical energy into electrical signals is the first step in mechanotransduction in the peripheral sensory nervous system and relies on the presence of mechanically gated ion ...channels within specialized sensory organs called mechanoreceptors. Piezo2 is a vertebrate stretch‐gated ion channel necessary for mechanosensitive channels in mammalian cells. Functionally, it is related to light touch, which has been detected in murine cutaneous Merkel cell–neurite complexes, Meissner‐like corpuscles and lanceolate nerve endings. To the best of our knowledge, the occurrence of Piezo2 in human cutaneous mechanoreceptors has never been investigated. Here, we used simple and double immunohistochemistry to investigate the occurrence of Piezo2 in human digital glabrous skin. Piezo2 immunoreactivity was detected in approximately 80% of morphologically and immunohistochemically characterized (cytokeratin 20+, chromogranin A+ and synaptophisin+) Merkel cells. Most of them were in close contact with Piezo2− nerve fibre profiles. Moreover, the axon, but not the lamellar cells, of Meissner's corpuscles was also Piezo2+, but other mechanoreceptors, i.e. Pacinian or Ruffini's corpuscles, were devoid of immunoreactivity. Piezo2 was also observed in non‐nervous tissue, especially the basal keratinocytes, endothelial cells and sweat glands. The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner's corpuscles) low‐threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch. These data offer additional insight into the molecular basis of mechanosensing in humans.
•Resource recovery from urban wastewater to promote shift towards a circular economy.•Pilot and full-scale studies show MBBR as suitable system for treated wastewater reuse.•Numerous methods ...developed for nutrient recovery from WWTP’s effluents.
Over the last years, an increasing concern has emerged regarding the eco-friendly management of wastewater. Apart from the role of wastewater treatment plants (WWTPs) for wastewater and sewage sludge treatment, the increasing need of the recovery of the resources contained in wastewater, such as nutrients and water, should be highlighted. This would allow for transforming a wastewater treatment plant (WWTP) into a sustainable technological system.
The objective of this review is to propose a moving bed biofilm reactor (MBBR) as a novel technology that contributes to the circularity of the wastewater treatment sector according to the principles of circular economy. In this regard, this paper aims to consider the MBBR process as the initial step for water reuse, and nutrient removal and recovery, within the circular economy model.
Background and Purpose
Immunomodulatory tetracyclines are well‐characterized drugs with a pharmacological potential beyond their antibiotic properties. Specifically, minocycline and doxycycline have ...shown beneficial effects in experimental colitis, although pro‐inflammatory actions have also been described in macrophages. Therefore, we aimed to characterize the mechanism behind their effect in acute intestinal inflammation.
Experimental Approach
A comparative pharmacological study was initially used to elucidate the most relevant actions of immunomodulatory tetracyclines: doxycycline, minocycline and tigecycline; other antibiotic or immunomodulatory drugs were assessed in bone marrow‐derived macrophages and in dextran sodium sulfate (DSS)‐induced mouse colitis, where different barrier markers, inflammatory mediators, microRNAs, TLRs, and the gut microbiota composition were evaluated. The sequential immune events that mediate the intestinal anti‐inflammatory effect of minocycline in DSS‐colitis were then characterized.
Key Results
Novel immunomodulatory activity of tetracyclines was identifed; they potentiated the innate immune response and enhanced resolution of inflammation. This is also the first report describing the intestinal anti‐inflammatory effect of tigecycline. A minor therapeutic benefit seems to derive from their antibiotic properties. Conversely, immunomodulatory tetracyclines potentiated macrophage cytokine release in vitro, and while improving mucosal recovery in colitic mice, they up‐regulated Ccl2, miR‐142, miR‐375 and Tlr4. In particular, minocycline initially enhanced IL‐1β, IL‐6, IL‐22, GM‐CSF and IL‐4 colonic production and monocyte recruitment to the intestine, subsequently increasing Ly6C−MHCII+ macrophages, Tregs and type 2 intestinal immune responses.
Conclusions and Implications
Immunomodulatory tetracyclines potentiate protective immune pathways leading to mucosal healing and resolution, representing a promising drug reposition strategy for the treatment of intestinal inflammation.
Introduction
Active surveillance (AS) is considered a suitable management practice for those patients with low‐risk prostate cancer (PCa). At present, however, the role of multiparametric magnetic ...resonance imaging (mpMRI) in AS protocols has not yet been clearly established.
Outcomes
To determine the role of mpMRI and its ability to detect significant prostate cancer (SigPCa) in PCa patients enrolled in AS protocols.
Materials and Methods
There were 229 patients enrolled in an AS protocol between 2011 and 2020 at Reina Sofía University Hospital. MRI interpretation was based on PIRADS v.1 or v.2/2.1 classification. Demographics, clinical, and analytical data were collected and analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for mpMRI in different scenarios. We defined SigPCa and reclassification/progression as a Gleason score (GS) ≥ 3 + 4, a clinical stage ≥T2b, or an increase in PCa volume. Kaplan–Meier and log‐rank tests were used to estimate progression‐free survival time.
Results
Median age was 69.02 (±7.73) at diagnosis, with a 0.15 (±0.08) PSA density (PSAD). Eighty‐six patients were reclassified after confirmatory biopsy, with a suspicious mpMRI an indication for a clear reclassification and risk‐predictor factor in disease progression (p < 0.05). During follow‐up, 46 patients were changed from AS to active treatment mainly due to disease progression. Ninety patients underwent ≥2mpMRI during follow‐up, with a median follow‐up of 29 (15–49) months. Thirty‐four patients had a baseline suspicious mpMRI (at diagnostic or confirmatory biopsy): 14 patients with a PIRADS 3 and 20 patients with ≥PIRADS 4. From 14 patients with a PIRADS 3 baseline mpMRI, 29% progressed radiologically, with a 50% progression rate versus 10% (1/10 patients) for those with similar or decreased mpMRI risk. Of the 56 patients with a non‐suspicious baseline mpMRI (PIRADS < 2), 14 patients (25%) had an increased degree of radiological suspicion, with a detection rate of SigPCa of 29%. The mpMRI NPV during follow‐up was 0.91.
Conclusion
A suspicious mpMRI increases the reclassification and disease progression risk during follow‐up and plays an important role in monitoring biopsies. In addition, a high NPV at mpMRI follow‐up can help to decrease the need to monitor biopsies during AS.
Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib ...was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).
A novel magnetic functionalized material based on graphene oxide and magnetic nanoparticles (MGO) was used to develop a magnetic solid phase extraction method (MSPE) to enrich both, inorganic and ...organic arsenic species in environmental waters and biological samples. An automatic flow injection (FI) system was used to preconcentrate the arsenic species simultaneously, while the ultra-trace separation and determination of arsenobetaine (AsBet), cacodylate, AsIII and AsV species were achieved by high performance liquid chromatography combined with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). The sample was introduced in the FI system where the MSPE was performed, then 1 mL of eluent was collected in a chromatographic vial, which was introduced in the autosampler of HPLC-ICP-MS. Therefore, preconcentration and separation/determination processes were automatic and conducted separately. To the best of our knowledge, this is the first method combining an automatic MSPE with HPLC-ICP-MS for arsenic speciation, using a magnetic nanomaterial based on MGO for automatic MSPE. Under the optimized conditions, the LODs for the arsenic species were 3.8 ng L−1 AsBet, 0.5 ng L−1 cacodylate, 1.1 ng L−1 AsIII and 0.2 ng L−1 AsV with RSDs <5%. The developed method was validated by analyzing Certified Reference Materials for total As concentration (fortified lake water TMDA 64.3 and seawater CASS-6 NRC) and also by recovery analysis of the arsenic species in urine, well-water and seawater samples collected in Málaga. The developed method has shown promise for routine monitoring of arsenic species in environmental waters and biological fluids.
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•Semiautomatic method for As speciation in environmental and biological samples.•First analytical method developed by using MGO-PSTH.•The proposed arsenic speciation method has very good LODs and precision.•Drinking water, seawater and urine samples were analyzed by external calibration.•First method combining automatic MSPE with MGO, and HPLC for As speciation.
Meissner’s and Pacinian corpuscles are cutaneous mechanoreceptors responsible for different modalities of touch. The development of these sensory formations in humans is poorly known, especially ...regarding the acquisition of the typical immunohistochemical profile related to their full functional maturity. Here we used a panel of antibodies (to specifically label the main corpuscular components: axon, Schwann-related cells and endoneurial-perineurial-related cells) to investigate the development of digital Meissner’s and Pacinian corpuscles in a representative sample covering from 11 weeks of estimated gestational age (wega) to adulthood. Development of Pacinian corpuscles starts at 13 wega, and it is completed at 4 months of life, although their basic structure and immunohistochemical characteristics are reached at 36 wega. During development, around the axon, a complex network of S100 positive Schwann-related processes is progressively compacted to form the inner core, while the surrounding mesenchyme is organized and forms the outer core and the capsule. Meissner’s corpuscles start to develop at 22 wega and complete their typical morphology and immunohistochemical profile at 8 months of life. In developing Meissner’s corpuscles, the axons establish complex relationships with the epidermis and are progressively covered by Schwann-like cells until they complete the mature arrangement late in postnatal life. The present results demonstrate an asynchronous development of the Meissner’s and Pacini’s corpuscles and show that there is not a total correlation between morphological and immunohistochemical maturation. The correlation of the present results with touch-induced cortical activity in developing humans is discussed.
We present deep spectra of ring nebulae associated with Wolf–Rayet (WR) and O-type stars: NGC 6888, G2.4+1.4, RCW 58, S 308, NGC 7635 and RCW 52. The data have been taken with the 10m Gran Telescopio ...Canarias and the 6.5m Clay Telescope. We extract spectra of several apertures in some of the objects. We derive C2+ and O2+ abundances from faint recombination lines in NGC 6888 and NGC 7635, permitting to derive their C/H and C/O ratios and estimate the abundance discrepancy factor (ADF) of O2+. The ADFs are larger than the typical ones of normal H ii regions but similar to those found in the ionized gas of star-forming dwarf galaxies. We find that chemical abundances are rather homogeneous in the nebulae where we have spectra of several apertures: NGC 6888, NGC 7635 and G2.4+1.4. We obtain very high values of electron temperature in a peripheral zone of NGC 6888, finding that shock excitation can reproduce its spectral properties. We find that all the objects associated with WR stars show N enrichment. Some of them also show He enrichment and O deficiency as well as a lower Ne/O than expected, this may indicate the strong action of the ON and NeNa cycles. We have compared the chemical composition of NGC 6888, G2.4+1.4, RCW 58 and S 308 with the nucleosynthesis predicted by stellar evolution models of massive stars. We find that non-rotational models of stars of initial masses between 25 and 40 M⊙ seem to reproduce the observed abundance ratios of most of the nebulae.
High-altitude peat bogs and lacustrine records are very sensitive to climate changes and atmospheric dust input. Recent studies have shown a close relationship between regional climate aridity and ...enhanced eolian input to lake sediments. However, changes in regional-scale dust fluxes due to climate variability at short scales and how alpine environments were impacted by climatic- and human-induced environmental changes are not completely understood. Here we present a multi-proxy (palynological, geochemical and magnetic susceptibility) lake sediment record of climate variability in the Sierra Nevada (southeastern Iberian Peninsula) over the Holocene. Magnetic susceptibility and geochemical proxies obtained from the high mountain lake record of Laguna Hondera evidence humid conditions during the early Holocene, while a trend towards more arid conditions is recognized since ∼7000 cal yr BP, with enhanced Saharan eolian dust deposition until the present. This trend towards enhanced arid conditions was modulated by millennial-scale climate variability. Relative humid conditions occurred during the Iberian Roman Humid Period (2600–1450 cal yr BP) and predominantly arid conditions occurred during the Dark Ages and the Medieval Climate Anomaly (1450–650 cal yr BP). The Little Ice Age (650–150 cal yr BP) is characterized in the Laguna Hondera record by an increase in runoff and a minimum in eolian input. In addition, we further suggest that human impact in the area is noticed through the record of Olea cultivation, Pinus reforestation and Pb pollution during the Industrial Period (150 cal yr BP–present). Furthermore, we estimated that the correlation between Zr and Ca concentrations stands for Saharan dust input to the Sierra Nevada lake records. These assumptions support that present-day biochemical observations, pointing to eolian input as the main inorganic nutrient source for oligotrophic mountain lakes, are comparable to the past record of eolian supply to these high-altitude lakes.
ABSTRACT
We present the analysis of physical conditions, chemical composition, and kinematic properties of two bow shocks – HH 529 II and HH 529 III – of the fully photoionized Herbig–Haro object ...HH 529 in the Orion Nebula. The data were obtained with the Ultraviolet and Visual Echelle Spectrograph at the 8.2m Very Large Telescope and 20 yr of Hubble Space Telescope imaging. We separate the emission of the high-velocity components of HH 529 II and III from the nebular one, determining ne and Te in all components through multiple diagnostics, including some based on recombination lines (RLs). We derive ionic abundances of several ions, based on collisionally excited lines and RLs. We find a good agreement between the predictions of the temperature fluctuation paradigm (t2) and the abundance discrepancy factor (ADF) in the main emission of the Orion Nebula. However, t2 cannot account for the higher ADF found in HH 529 II and III. We estimate 6 per cent of Fe in the gas phase of the Orion Nebula, while this value increases to 14 per cent in HH 529 II and between 10 and 25 per cent in HH 529 III. We find that such increase is probably due to the destruction of dust grains in the bow shocks. We find an overabundance of C, O, Ne, S, Cl, and Ar of about 0.1 dex in HH 529 II and III that might be related to the inclusion of H-deficient material from the source of the HH 529 flow. We determine the proper motions of HH 529 finding multiple discrete features. We estimate a flow angle with respect to the sky plane of 58° ± 4° for HH 529.
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