MicroRNAs regulate Ca2+ homeostasis in murine embryonic stem cells

MicroRNAs (miRNAs) are important regulators of embryonic stem cell (ESC) biology, and their study has identified key regulatory mechanisms. To find novel pathways regulated by miRNAs in ESCs, we undertook a bioinformatics analysis of gene pathways differently expressed in the absence of miRNAs due to the deletion of Dicer, which encodes an RNase that is essential for the synthesis of miRNAs. One pathway that stood out was Ca2+ signaling. Interestingly, we found that Dicer-/- ESCs had no difference in basal cytoplasmic Ca2+ levels but were hyperresponsive when Ca2+ import into the endoplasmic reticulum (ER) was blocked by thapsigargin. Remarkably, the increased Ca2+ response to thapsigargin in ESCs resulted in almost no increase in apoptosis and no differences in stress response pathways, despite the importance of miRNAs in the stress response of other cell types. The increased Ca2+ response in Dicer-/- ESCs was also observed during purinergic receptor activation, demonstrating a physiological role for the miRNA regulation of Ca2+ signaling pathways. In examining the mechanism of increased Ca2+ responsiveness to thapsigargin, neither store-operated Ca2+ entry nor Ca2+ clearance mechanisms from the cytoplasm appeared to be involved. Rather, it appeared to involve an increase in the expression of one isoform of the IP3 receptors (Itpr2). miRNA regulation of Itpr2 expression primarily appeared to be indirect, with transcriptional regulation playing a major role. Therefore, the miRNA regulation of Itpr2 expression offers a unique mechanism to regulate Ca2+ signaling pathways in the physiology of pluripotent stem cells

Trace elements and lead isotopic composition of copper deposits from the eastern part of the Internal Zone of the Betic Cordillera (SE Iberia): application to provenance of archaeological materials

This paper presents trace element compositions and lead isotope analyses by MC-ICP-MS of 34 copper ore samples from the Internal Zone of the Betic Range, Southeast Spain. Samples were collected during a fieldwork campaign in the mines of Cerro Minado, Pinar de Bédar, Sierra Cabrera and Sierra Almagrera/Herrerías. Most samples are copper oxide minerals from the near surface alteration of the sulfide ore deposits. The aim of the study is to supplement the existing reference data bank on lead isotopic compositions of ancient copper mines from the Iberian Peninsula, complementing this data with trace element compositions. The latter can be useful for discriminating when isotopic overlaps occur. This characterisation will be of great usefulness for provenancing further archaeological materials. Lead isotope ratios range from 18.603 to 20.327 (206Pb/204Pb); from 15.685 to 15.779 (207Pb/204Pb) and from 38.728 to 39.702 (208Pb/204Pb). Data from the literature analysed by TIMS have been also considered for comparison although the larger analytical error is highlighted, especially for isotope 204Pb. The lead isotopic signature of the analysed samples shows three separate isotopic fields. These fields are also consistent with differences in compositions evidenced by principal component analyses

Effectiveness of individualized inhaler technique training on low adherence (LowAd) in ambulatory patients with COPD and asthma

© 2022. This document is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by /4.0/ This document is the published version of a published work that appeared in final form in npj primary care respiratory medicineTo analyze whether there is improvement in adherence to inhaled treatment in patients with COPD and asthma after an educational intervention based on the teach-to-goal method. This is a prospective, non-randomized, single-group study, with intervention and before-after evaluation. The study population included 120 patients (67 females and 53 males) diagnosed with asthma (70.8%) and COPD (29.1%). The level of adherence (low and optimal) and the noncompliance behavior pattern (erratic, deliberate and unwitting) were determined by the Test of the adherence to Inhalers (TAI). This questionnaire allows you to determine the level of adherence and the types of noncompliance. Low Adherence (LowAd) was defined as a score less than 49 points. All patients received individualized educational inhaler technique intervention (IEITI). Before the IEITI, 67.5% of the patients had LowAd. Following IEITI, on week 24, LowAd was 55% (p = 0.024). Each patient can present one or more types of noncompliance. The most frequent type was forgetting to use the inhaler (erratic), 65.8%. The other types were deliberate: 43.3%, and unwitting: 57.5%. All of them had decreased on the final visit: 51.7% (p = 0.009), 25.8% (p = 0.002), 39.2% (p = 0.002). There were no significant differences in adherence between asthma and COPD patients at the start of the study. The only predicting factor of LowAd was the female gender. An individualized educational intervention, in ambulatory patients with COPD and asthma, in real-world clinical practice conditions, improves adherence to the inhaled treatment

Sigma-1 receptors control neuropathic pain and macrophage infiltration into the dorsal root ganglion after peripheral nerve injury

Neuron-immune interaction in the dorsal root ganglia (DRG) plays a pivotal role in the neuropathic pain development after nerve injury. Sigma-1 receptor (Sig-1R) is expressed by DRG neurons but its role in neuropathic pain is not fully understood. We investigated the effect of peripheral Sig-1R on neuroinflammation in the DRG after spared (sciatic) nerve injury (SNI) in mice. Nerve injury induced a decrease in NeuN staining along with the nuclear eccentricity and ATF3 expression in the injured DRG. Sig-1R was present in all DRG neurons examined, and after SNI this receptor translocated to the periphery of the soma and the vicinity of the nucleus, especially in injured ATF3 + neurons. In WT mice, injured DRG produced the chemokine CCL2, and this was followed by massive infiltration of macrophages/monocytes, which clustered mainly around sensory neurons with translocated Sig-1R, accompanied by robust IL-6 increase and mechanical allodynia. In contrast, Sig-1R knockout (Sig-1R-KO) mice showed reduced levels of CCL2, decreased macrophage/monocyte infiltration into DRG, and less IL-6 and neuropathic mechanical allodynia after SNI. Our findings point to an important role of peripheral Sig-1R in sensory neuron-macrophage/monocyte communication in the DRG after peripheral nerve injury; thus, these receptors may contribute to the neuropathic pain phenotypeNeurofarmacología del dolor de la Universidad de Granada (CTS-109)FPU grants from the Spanish Ministry of Education, Culture and Sports.Spanish Ministry of Economy and Competitiveness (MINECO, grant SAF2016-80540-R)the Junta de Andalucía (grant CTS 109)Esteve PharmaceuticalsEuropean Regional Development Fund (ERDF

The Pioneer Anomaly

Radio-metric Doppler tracking data received from the Pioneer 10 and 11 spacecraft from heliocentric distances of 20-70 AU has consistently indicated the presence of a small, anomalous, blue-shifted frequency drift uniformly changing with a rate of ~6 x 10^{-9} Hz/s. Ultimately, the drift was interpreted as a constant sunward deceleration of each particular spacecraft at the level of a_P = (8.74 +/- 1.33) x 10^{-10} m/s^2. This apparent violation of the Newton's gravitational inverse-square law has become known as the Pioneer anomaly; the nature of this anomaly remains unexplained. In this review, we summarize the current knowledge of the physical properties of the anomaly and the conditions that led to its detection and characterization. We review various mechanisms proposed to explain the anomaly and discuss the current state of efforts to determine its nature. A comprehensive new investigation of the anomalous behavior of the two Pioneers has begun recently. The new efforts rely on the much-extended set of radio-metric Doppler data for both spacecraft in conjunction with the newly available complete record of their telemetry files and a large archive of original project documentation. As the new study is yet to report its findings, this review provides the necessary background for the new results to appear in the near future. In particular, we provide a significant amount of information on the design, operations and behavior of the two Pioneers during their entire missions, including descriptions of various data formats and techniques used for their navigation and radio-science data analysis. As most of this information was recovered relatively recently, it was not used in the previous studies of the Pioneer anomaly, but it is critical for the new investigation.Comment: 165 pages, 40 figures, 16 tables; accepted for publication in Living Reviews in Relativit

Differential Regulation of Horizontally Acquired and Core Genome Genes by the Bacterial Modulator H-NS

Horizontal acquisition of DNA by bacteria dramatically increases genetic diversity and hence successful bacterial colonization of several niches, including the human host. A relevant issue is how this newly acquired DNA interacts and integrates in the regulatory networks of the bacterial cell. The global modulator H-NS targets both core genome and HGT genes and silences gene expression in response to external stimuli such as osmolarity and temperature. Here we provide evidence that H-NS discriminates and differentially modulates core and HGT DNA. As an example of this, plasmid R27-encoded H-NS protein has evolved to selectively silence HGT genes and does not interfere with core genome regulation. In turn, differential regulation of both gene lineages by resident chromosomal H-NS requires a helper protein: the Hha protein. Tight silencing of HGT DNA is accomplished by H-NS-Hha complexes. In contrast, core genes are modulated by H-NS homoligomers. Remarkably, the presence of Hha-like proteins is restricted to the Enterobacteriaceae. In addition, conjugative plasmids encoding H-NS variants have hitherto been isolated only from members of the family. Thus, the H-NS system in enteric bacteria presents unique evolutionary features. The capacity to selectively discriminate between core and HGT DNA may help to maintain horizontally transmitted DNA in silent form and may give these bacteria a competitive advantage in adapting to new environments, including host colonization

Does hypoglycemia following a glucose challenge test identify a high risk pregnancy?

<p>Abstract</p> <p>Objective</p> <p>An association between maternal hypoglycemia during pregnancy with fetal growth restriction and overall perinatal mortality has been reported. In a retrospective pilot study we found that hypoglycemia was linked with a greater number of special care/neonatal intensive care unit admissions and approached significance in the number of women who developed preeclampsia. That study was limited by its retrospective design, a narrow patient population and the inability to perform multivariate analysis because of the limitations in the data points collected. This study was undertaken to compare the perinatal outcome in pregnancies with hyoglycemia following a glucose challenge test (GCT) to pregnancies with a normal GCT.</p> <p>Methods</p> <p>Obstetric patients (not pre-gestational diabetics or gestational diabetes before 24 weeks were eligible. Women with a 1 hour glucose ≤ 88 mg/dL (4.8 m/mol) following a 50-gram oral GCT were matched with the next patient with a 1 hour glucose of 89–139 mg/dL. Pregnancy outcomes were evaluated.</p> <p>Results</p> <p>Over 22 months, 436 hypoglycemic patients and 434 normal subjects were identified. Hypoglycemia was increased in women < 25 (p = 0.003) and with pre-existing medical conditions (p < 0.001). Hypoglycemia was decreased if pre-pregnancy BMI ≥ 30 (p = 0.008).</p> <p>Preeclampsia/eclampsia was more common in hypoglycemic women. (OR = 3.13, 95% CI 1.51 – 6.51, p = 0.002) but not other intrapartum and perinatal outcomes.</p> <p>Conclusion</p> <p>Hypoglycemic patients are younger, have reduced pre-pregnancy weight, lower BMIs, and are more likely to develop preeclampsia than normoglycemic women.</p

Comparison of risk patterns in carcinoma and melanoma of the skin in men: a multi-centre case–case–control study

We directly compared risk factors between 214 histologically confirmed melanomas (CMM), 215 basal-cell carcinomas (BCC) and 139 squamous-cell carcinomas (SCC) in a multiple case–case–control study with 349 controls from patients without dermatological disease admitted to the same hospitals. Subjects with fair hair had a significant risk increase for all types of tumours at a comparable level (ORadj for blonde hair: CMM 2.3; SCC 2.4; BCC 2.3). The effect of pale eyes was significant and similar for CMM and BCC (ORadj 2.6). Intermittent sun exposure measured in hours spent at beach during holidays was significant for both CMM (ORadj 2.6 for more than 7000 lifelong hours) and BCC (ORadj 2.1 for more than 7000 lifelong hours), while SCC exhibited a significant risk increase for chronic exposure to sunlight measured in hours of outdoor work (ORadj 2.2 for more than 6000 lifelong hours). In the case–case comparison using a multinomial logistic regression model, we found a statistically significant risk difference for pale eyes, and number of naevi in the CMM group, compared to other skin cancers. For intermittent sun exposure, there was a significant risk difference of BCC when compared to the risk of SCC. Factors influencing risk of SCC are different, with chronic exposure to sun playing a major role in causing this type of carcinoma

Simultaneous sleep study and nasoendoscopic investigation in a patient with obstructive sleep apnoea syndrome refractory to continuous positive airway pressure: a case report

<p>Abstract</p> <p>Introduction</p> <p>The standard treatment for obstructive sleep apnoea syndrome is nasal continuous positive airway pressure. In most cases the obstruction is located at the oropharyngeal level, and nasal continuous positive airway pressure is usually effective. In cases of non-response to nasal continuous positive airway pressure other treatments like mandibular advancement devices or upper airway surgery (especially bi-maxillary advancement) may also be considered.</p> <p>Case presentation</p> <p>We report the case of a 38-year-old Caucasian man with severe obstructive sleep apnoea syndrome, initially refractory to nasal continuous positive airway pressure (and subsequently also to a mandibular advancement devices), in which the visualization of the upper airway with sleep endoscopy and the concomitant titration of positive pressure were useful in the investigation and resolution of sleep disordered breathing. In fact, there was a marked reduction in the size of his nasopharynx, and a paresis of his left aryepiglotic fold with hypertrophy of the right aryepiglotic fold. The application of bi-level positive airway pressure and an oral interface successfully managed his obstructive sleep apnoea.</p> <p>Conclusion</p> <p>This is a rare case of obstructive sleep apnoea syndrome refractory to treatment with nocturnal ventilatory support. Visualization of the endoscopic changes, during sleep and under positive pressure, was of great value to understanding the mechanisms of refractoriness. It also oriented the therapeutic option. Refractoriness to obstructive sleep apnoea therapy with continuous positive airway pressure is rare, and each case should be approached individually.</p

Discovery of VHE Gamma Radiation from IC443 with the MAGIC Telescope

We report the detection of a new source of very high energy (VHE, E_gamma >= 100GeV) gamma-ray emission located close to the Galactic Plane, MAGIC J0616+225, which is spatially coincident with SNR IC443. The observations were carried out with the MAGIC telescope in the periods December 2005 - January 2006 and December 2006 - January 2007. Here we present results from this source, leading to a VHE gamma-ray signal with a statistical significance of 5.7 sigma in the 2006/7 data and a measured differential gamma-ray flux consistent with a power law, described as dN_gamma/(dA dt dE) = (1.0 +/- 0.2)*10^(-11)(E/0.4 TeV)^(-3.1 +/- 0.3) cm^(-2)s^(-1)TeV^(-1). We briefly discuss the observational technique used and the procedure implemented for the data analysis. The results are put in the perspective of the multiwavelength emission and the molecular environment found in the region of IC443.Comment: Accepted by ApJ Letter