Although glucose-sensing neurons were identified more than 50 years ago, the physiological role of glucose sensing in metazoans remains unclear. Here we identify a pair of glucose-sensing neurons ...with bifurcated axons in the brain of Drosophila. One axon branch projects to insulin-producing cells to trigger the release of Drosophila insulin-like peptide 2 (dilp2) and the other extends to adipokinetic hormone (AKH)-producing cells to inhibit secretion of AKH, the fly analogue of glucagon. These axonal branches undergo synaptic remodelling in response to changes in their internal energy status. Silencing of these glucose-sensing neurons largely disabled the response of insulin-producing cells to glucose and dilp2 secretion, disinhibited AKH secretion in corpora cardiaca and caused hyperglycaemia, a hallmark feature of diabetes mellitus. We propose that these glucose-sensing neurons maintain glucose homeostasis by promoting the secretion of dilp2 and suppressing the release of AKH when haemolymph glucose levels are high.
In this article, we present an overview of the different strategies for sample preparation for identification by mass spectrometry (MS) of biomarkers from serum and/or plasma. We consider the effects ...of the variables involved in sample collection, handling and storage, and describe different approaches for removal of high abundance proteins and serum/plasma fractionation. We review the advantages and disadvantages of such techniques as centrifugal ultrafiltration, different formats for solid phase extraction, organic solvent extraction, gel and capillary electrophoresis, and liquid chromatography. We also discuss a variety of current proteomic methods and their main applications for biomarker-related studies.
Although laboratory studies indicate alcohol reduces pain intensity and increases pain threshold, these effects likely do not completely explain perceived pain relief from alcohol intake. In this ...study, we tested expectancy of alcohol analgesia (EAA) as a moderator of subjective pain relief following oral alcohol challenge in individuals with and without chronic orofacial pain. Social drinkers (N = 48; 19 chronic pain; 29 pain-free controls) completed two testing sessions: alcohol administration (BrAC: 0.08 g/dL) and placebo. Alcohol expectancy (AE) was assessed using the EAA questionnaire and two 100-mm Visual Analogue Scales (VASs) regarding strength of belief that alcohol provides pain relief (AE VAS 1) or reduces pain sensitivity (AE VAS 2). Participants completed quantitative sensory testing (QST) involving application of pressure to the masseter insertion. Pain threshold (lbf; three repetitions) and pain intensity (4, 5, and 6 lbf; three repetitions each; 100-mm VAS) were collected. After each stimulus, participants rated perceived pain relief due to consumption of the study beverage (0-100 VAS). Higher EAA and AE VAS 1 ratings were associated with stronger perceived relief in the alcohol, but not placebo, condition. However, expectancy specifically related to reduction in pain sensitivity (AE VAS 2) was not associated with relief. Additionally, changes in pain threshold and intensity were not significantly correlated with perceived relief. Taken together, results suggest expectancy that alcohol provides pain relief is an important determinant of its negative reinforcing effects. Future studies should investigate challenging these expectancies as a means of reducing alcohol-related risk in people with pain.
Public Health Significance
This study suggests that expectancies of alcohol's pain-relieving effects may be a valuable therapeutic target for reducing the risk of alcohol-related consequences in people with and without pain. The lack of association between pain sensitivity change scores with perceived relief suggests additional research is needed to determine effective interventions using alcohol expectancies and individual perceptions that alcohol relieved pain.
Asteroid 2024 BX1 was the eighth asteroid that was discovered shortly before colliding with the Earth. The associated bolide was recorded by dedicated instruments of the European Fireball Network and ...the AllSky7 network on 2024 January 21 at 0:32:38–44 UT. We report a comprehensive analysis of this instrumentally observed meteorite fall, which occurred as predicted west of Berlin, Germany. The atmospheric trajectory was quite steep, with an average slope to the Earth’s surface of 75°.6. The entry speed was 15.20 km s −1 . The heliocentric orbit calculated from the bolide data agrees very well with the asteroid data. However, the bolide was fainter than expected for a reportedly meter-sized asteroid. The absolute magnitude reached −14.4, and the entry mass was estimated to be 140 kg. The recorded bolide spectrum was low in iron, based on which, the meteorite was expected to be rich in enstatite. The recovered meteorites, called Ribbeck, were classified as aubrites. The high albedo of enstatite (E-type) asteroids can explain the size discrepancy. The asteroid was likely smaller than 0.5 meter and should rather be called a meteoroid. During the atmospheric entry, the meteoroid severely fragmented into much smaller pieces already at a height of 55 km under an aerodynamic pressure of 0.12 MPa. The primary fragments then broke up again, most frequently at heights 39−29 km (0.9–2.2 MPa). Numerous small meteorites and up to four stones larger than 100 g were expected to land. Within a few days of publication of the location of the strewn field, dozens of meteorites were found in the area we had predicted.
The outermost layer of the mammalian skin, the stratum corneum (SC), is a very thin structure and realizes simultaneously the main barrier properties. The penetration barrier for xenobiotica is ...mostly represented by a complex lipid matrix. There is great interest in the subject of getting information about the arrangement of the lipids, which are mainly ceramides (CER), free fatty acids (FFA) and cholesterol (CHOL). SC lipid model membranes containing synthetically derived lipids in a non-physiological ratio were investigated. To compare the study to a former experiment, a methyl-branched ceramide EOS species in presence of the ultra-long chain CERAP, CHOL and behenic acid (23/10/33/33, wt%) was applied. The membrane structure was studied using the very versatile technique of neutron diffraction. We were able to identify a long-periodicity phase (LPP) with a size of 114Å or 118Å with CEREOS-br in a ratio of >60wt% of the ceramides. Furthermore, we figured out two additional coexisting short-periodicity phases (SPP) with repeat distances of 48Å and 45Å, respectively. Partial deuterations of CEREOS-br and CERAP enabled the localization of the molecules within the multiphase system. CEREOS-d3 was present in the LPP, but absent in both SPP. CERAP-d3 was determined in both short phases but not localized within the LPP. Besides, we revealed influences of humidity and time with respect to the long-periodicity phase.
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•A specific deuteration enabled CERAP-C18 localization in short-periodicity phases in stratum corneum lipid model membranes.•A partially deuterated ultra-long chain CEREOS analog was determined in a coexisting long-periodicity phase.•The long-periodicity phase was influenceable by humidity and time, as due to both impacts, the lamellar spacing increased.
Lipid metabolism plays an important role in the regulation of cellular homeostasis. However, because it is difficult to measure the actual rates of synthesis and degradation of individual lipid ...species, lipid compositions are often used as a surrogate to evaluate lipid metabolism even though they provide only static snapshots of the lipodome. Here, we designed a simple method to determine the turnover rate of phospholipid and acylglycerol species based on the incorporation of 13C6-glucose combined with LC-MS/MS. We labeled adult Drosophila melanogaster with 13C6-glucose that incorporates into the entire lipidome, derived kinetic parameters from mass spectra, and studied effects of deletion of CG6718, the fly homolog of the calcium-independent phospholipase A2β, on lipid metabolism. Although 13C6-glucose gave rise to a complex pattern of 13C incorporation, we were able to identify discrete isotopomers in which 13C atoms were confined to the glycerol group. With these isotopomers, we calculated turnover rate constants, half-life times, and fluxes of the glycerol backbone of multiple lipid species. To perform these calculations, we estimated the fraction of labeled molecules in glycerol-3-phosphate, the lipid precursor, by mass isotopomer distribution analysis of the spectra of phosphatidylglycerol. When we applied this method to D. melanogaster, we found a range of lipid half-lives from 2 to 200 days, demonstrated tissue-specific fluxes of individual lipid species, and identified a novel function of CG6718 in triacylglycerol metabolism. This method provides fluxomics-type data with significant potential to improve the understanding of complex lipid regulation in a variety of research models.
This study examined the differences in neck muscle activity at various neck flexion angles in smartphone users with and without neck pain. Forty-four participants performed texting tasks for 1 min ...and 30 s. Neck muscle activity and pain in the neck were measured at different neck flexion angles. There was a difference in neck muscle activity for each of the neck flexion angles; the Cervical Erector Spinae (CES) muscle activity increased while the Upper Trapezius (UT) muscle activity decreased when at increased neck flexion angles. At neck flexion angle of 0°-15°, the activity of both CES and UT muscles were acceptably low. Smartphone users with neck pain had slightly higher muscle activity levels than smartphone users without neck pain. In conclusion, smartphone users should consider adopting neck flexion angles between 0 and 15 degrees during smartphone use as there is an association between this neck flexion angle range and reduced CES muscle activity.
Practitioner summary: This study demonstrated that both smartphone users with and without neck pain should try to keep their neck flexion angle between 0° and 15° when using their smartphone. This would reduce neck muscle activity and the risk of developing neck disorders associated with smartphone use.
Practitioners are seeking information and ethical guidance related to the design and utilization of artificial intelligence (AI) across a variety of applications. Developments at Google illustrate ...the potential good of AI as well as potential concerns. In this article, we use Google to create a context that demonstrates the relevance of virtue for the ethical design and use of AI. We describe a set of ethical challenges encountered by Google and introduce virtue as a framework for ethical decision making that can be applied broadly to numerous organizations. We also examine support for virtue in ethical decision making as well as its power in attracting and retaining the employees who develop AI and the customers who use it. To conclude, we apply the virtue framework to Google’s AI challenges and offer suggestions for its use in other organizations.
Epicutaneous application of capsaicin causes a long-lasting analgesic effect by binding to the membrane transient receptor potential vanilloid 1 (TRPV1) on mechanoheat-sensitive C and Aδ fibres, ...changing axonal integrity and inhibiting neurogenic inflammatory processes. To date, no information is available regarding the cutaneous drug delivery of capsaicin following patch application.
Using a Franz diffusion cell, the cutaneous concentration-time profiles 30, 60 and 90 min after application of a patch containing 8% capsaicin (640 µg/cm(2)) on ex vivo thin (mamma) and thick (plantar) human skin were investigated at 32 °C, and additionally at 42 °C for thin skin and 10 °C for thick skin. An HPLC-MS method was used for the analytic detection of capsaicin.
The results show that already after a 30-min application of the 8% capsaicin patch, an equilibrium reservoir can be found in the stratum corneum in both thick and thin skin. Under physiological temperature conditions, a sufficient bioavailability of capsaicin in the cutaneous target compartments can be found. Raising the temperature to 42 °C has no relevant impact on the concentration-time profile, while reducing the temperature to 10°C leads to a significantly lower bioavailability.
After 30 min of application, a sufficient cutaneous bioavailability of capsaicin is reached in thick as well as thin skin. Whether shorter application times may suffice to achieve therapeutic effectiveness requires further investigation.
The detection of cool temperatures is thought to be mediated by primary afferent neurons that express the cool temperature sensing protein Transient Receptor Potential Cation Channel, Subfamily M, ...Member 8 (TRPM8). Using mice, this study tested the hypothesis that sex differences in sensitivity to cool temperatures were mediated by differences in neurons that express TRPM8. Ion currents from TRPM8 expressing trigeminal ganglion (TRG) neurons in females demonstrated larger hyperpolarization-activated cyclic nucleotide-gated currents (Ih) than male neurons at both 30° and 18°C. Additionally, female neurons' voltage gated potassium currents (Ik) were suppressed by cooling, whereas male Ik was not significantly affected. At the holding potential tested (-60mV) TRPM8 currents were not visibly activated in either sex by cooling. Modeling the effect of Ih and Ik on membrane potentials demonstrated that at 30° the membrane potential in both sexes is unstable. At 18°, female TRPM8 TRG neurons develop a large oscillating pattern in their membrane potential, whereas male neurons become highly stable. These findings suggest that the differences in Ih and Ik in the TRPM8 TRG neurons of male and female mice likely leads to greater sensitivity of female mice to the cool temperature. This hypothesis was confirmed in an operant reward/conflict assay. Female mice contacted an 18°C surface for approximately half the time that males contacted the cool surface. At 33° and 10°C male and female mice contacted the stimulus for similar amounts of time. These data suggest that sex differences in the functioning of Ih and Ik in TRPM8 expressing primary afferent neurons leads to differences in cool temperature sensitivity.
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