Inhibition of c-Kit signaling is associated with reduced heat and cold pain sensitivity in humans

The tyrosine kinase receptor c-Kit is critically involved in the modulation of nociceptive sensitivity in mice. Ablation of the c-Kit gene results in hyposensitivity to thermal pain, while c-Kit activation produces hypersensitivity to the noxious heat, without altering sensitivity to innocuous mechanical stimuli. In this study we investigated the role of c-Kit signalling in human pain perception. We hypothesized that subjects treated with Imatinib or Nilotinib, potent inhibitors of tyrosine kinases including c-Kit, but also Abl1, PDFGFR{alpha}, and PDFGFR{beta}, that are used to treat chronic myeloid leukemia (CML), would experience changes in thermal pain sensitivity. We examined 31 asymptomatic CML patients (14 male, 17 female) under Imatinib/Nilotinib treatment and compared them to 39 age- and sex-matched healthy controls (12 male, 27 female). We used cutaneous heat and cold stimulation to test normal and noxious thermal sensitivity, and a grating orientation task to assess tactile acuity. Thermal pain thresholds were significantly increased in the Imatinib/Nilotinib-treated group, while innocuous thermal and tactile thresholds were unchanged compared to the control group. In conclusion, our findings suggest that the biological effects of c-Kit inhibition are comparable in mice and humans in that c-Kit activity is required to regulate thermal pain sensitivity, but does not affect innocuous thermal and mechanical sensation. The effect on experimental heat pain observed in our study is comparable to that of several common analgesics, thus modulation of the c-Kit pathway can be used to specifically modulate noxious heat and cold sensitivity in humans

A somatosensory circuit for cooling perception in mice

The temperature of an object provides important somatosensory information for animals performing tactile tasks. Humans can perceive skin cooling of less than one degree, but the sensory afferents and central circuits that they engage to enable the perception of surface temperature are poorly understood. To address these questions, we examined the perception of glabrous skin cooling in mice. We found that mice were also capable of perceiving small amplitude skin cooling and that primary somatosensory (S1) cortical neurons were required for cooling perception. Moreover, the absence of the menthol-gated transient receptor potential melastatin 8 ion channel in sensory afferent fibers eliminated the ability to perceive cold and the corresponding activation of S1 neurons. Our results identify parts of a neural circuit underlying cold perception in mice and provide a new model system for the analysis of thermal processing and perception and multimodal integration

The Effects of Dietary Polyphenols on Circulating Cardiovascular Disease Biomarkers and Iron Status:A Systematic Review

The prevalence of cardiovascular disease (CVD) is rising worldwide, remaining the major cause of death in developed countries. Polyphenols have been shown to have cardioprotective properties; however, their impact on iron bioavailability and potential impact on other aspects of health is unclear. A systematic review was undertaken to evaluate the current status of the relationship between habitual polyphenol consumption, iron status, and circulating biomarkers of CVD. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2009 guidelines, searches were performed across 5 electronic databases (PubMed, Cochrane Library, Scopus, Web of Science, and CINAHL) to identify randomized controlled trials which investigated the effects of polyphenol consumption on inflammatory markers, serum lipid profile, and iron absorption and bioavailability. In total, 1174 records were identified, with only 7 studies meeting the inclusion criteria. The selected studies involved 133 participants and used a variety of foods and supplements, including olive oil and cherries, rich in polyphenols including hydroxytyrosol, quercetin, and resveratrol, as well as catechin enriched drinks. The duration of the studies ranged from between 56 and 145 days, with total polyphenolic content of the food items and supplements ranging from 45 to 1015 mg (per 100 g). Polyphenols did not appear to interfere with iron status, and most studies reported improvements in inflammatory markers and lipid profile. While these results are promising, the limited number of studies and considerable heterogeneity across the interventions support the need for more extensive trials assessing the relationship between polyphenol intake, iron bioavailability, and CVD risk

Kvalitet mleka i osobine surutke dobijene pri proizvodnji Sjeničkog sira u industrijskim uslovima

Sjenica cheese is one of our best kinds of cheese from the group of white cheese in brine. Since the quality and overall value of the cheese depend on the quality and chemical composition of milk, before making cheese it is necessary to determine these parameters. Milk fat content in cow milk was 3.1%, protein 31.3%, dry matter 10.96%, casein 2.85%. Sheep milk of richer chemical composition had a dry matter 8.14%, fat 6.80%, protein 5.97%, casein 20.5%. Chemical composition of whey gauge the validity of keeping the process of making cheese. On the basis of dry matter content (cow whey 5.65% and sheep whey 7.5%), fat (cow whey 0.023%, sheep whey 0.62%), protein (cow whey 0.81% , sheep whey 1.44%), it is seen that the process of producing cheese is well managed with optimal utilization of milk ingredients.Sjenički sir je jedan od naših najboljih sireva iz grupe belih sireva u salamuri. Proizvodi se na individualnim gazdinstvima područja Sjeničko-pešterske visoravni. Sir se proizvodi od svežeg punomasnog kravljeg i očijeg mleka bez termičkog tretmana. Pošto kvalitet i opšte vrednosti sira zavise od kvaliteta i hemijskog sastava mleka , pre izrade sireva neophodno je odrediti te parametre. Sadržaj mlečne masti kod kravljeg mleka bio je 3.1%, proteina 3.31%, suve materije 10.96%, kazeina 2.85%. Ovčije mleko koje je bogatijeg hemijskog sastava imalo je suve materije 18.14%, masti 6.80%, proteina 5.97%, kazeina 5.20%. Na osnovu sadržaja suve materije (5.65% kravlja i 7.05% ovčja ) , masti ( 0.23% kravlja; 0.62% ovčija), proteina ( 0.81% kravlja, 1.44% ovčja), kod surutke vidi se da je proces proizvodnje sireva dobro vođen uz optimalnu iskorišćenost sastojaka mleka

The Enigma of the Respiratory Chain Supercomplex

Respiratory chain dysfunction plays an important role in human disease and aging. It is now well established that the individual respiratory complexes can be organized into supercomplexes, and structures for these macromolecular assemblies, determined by electron cryo-microscopy, have been described recently. Nevertheless, the reason why supercomplexes exist remains an enigma. The widely held view that they enhance catalysis by channeling substrates is challenged by both structural and biophysical information. Here, we evaluate and discuss data and hypotheses on the structures, roles, and assembly of respiratory-chain supercomplexes and propose a future research agenda to address unanswered questions.N.G.L. receives support from the Max Planck Society, the Swedish Research Council (2015-00418), and the Knut and Alice Wallenberg foundation. J.H. and J.N.B. are supported by The Medical Research Council (U105663141 to J.H.)

Refinement of Individual Tree Detection Results Obtained from Airborne Laser Scanning Data for a Mixed Natural Forest

Numerous semi- and fully-automatic algorithms have been developed for individual tree detection from airborne laser-scanning data, but different rates of falsely detected treetops also accompany their results. In this paper, we proposed an approach that includes a machine learning-based refinement step to reduce the number of falsely detected treetops. The approach involves the local maxima filtering and segmentation of the canopy height model to extract different segment-level features used for the classification of treetop candidates. The study was conducted in a mixed temperate forest, predominantly deciduous, with a complex topography and an area size of 0.6 km × 4 km. The classification model’s training was performed by five machine learning approaches: Random Forest (RF), Extreme Gradient Boosting, Artificial Neural Network, the Support Vector Machine, and Logistic Regression. The final classification model with optimal hyperparameters was adopted based on the best-performing classifier (RF). The overall accuracy (OA) and kappa coefficient (κ) obtained from the ten-fold cross validation for the training data were 90.4% and 0.808, respectively. The prediction of the test data resulted in an OA = 89.0% and a κ = 0.757. This indicates that the proposed method could be an adequate solution for the reduction of falsely detected treetops before tree crown segmentation, especially in deciduous forests

OEMC D2.1 Report "Stakeholder Committee and Open- Earth-Monitor Design" workshop

This deliverable of the Open-Earth-Monitor project describes the approach taken to compile and categorize the project's stakeholders, and provides recommendations for the future stakeholder interactions based on the results of a survey from the OEMC design workshop, which took place during the project's kick-off meeting in July, 2022

Current Methods to Unravel the Functional Properties of Lysosomal Ion Channels and Transporters

open18siA distinct set of channels and transporters regulates the ion fluxes across the lysosomal membrane. Malfunctioning of these transport proteins and the resulting ionic imbalance is involved in various human diseases, such as lysosomal storage disorders, cancer, as well as metabolic and neurodegenerative diseases. As a consequence, these proteins have stimulated strong interest for their suitability as possible drug targets. A detailed functional characterization of many lysosomal channels and transporters is lacking, mainly due to technical difficulties in applying the standard patch-clamp technique to these small intracellular compartments. In this review, we focus on current methods used to unravel the functional properties of lysosomal ion channels and transporters, stressing their advantages and disadvantages and evaluating their fields of applicability.openFesta M.; Minicozzi V.; Boccaccio A.; Lagostena L.; Gradogna A.; Qi T.; Costa A.; Larisch N.; Hamamoto S.; Pedrazzini E.; Milenkovic S.; Scholz-Starke J.; Ceccarelli M.; Vitale A.; Dietrich P.; Uozumi N.; Gambale F.; Carpaneto A.Festa, M.; Minicozzi, V.; Boccaccio, A.; Lagostena, L.; Gradogna, A.; Qi, T.; Costa, A.; Larisch, N.; Hamamoto, S.; Pedrazzini, E.; Milenkovic, S.; Scholz-Starke, J.; Ceccarelli, M.; Vitale, A.; Dietrich, P.; Uozumi, N.; Gambale, F.; Carpaneto, A

The Parkinson's disease VPS35[D620N] mutation enhances LRRK2 mediated Rab protein phosphorylation in mouse and human

Missense mutations in the LRRK2 and VPS35 genes result in autosomal dominant Parkinson’s disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. It is not known how the only thus far described pathogenic VPS35 mutation, [D620N] exerts its effects. We reveal that the VPS35[D620N] knock-in mutation, strikingly elevates LRRK2 mediated phosphorylation of Rab8A, Rab10 and Rab12 in mouse embryonic fibroblasts. The VPS35[D620N] mutation also increases Rab10 phosphorylation in mouse tissues (lung, kidney, spleen and brain). Furthermore, LRRK2 mediated Rab10 phosphorylation is increased in neutrophils as well as monocytes isolated from three Parkinson’s patients with a heterozygous VPS35[D620N] mutation compared to healthy donors and idiopathic Parkinson’s patients. LRRK2 mediated Rab10 phosphorylation is significantly suppressed by knock-out or knock-down of VPS35 in wild type, LRRK2[R1441C] or VPS35[D620N] cells. Finally, VPS35[D620N] mutation promotes Rab10 phosphorylation more potently than LRRK2 pathogenic mutations. Available data suggest that Parkinson’s patients with VPS35[D620N] develop the disease at a younger age than those with LRRK2 mutations. Our observations indicate that VPS35 controls LRRK2 activity and that the VPS35[D620N] mutation results in a gain of function, potentially causing Parkinson’s disease through hyperactivation of the LRRK2 kinase. Our findings suggest that it may be possible to elaborate compounds that target the retromer complex to suppress LRRK2 activity. Moreover, patients with VPS35[D620N] associated Parkinson’s might benefit from LRRK2 inhibitor treatment that have entered clinical trials in humans