On BH3 mimetics and Ca2+ signaling

BH3 mimetics are anticancer agents that reproduce the spatial arrangement of the BH3 domain of Bcl-2 family proteins. Just like the BH3-only proteins, these compounds bind to the hydrophobic cleft of the pro-survival Bcl-2 members such as Bcl-2 or Bcl-xL, and disrupt their heterodimerization with pro-apoptotic Bax or Bak, sensitizing cells to chemotherapy. In recent years, it has become clear that Bcl-2 family proteins are engaged in regulation of intracellular Ca2+ homeostasis, including Ca2+ release from the intracellular stores as well as Ca2+ fluxes across the plasma membrane. Given that BH3 mimetics shift the balance between the prosurvival and proapoptotic Bcl-2 members, they might indirectly exert effects on intracellular Ca2+ signals. Indeed, it has been reported that some BH3 mimetics release Ca2+ from the intracellular stores causing Ca2+ overload in the cytosol. Therefore, the effects of any new BH3 mimetics on cellular Ca2+ homeostasis should be tested before these compounds progres

Biology of pancreatic stellate cells—more than just pancreatic cancer

Pancreatic stellate cells, normally quiescent, are capable of remarkable transition into their activated myofibroblast-like phenotype. It is now commonly accepted that these cells play a pivotal role in the desmoplastic reaction present in severe pancreatic disorders. In recent years, enormous scientific effort has been devoted to understanding their roles in pancreatic cancer, which continues to remain one of the most deadly diseases. Therefore, it is not surprising that considerably less attention has been given to studying physiological functions of pancreatic stellate cells. Here, we review recent advances not only in the field of pancreatic stellate cell pathophysiology but also emphasise their roles in physiological processes

Particle identification with machine learning in ALICE Run 3

The main focus of the ALICE experiment, quark--gluon plasma measurements, requires accurate particle identification (PID). The ALICE subdetectors allow identifying particles over a broad momentum interval ranging from about 100 MeV/c up to 20 GeV/c. However, a machine learning (ML) model can explore more detector information. During LHC Run 2, preliminary studies with Random Forests obtained much higher efficiencies and purities for selected particles than standard techniques. For Run 3, we investigate Domain Adaptation Neural Networks that account for the discrepancies between the Monte Carlo simulations and the experimental data. Preliminary studies show that domain adaptation improves particle classification. Moreover, the solution is extended with Feature Set Embedding and attention to give the network more flexibility to train on data with various sets of detector signals. PID ML is already integrated with the ALICE Run 3 Analysis Framework. Preliminary results for the PID of selected particle species, including real-world analyzes, are discussed as well as the possible optimizations.Comment: Proceedings of the 26th International Conference on Computing in High Energy and Nuclear Physics (CHEP 2023) in Norfolk, Virginia, USA, 8-12 May, 202

Splenic melanosis during normal murine C57BL/6 hair cycle and after chemotherapy

Cancer chemotherapy is associated with serious side effects, including temporary hair loss and impairment of pigmentation. We suspect that ectopic melanin deposition occurring due to chemotherapy may add to these effects worsening the already unpleasant symptoms. We associated the ectopic occurrence of follicular melanin after chemotherapy with splenic melanosis an interesting example of extradermal melanin localization and we expected an increase in splenic melanin deposition after chemotherapy. Using the C57BL/6 murine model of synchronized hair cycle induced by depilation, we visualized splenic melanin by means of several histological and histochemical protocols of staining: hematoxylin and eosin, May-Grunwald-Giemsa and Fontana-Masson. Unexpectedly, the splenic deposition of melanin decreased due to application of cyclophosphamide (i.p. 120 mg/kg body weight on day 9 post depilation). The drop was abrupt and lasted for at least 5 days (day 13-18 post depilation), as compared with normal hair cycle. Moreover, in mice with normal, depilation-induced hair cycle we observed a similar drop shortly before entering catagen (day 15 post depilation), followed by a slow and partial increase in splenic melanization up to day 27 post depilation in both groups. We conclude that cyclophosphamide negatively affects splenic melanization and/or extradermal transfer of ectopic melanin from the dystrophic hair follicles, but the most powerful down-regulator of splenic melanosis is normal and dystrophic catagen the phase of hair follicle involution and re-modelling

Postawy młodych konsumentów wobec ekologicznych produktów piekarniczych i cukierniczych – studium przypadku

W pracy przedstawiono wyniki badań dotyczące postaw młodych konsumentów wobec nowo zaprojektowanych, niedostępnych w sprzedaży ekologicznych produktów piekarniczych (10 wariantów rogali) oraz cukierniczych (10 wariantów muffin). Receptura poddanych ocenie produktów ekologicznych nie uwzględniała dodatku sacharozy i substancji słodzących. Ciasto wzbogacono kombinacją owoców i warzyw tj. suszone i świeże jabłka, rodzynki, burak czerwony, burak biały, dynia, marchew, śliwka, czereśnia oraz twarogiem. Badania wykazały, iż młodzi konsumenci nie są potencjalnym segmentem nabywców produktów ekologicznych cechujących się otrzymanymi walorami sensorycznymi. Jedynie nieliczne spośród poddanych ocenie produktów były przez badaną grupę akceptowane. Z kolei najbardziej akceptowane produkty cechowały się jedynie umiarkowanym stopniem akceptowalności. Stwierdzono, iż dla młodych konsumentów walory sensoryczne (smak) żywności ekologicznej są kluczowym czynnikiem wpływającym na postawy wobec tej żywności oraz chęci jej zakupu. Wykazano, iż świadomość cech prozdrowotnych żywności ekologicznej nie gwarantuje jej nabywania

Zaburzenia gospodarki węglowodanowej u kobiet z zespołem wielotorbielowatych jajników (PCOS)

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. Apart from menstrual disturbances and hyperandrogenism, PCOS is characterized by central obesity which leads to the disturbances of carbohydrate and lipid metabolism as well as the development of arterial hypertension. The profile of metabolic disturbances seen in women with PCOS is very similar to those seen in the metabolic syndrome (MS). The culprit in both is the insulin resistance and its ensuing hyperinsulinemia which in turn lead to the disturbances of carbohydrate metabolism. Therefore, the diagnosis of PCOS might also point to an increased risk of diabetes type 2 (T2DM) and cardiovascular disease development, which actually has been shown in several studies conducted in the last ten years. Thus, the pharmacological treatment of PCOS should not only concentrate on the alleviation of signs of hyperandrogenism and menstrual disturbances but also prevent the consequences of the existing metabolic disturbances. Insulin sensitizing drugs are commonly used in the treatment of women with PCOS not only to improve the existing metabolic dearrangements but also in the induction of ovulation. Nevertheless, non-pharmacologic strategies which improve insulin sensitivity such as weight loss, physical activity and restriction of foods with high glycemic index should be the first line of therapy in these women. This review presents recent advances in the diagnosis and the prevention of carbohydrate metabolism disorders in women with PCOS.Zespół wielotorbielowatych jajników (z ang. polycystic ovary syndrome - PCOS) jest najczęściej występującą endokrynopatią u kobiet w wieku rozrodczym. Poza zaburzeniami miesiączkowania i hiperandrogenizmem, PCOS charakteryzuje obecność otyłości, zwłaszcza typu brzusznego, która prowadzi do zaburzeń gospodarki węglowodanowej i lipidowej oraz zwiększa ryzyko rozwoju nadciśnienia tętniczego. Profil zaburzeń przemiany materii kobiet z PCOS jest bardzo podobny do tych stwierdzanych w zespole metabolicznym (MS – metabolic syndrome). Kluczowym czynnikiem sprawczym w obu tych zespołach jest insulinooporność i wynikająca z niej hiperinsulinemia, które w konsekwencji prowadzą do zaburzeń gospodarki węglowodanowej. Rozpoznanie PCOS może więc wskazywać na zwiększone ryzyko rozwoju cukrzycy typu 2 i chorób układu sercowo-naczyniowego, co sugerują wyniki badań przeprowadzonych w ostatnim dziesięcioleciu. Leczenie farmakologiczne PCOS nie powinno więc jedynie koncentrować się na niwelowaniu objawów hiperandrogenemii i zaburzeń miesiączkowania, ale również uwzględniać istniejące zaburzenia metaboliczne i zapobiegać ich konsekwencjom. Leki poprawiające wrażliwość tkanek docelowych na działanie insuliny od dawna znajdują zastosowanie w leczeniu PCOS, zarówno w indukcji owulacji, jak i w uzyskaniu poprawy istniejących zaburzeń metabolicznych. Leczeniem pierwszego rzutu zmniejszającym insulinooporność powinno być jednak zawsze postępowanie niefarmakologiczne polegające na redukcji masy ciała, zwiększeniu aktywności fizycznej i unikaniu produktów żywnościowych o wysokim indeksie glikemicznym. W niniejszym opracowaniu przedstawiono obecny stan wiedzy w zakresie diagnostyki i leczenia zaburzeń gospodarki węglowodanowej u kobiet z PCOS

Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake

Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca2+ signals and necrosis in acinar cells. However, bile acid-elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca2+ elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3-sulfate (TLC-S), known to induce Ca2+ oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca2+ signals on extracellular Na+ and the presence of sodium-taurocholate cotransporting polypeptide (NTCP) indicate a Na+-dependent bile acid uptake mechanism in stellate cells. Bile acid treatment caused necrosis predominantly in stellate cells, which was abolished by removal of extracellular Ca2+ and significantly reduced in the absence of Na+, showing that bile-dependent cell death was a downstream event of Ca2+ signals. Finally, combined application of TLC-S and the inflammatory mediator bradykinin caused more extensive necrosis in both stellate and acinar cells than TLC-S alone. Our findings shed new light on the mechanism by which bile acids promote pancreatic pathology. This involves not only signalling in acinar cells but also in stellate cells