Flares from tidal disruption events are unique tracers of quiescent black holes at the centre of galaxies. The appearance of these flares is very sensitive to whether the star is totally or partially ...disrupted, and in this paper we seek to identify the critical distance of the star from the black hole (rd) that enables us to distinguish between these two outcomes. We perform here mesh-free finite mass, traditional, and modern smoothed particle hydrodynamical simulations of star-black hole close encounters, with the aim of checking if the value of rd depends on the simulation technique. We find that the critical distance (or the so-called critical disruption parameter βd) depends only weakly on the adopted simulation method, being βd = 0.92 ± 0.02 for a γ = 5/3 polytrope and βd = 2.01 ± 0.01 for a γ = 4/3 polytrope.
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FMFMET, NUK, UL, UM, UPUK
Both experimental and modeling studies have attempted to determine mechanisms by which a small anatomical region, such as the sinoatrial node (SAN), can robustly drive electrical activity in the ...human heart. However, despite many advances from prior research, important questions remain unanswered. This study aimed to investigate, through mathematical modeling, the roles of intercellular coupling and cellular heterogeneity in synchronization and pacemaking within the healthy and diseased SAN. In a multicellular computational model of a monolayer of either human or rabbit SAN cells, simulations revealed that heterogenous cells synchronize their discharge frequency into a unique beating rhythm across a wide range of heterogeneity and intercellular coupling values. However, an unanticipated behavior appeared under pathological conditions where perturbation of ionic currents led to reduced excitability. Under these conditions, an intermediate range of intercellular coupling (900-4000 MΩ) was beneficial to SAN automaticity, enabling a very small portion of tissue (3.4%) to drive propagation, with propagation failure occurring at both lower and higher resistances. This protective effect of intercellular coupling and heterogeneity, seen in both human and rabbit tissues, highlights the remarkable resilience of the SAN. Overall, the model presented in this work allowed insight into how spontaneous beating of the SAN tissue may be preserved in the face of perturbations that can cause individual cells to lose automaticity. The simulations suggest that certain degrees of gap junctional coupling protect the SAN from ionic perturbations that can be caused by drugs or mutations.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This phase 1b, open-label, dose-escalation study assessed the safety, efficacy, and pharmacokinetics of anti-CD38 monoclonal antibody isatuximab given in 2 schedules (3, 5, or 10 mg/kg every other ...week Q2W or 10 or 20 mg/kg weekly QW for 4 weeks and then Q2W thereafter QW/Q2W), in combination with lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (QW), in patients with relapsed/refractory multiple myeloma (RRMM). Patients received 28-day treatment cycles; the primary objective was to determine the maximum tolerated dose (MTD) of isatuximab with lenalidomide and dexamethasone. Fifty-seven patients (median 5 range 1-12 prior regimens; 83% refractory to previous lenalidomide therapy) were treated. Median duration of dosing was 36.4 weeks; 15 patients remained on treatment at data cutoff. Isatuximab-lenalidomide-dexamethasone was generally well tolerated with only 1 dose-limiting toxicity reported (grade 3 pneumonia at 20 mg/kg QW/Q2W); the MTD was not reached. The most common isatuximab-related adverse events were infusion-associated reactions (IARs) (56%), which were grade 1/2 in 84% of patients who had an IAR and predominantly occurred during the first infusion. In the efficacy-evaluable population, the overall response rate (ORR) was 56% (29/52) and was similar between the 10 mg/kg Q2W and 10 and 20 mg/kg QW/Q2W cohorts. The ORR was 52% in 42 evaluable lenalidomide-refractory patients. Overall median progression-free survival was 8.5 months. Isatuximab exposure increased in a greater than dose-proportional manner; isatuximab and lenalidomide pharmacokinetic parameters appeared independent. These data suggest that isatuximab combined with lenalidomide and dexamethasone is active and tolerated in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as #NCT01749969.
•Isatuximab (anti-CD38 monoclonal antibody) given with lenalidomide/ dexamethasone is active in heavily pretreated relapsed/refractory myeloma•Overall, the safety profile of this combination is similar to the characteristic safety profiles of the individual agents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ANG II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative ...contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (∼65% increase, P < 0.001), an effect that was blunted in the absence of functional TLR4. ANG II increased ROS production, as indicated by dihydroethidium fluorescence, within the PVN of rats and mice (P < 0.0001 in both cases), effects that were also dependent on the presence of functional TLR4. The microglial inhibitor minocycline attenuated ANG II-mediated ROS production, yet ANG II effects persisted in PVN single-minded 1-AT1a knockout mice, supporting the contribution of a non-neuronal source (likely microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT1 receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN.
One main mechanism of insulin resistance (IR), a key feature of type 2 diabetes, is the accumulation of saturated fatty acids (FAs) in the muscles of obese patients with type 2 diabetes. ...Understanding the mechanism that underlies lipid-induced IR is an important challenge. Saturated FAs are metabolized into lipid derivatives called ceramides, and their accumulation plays a central role in the development of muscle IR. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi apparatus through a transporter called CERT, where they are converted into various sphingolipid species. We show that CERT protein expression is reduced in all IR models studied because of a caspase-dependent cleavage. Inhibiting CERT activity in vitro potentiates the deleterious action of lipotoxicity on insulin signaling, whereas overexpression of CERT in vitro or in vivo decreases muscle ceramide content and improves insulin signaling. In addition, inhibition of caspase activity prevents ceramide-induced insulin signaling defects in C2C12 muscle cells. Altogether, these results demonstrate the importance of physiological ER-to-Golgi ceramide traffic to preserve muscle cell insulin signaling and identify CERT as a major actor in this process.
Hoolihan, J. P., Luo, J., Abascal, F. J., Campana, S. E., De Metrio, G., Dewar, H., Domeier, M. L., Howey, L. A., Lutcavage, M. E., Musyl, M. K., Neilson, J. D., Orbesen, E. S., Prince, E. D., and ...Rooker, J. R. 2011. Evaluating post-release behaviour modification in large pelagic fish deployed with pop-up satellite archival tags. - ICES Journal of Marine Science, 68: 880-889.Post-release behaviour modification, possibly a result of capture and handling stress, was evaluated using empirical eigenfunction analysis to detect changes in vertical movement patterns recorded by 183 pop-up satellite archival tags (PSATs) deployed on large pelagic fish. Argos-transmitted summary, timed interval, and some archival data were included. Scoring of irregular post-release behaviour was based on a separation of plotted eigenfunction coefficient values by their mean, with the transection across the mean reference line denoting the duration of irregular behaviour. In all, 67 (36.6%) individual fish exhibited irregular behaviour, lasting from 3 to 60 d (mean = 15.8, s.d. = 10.4). An additional 27 (14.8%) displayed patterns suggestive of irregular behaviour. Data quality and quantity were important criteria for revealing behaviour patterns. Irregular behaviour was detected in 32.6% of Argos-transmitted dataseries, increasing to 60.6% in the higher-resolution archival series. Decreased vertical movement characterized the irregular behaviour of blue sharks (Prionace glauca) and porbeagles (Lamna nasus), whereas all other species showed increased vertical activity. The approach described provides a useful method of revealing behavioural modification during the post-release recovery period of PSAT-tagged large pelagic fish, although the extent of influence on normal behaviour is not fully understood.
Understanding the effects of anthropogenic disturbance on zoonotic disease risk is both a critical conservation objective and a public health priority. Here, we evaluate the effects of multiple forms ...of anthropogenic disturbance across a precipitation gradient on the abundance of pathogen-infected small mammal hosts in a multi-host, multi-pathogen system in central Kenya. Our results suggest that conversion to cropland and wildlife loss alone drive systematic increases in rodent-borne pathogen prevalence, but that pastoral conversion has no such systematic effects. The effects are most likely explained both by changes in total small mammal abundance, and by changes in relative abundance of a few high-competence species, although changes in vector assemblages may also be involved. Several pathogens responded to interactions between disturbance type and climatic conditions, suggesting the potential for synergistic effects of anthropogenic disturbance and climate change on the distribution of disease risk. Overall, these results indicate that conservation can be an effective tool for reducing abundance of rodent-borne pathogens in some contexts (e.g. wildlife loss alone); however, given the strong variation in effects across disturbance types, pathogen taxa and environmental conditions, the use of conservation as public health interventions will need to be carefully tailored to specific pathogens and human contexts.
This article is part of the themed issue ‘Conservation, biodiversity and infectious disease: scientific evidence and policy implications’.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Numerous commonly prescribed drugs, including antiarrhythmics, antihistamines, and antibiotics, carry a proarrhythmic risk and may induce dangerous arrhythmias, including the potentially fatal ...Torsades de Pointes. For this reason, cardiotoxicity testing has become essential in drug development and a required step in the approval of any medication for use in humans. Blockade of the hERG K
channel and the consequent prolongation of the QT interval on the ECG have been considered the gold standard to predict the arrhythmogenic risk of drugs. In recent years, however, preclinical safety pharmacology has begun to adopt a more integrative approach that incorporates mathematical modeling and considers the effects of drugs on multiple ion channels. Despite these advances, early stage drug screening research only evaluates QT prolongation in experimental and computational models that represent healthy individuals. We suggest here that integrating disease modeling with cardiotoxicity testing can improve drug risk stratification by predicting how disease processes and additional comorbidities may influence the risks posed by specific drugs. In particular, chronic systemic inflammation, a condition associated with many diseases, affects heart function and can exacerbate medications' cardiotoxic effects. We discuss emerging research implicating the role of inflammation in cardiac electrophysiology, and we offer a perspective on how
modeling of inflammation may lead to improved evaluation of the proarrhythmic risk of drugs at their early stage of development.
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