Paradoxes of causal loops in spacetime

There is, among some scientists and philosophers, the idea that any theory that would allow the time travel would introduce causal issues. These types of temporal paradoxes can be avoided by the Novikov self-consistency principle or by a variation in the interpretation of many worlds with interacting worlds. The world in which we live has, according to David Lewis, a Parmenidean ontology: "a manifold of events in four dimensions," and the occupants of the world are the 4-dimensional aggregates of the stages - "temporal lines". The causal loops in backwards time travel involve events that appear to "come from nowhere," paradoxical "self-existent" objects or information, resulting in a bootstrap paradox. Many believe that causality loops are not impossible or unacceptable, but only inexplicable. DOI: 10.13140/RG.2.2.28792.7040

Support Vector Machine Algorithm for Real-Time Detection of VF Signals

AbstractAn algorithm for detecting ventricular fibrillation (VF) by the method of support vector machine is presented. The algorithm first extracts the feature of electrocardiogram in every 4s sliding window by the improved time delay method and the parameter d is obtained as feature; the support vector machine method is used to realize the discrimination of VF and non-VF signals. For evaluating the new algorithm, the complete BIH-MIT arrhythmia database and the CU database were used to simulate without any pre-selection. The sensitivity, specificity, positive predictability and accuracy were calculated and compared these values with results from an earlier investigation of several different ventricular fibrillation detection algorithms. It shows that the new algorithm has good performance and has greater advantages in real-time execution

Evaluating the Role of the Steroid and Xenobiotic Receptor (SXR/PXR) in PCB-153 Metabolism and Protection against Associated Adverse Effects during Perinatal and Chronic Exposure in Mice.

BACKGROUND:Polychlorinated biphenyls (PCBs) are environmental toxicants; PCB exposure has been associated with adverse effects on wildlife and humans. However, the mechanisms underlying these adverse effects are not fully understood. The steroid and xenobiotic receptor [SXR; also known as the pregnane X receptor (PXR) and formally known as NR1I2] is a nuclear hormone receptor that regulates inducible metabolism of drugs and xenobiotics and is activated or inhibited by various PCB congeners. OBJECTIVES:The aim of this study was to investigate the effects of exposure to PCB-153, the most prevalent PCB congener in human tissues, on SXR knockout mice (SXRKO) and to elucidate the role of SXR in PCB-153 metabolism and promotion of its harmful effects. METHODS:Wild-type (WT) and SXRKO mice were chronically or perinatally exposed to a low dose (54μg/kg/d) of PCB-153. Blood, livers, and spleens were analyzed using transcriptome sequencing (RNA-seq) and molecular techniques to investigate the impacts of exposure on metabolism, oxidative stress, and hematological parameters. RESULTS:SXRKO mice perinatally exposed to PCB-153 displayed elevated oxidative stress, symptoms of hemolytic anemia, and premature death. Transcriptomal analysis revealed that expression of genes involved in metabolic processes was altered in SXRKO mice. Elevated levels of the PCB-153 metabolite, 3-OH-PCB-153, were found in exposed SXRKO mice compared to exposed WT mice. Blood hemoglobin (HGB) levels were lower throughout the lifespan, and the occurrence of intestinal tumors was larger in SXRKO mice chronically exposed to PCB-153 compared to vehicle and WT controls. DISCUSSION:Our results suggest that altered metabolism induced by SXR loss of function resulted in the accumulation of hydroxylated metabolites upon exposure to PCB-153, leading to oxidative stress, hemolytic anemia, and tumor development in a mouse model. These results support a major role for SXR/PXR in protection against xenobiotic-induced oxidative stress by maintaining proper metabolism in response to PCB-153 exposure. This role of SXR could be generally applicable to other environmental toxicants as well as pharmaceutical drugs. https://doi.org/10.1289/EHP6262

Identification through action potential clamp of proarrhythmic consequences of the short QT syndrome T618I hERG 'hotspot' mutation

The T618I KCNH2-encoded hERG mutation is the most frequently observed mutation in genotyped cases of the congenital short QT syndrome (SQTS), a cardiac condition associated with ventricular fibrillation and sudden death. Most T618I hERG carriers exhibit a pronounced U wave on the electrocardiogram and appear vulnerable to ventricular, but not atrial fibrillation (AF). The basis for these effects is unclear. This study used the action potential (AP) voltage clamp technique to determine effects of the T618I mutation on hERG current (I(hERG)) elicited by APs from different cardiac regions. Whole-cell patch-clamp recordings were made at 37 °C of I(hERG) from hERG-transfected HEK-293 cells. Maximal I(hERG) during a ventricular AP command was increased ∼4-fold for T618I I(hERG) and occurred much earlier during AP repolarization. The mutation also increased peak repolarizing currents elicited by Purkinje fibre (PF) APs. Maximal wild-type (WT) I(hERG) current during the PF waveform was 87.2 ± 4.5% of maximal ventricular repolarizing current whilst for the T618I mutant, the comparable value was 47.7 ± 2.7%. Thus, the T618I mutation exacerbated differences in repolarizing I(hERG) between PF and ventricular APs; this could contribute to heterogeneity of ventricular-PF repolarization and consequently to the U waves seen in T618I carriers. The comparatively shorter duration and lack of pronounced plateau of the atrial AP led to a smaller effect of the T618I mutation during the atrial AP, which may help account for the lack of reported AF in T618I carriers. Use of a paired ventricular AP protocol revealed an alteration to protective I(hERG) transients that affect susceptibility to premature excitation late in AP repolarization/early in diastole. These observations may help explain altered arrhythmia susceptibility in this form of the SQTS

Optimizing glycerosome formulations via an orthogonal experimental design to enhance transdermal triptolide delivery

Triptolide exerts strong anti-inflammatory and immunomodulatory effects; however, its oral administration might be associated with side effects. Transdermal administration can improve the safety of triptolide. In this study, glycerosomes were prepared as the transdermal vehicle to enhance the transdermal delivery of triptolide. With entrapment efficiency and drug loading as dependent variables, the glycerosome formulation was optimized using an orthogonal experimental design. Phospholipid-to-cholesterol and phospholipid-to-triptolide mass ratios of 30:1 and 5:1, respectively and a glycerol concentration of 20 % (v/v) were used in the optimization. The glycerosomes prepared with the optimized formulation showed good stability, with an average particle size of 153.10 ± 2.69 nm, a zeta potential of –45.73 ± 0.60 mV and an entrapment greater than 75 %. Glycerosomes significantly increased the transdermal delivery of triptolide compared to conventional liposomes. As efficient carriers for the transdermal delivery of drugs, glycerosomes can potentially be used as an alternative to oral triptolide administration

Do We Fully Understand Students' Knowledge States? Identifying and Mitigating Answer Bias in Knowledge Tracing

Knowledge tracing (KT) aims to monitor students' evolving knowledge states through their learning interactions with concept-related questions, and can be indirectly evaluated by predicting how students will perform on future questions. In this paper, we observe that there is a common phenomenon of answer bias, i.e., a highly unbalanced distribution of correct and incorrect answers for each question. Existing models tend to memorize the answer bias as a shortcut for achieving high prediction performance in KT, thereby failing to fully understand students' knowledge states. To address this issue, we approach the KT task from a causality perspective. A causal graph of KT is first established, from which we identify that the impact of answer bias lies in the direct causal effect of questions on students' responses. A novel COunterfactual REasoning (CORE) framework for KT is further proposed, which separately captures the total causal effect and direct causal effect during training, and mitigates answer bias by subtracting the latter from the former in testing. The CORE framework is applicable to various existing KT models, and we implement it based on the prevailing DKT, DKVMN, and AKT models, respectively. Extensive experiments on three benchmark datasets demonstrate the effectiveness of CORE in making the debiased inference for KT.Comment: 13 page

Ranolazine inhibition of hERG potassium channels: Drug–pore interactions and reduced potency against inactivation mutants

AbstractThe antianginal drug ranolazine, which combines inhibitory actions on rapid and sustained sodium currents with inhibition of the hERG/IKr potassium channel, shows promise as an antiarrhythmic agent. This study investigated the structural basis of hERG block by ranolazine, with lidocaine used as a low potency, structurally similar comparator. Recordings of hERG current (IhERG) were made from cell lines expressing wild-type (WT) or mutant hERG channels. Docking simulations were performed using homology models built on MthK and KvAP templates. In conventional voltage clamp, ranolazine inhibited IhERG with an IC50 of 8.03μM; peak IhERG during ventricular action potential clamp was inhibited ~62% at 10μM. The IC50 values for ranolazine inhibition of the S620T inactivation deficient and N588K attenuated inactivation mutants were respectively ~73-fold and ~15-fold that for WT IhERG. Mutations near the bottom of the selectivity filter (V625A, S624A, T623A) exhibited IC50s between ~8 and 19-fold that for WT IhERG, whilst the Y652A and F656A S6 mutations had IC50s ~22-fold and 53-fold WT controls. Low potency lidocaine was comparatively insensitive to both pore helix and S6 mutations, but was sensitive to direction of K+ flux and particularly to loss of inactivation, with an IC50 for S620T-hERG ~49-fold that for WT IhERG. Docking simulations indicated that the larger size of ranolazine gives it potential for a greater range of interactions with hERG pore side chains compared to lidocaine, in particular enabling interaction of its two aromatic groups with side chains of both Y652 and F656. The N588K mutation is responsible for the SQT1 variant of short QT syndrome and our data suggest that ranolazine is unlikely to be effective against IKr/hERG in SQT1 patients