Noncommutative Quantum Field Theory: A Confrontation of Symmetries

The concept of a noncommutative field is formulated based on the interplay between twisted Poincar\'e symmetry and residual symmetry of the Lorentz group. Various general dynamical results supporting this construction, such as the light-wedge causality condition and the integrability condition for Tomonaga-Schwinger equation, are presented. Based on this analysis, the claim of the identity between commutative QFT and noncommutative QFT with twisted Poincar\'e symmetry is refuted.Comment: 20 page

Crizotinib and Ceritinib Induce Apoptosis and Necrosis in Primary Rat Hepatocytes with Distinct Capacity

Drug development makes up a major portion of biomedical engineering research interests. The FDA oversees the introduction, experimentation, and implementation of all drugs before market approval is granted. Even after market approval is granted, the FDA continues to monitor the safety of all drugs. Crizotinib and ceritinib are two anaplastic lymphoma kinase (ALK) inhibitors recently approved by the FDA. Both drugs are indicated for treatment of non-small cell lung cancers (NSCLC) with abnormal ALK gene, and they are approved with a companion diagnostic test that determines ALK abnormality. Clinical trial data suggest that crizotinib and ceritinib can cause liver injury, and this information has been included in the “Warnings and Precautions” section of their labeling. The mechanism of ALK inhibitor induced hepatotoxicity is unknown. This study aimed to observe if crizotinib and ceritinib are directly toxic to liver cells. Primary cultured rat hepatocytes were treated with crizotinib and ceritinib at clinically relevant concentrations for 4, 8 and 24 h, and apoptosis and necrosis were measured. A ~125% to ~150% increase in caspase 3/7 activity was observed at 8 h for ceritinib treated hepatocytes, and significant necrosis (~40%) occurred at 24 h. Ceritinib treated hepatocytes also showed remarkable cytochrome c release at 4 h, the time point when no cell death was detectable. Crizotinib showed no toxicity at 10-fold the maximal blood concentration (Cmax), while ceritinib became toxic at 3-fold Cmax and caused ~40% cell death at 6-fold Cmax, indicating that ceritinib, the second-generation ALK inhibitor, is significantly more toxic than the first-generation drug crizotinib. These data provide novel insights into the mechanisms of ALK inhibitors associated hepatotoxicity

Mouse MIM, a tissue-specific regulator of cytoskeletal dynamics, interacts with ATP-actin monomers through its C-terminal WH2 domain

The WH2 (WASP homology domain-2) is a small actin monomer-binding motif and is found in many proteins that regulate the actin cytoskeleton, including the beta-thymosins, ciboulot, WASP, and verprolin/WIP (WASP-interacting protein). In sequence database searches we identified a novel mouse protein containing a WH2 domain in its C-terminal region. This mouse gene also shows strong sequence homology to human MIM (Missing in Metastasis), a cDNA fragment that is present in non-metastatic but absent in metastatic bladder cancer cell lines. Northern blot and in situ hybridizations show that MIM is strongly expressed in the developing neurons and skeletal and cardiac muscles in mouse embryos. In adult mice, the strongest expression of MIM mRNA is in liver, outer layers of the kidney, and in the Purkinje cells of the brain. Recombinant MIM protein interacts with actin monomers and inhibits actin filament nucleation in vitro. However, the MIM/ATP-G-actin complex can participate in actin filament assembly at the barbed end. MIM binds ATP-G-actin with a higher affinity (K-D = 0.06 muM) than ADP-G-actin (K-D = 0.3 muM) and inhibits the nucleotide exchange on actin monomers. Site-directed mutagenesis demonstrates that the actin monomer-binding site resides in the C-terminal WH2 domain of MIM. Overexpression of mouse MIM in NIH 3T3 cells results in the disappearance of actin stress fibers and appearance of abnormal actin filament structures. These data show that MIM is an ATP-G-actin binding protein that regulates cytoskeletal dynamics in specialized mammalian cell-types

A common periodic representation of interaural time differences in mammalian cortex

Binaural hearing, the ability to detect small differences in the timing and level of sounds at the two ears, underpins the ability to localize sound sources along the horizontal plane, and is important for decoding complex spatial listening environments into separate objects - a critical factor in 'cocktail-party listening'. For human listeners, the most important spatial cue is the interaural time difference (ITD). Despite many decades of neurophysiological investigations of ITD sensitivity in small mammals, and computational models aimed at accounting for human perception, a lack of concordance between these studies has hampered our understanding of how the human brain represents and processes ITDs. Further, neural coding of spatial cues might depend on factors such as head-size or hearing range, which differ considerably between humans and commonly used experimental animals. Here, using magnetoencephalography (MEG) in human listeners, and electro-corticography (ECoG) recordings in guinea pig-a small mammal representative of a range of animals in which ITD coding has been assessed at the level of single-neuron recordings-we tested whether processing of ITDs in human auditory cortex accords with a frequency-dependent periodic code of ITD reported in small mammals, or whether alternative or additional processing stages implemented in psychoacoustic models of human binaural hearing must be assumed. Our data were well accounted for by a model consisting of periodically tuned ITD-detectors, and were highly consistent across the two species. The results suggest that the representation of ITD in human auditory cortex is similar to that found in other mammalian species, a representation in which neural responses to ITD are determined by phase differences relative to sound frequency rather than, for instance, the range of ITDs permitted by head size or the absolute magnitude or direction of ITD

On h h -transforms of one-dimensional diffusions stopped upon hitting zero

For a one-dimensional diffusion on an interval for which 0 is the regular-reflecting left boundary, three kinds of conditionings to avoid zero are studied. The limit processes are $h$-transforms of the process stopped upon hitting zero, where $h$'s are the ground state, the scale function, and the renormalized zero-resolvent. Several properties of the $h$-transforms are investigated

Predictors of blood pressure and hypertension long-term after treatment of isolated coarctation of the aorta in children-a population-based study

OBJECTIVES The aim of this study was to assess predictors of BP and hypertension and relations between BP and LV mass in a population-based retrospective study of repaired isolated coarctation of aorta. METHODS We collected follow-up data until 2018 of 284/304 (93%) patients with coarctation treated by surgery (n = 235) or balloon angioplasty/stent (n = 37/12) in our unit 2000-2012. Systolic hypertension was defined as systolic BP (SBP) z-score >=+2 standard deviation (SD) or regular use of BP medication. LV hypertrophy was defined as LV mass z-score >=+2 SD or LV mass index g/m(2.7) >= 95th percentile. RESULTS The median (25-75th percentiles) follow-up time and age at follow-up were 9.7 years (6.9-13.2) and 11.8 years (7.9-16.0), respectively. Age at first procedure (P = 0.011) and systolic arm-leg-gradient (P = 0.007) were positively and transverse arch (P = 0.007) and isthmus diameter (P = 0.001) z-scores at follow-up were negatively associated with SBP z-score adjusted for age at follow-up and need for reintervention for coarctation. Systolic hypertension was present in 53/284 (18.7%) and related with increasing age at first procedure (median 33.2 vs 0.6 months; P < 0.001) and arm-leg-gradient at follow-up (mean +/- SD, -0.3 +/- 14.6 vs -6.4 +/- 11.6 mmHg; P = 0.047) adjusted for reintervention for coarctation and age at follow-up. LV hypertrophy was present in 20/227 (9.3%) and related with SBP z-score. CONCLUSIONS Higher SBP and hypertension in repaired coarctation of aorta are related with increasing age at first procedure and arm-leg-gradient at follow-up. Transverse arch and isthmus diameters at follow-up are inversely related with SBP.Peer reviewe

Travertine precipitation in the Paleoproterozoic Kuetsjärvi Sedimentary Formation, Pechenga Greenstone Belt, NE Fennoscandian Shield

PES was supported by Väisälä Foundation (Finnish Academy of Science and Letters) and the Finnish Doctoral Program in Geology. ATB was supported by NERC grant NE/G00398X/1. VAM was supported by NFR grant 191530/V30 (projects 331000 and 802795). This is a contribution (paper) # 18 to the ICDP FAR-DEEP project.Peer reviewedPublisher PD

Cyclase-associated protein 1 (CAP1) promotes cofilin-induced actin dynamics in mammalian nonmuscle cells

Cyclase-associated proteins (CAPs) are highly conserved actin monomer binding proteins present in all eukaryotes. However, the mechanism by which CAPs contribute to actin dynamics has been elusive. In mammals, the situation is further complicated by the presence of two CAP isoforms whose differences have not been characterized. Here, we show that CAP1 is widely expressed in mouse nonmuscle cells, whereas CAP2 is the predominant isoform in developing striated muscles. In cultured NIH3T3 and 1316171 cells, CAP1 is a highly abundant protein that colocalizes with cofilin-1 to dynamic regions of the cortical actin cytoskeleton. Analysis of CAP1 knockdown cells demonstrated that this protein promotes rapid actin filament depolymerization and is important for cell morphology, migration, and endocytosis. Interestingly, depletion of CAP1 leads to an accumulation of cofilin-1 into abnormal cytoplasmic aggregates and to similar cytoskeletal defects to those seen in cofilin-1 knockdown cells, demonstrating that CAP1 is required for proper subcellular localization and function of ADF/cofilin. Together, these data provide the first direct in vivo evidence that CAP promotes rapid actin dynamics in conjunction with ADF/cofilin and is required for several central cellular processes in mammals

Lethal Interaction of Nuclear and Mitochondrial Genotypes in Drosophila melanogaster

Drosophila melanogaster, like most animal species, displays considerable genetic variation in both nuclear and mitochondrial DNA (mtDNA). Here we tested whether any of four natural mtDNA variants was able to modify the effect of the phenotypically mild, nuclear tko(25t) mutation, affecting mitochondrial protein synthesis. When combined with tko(25t), the mtDNA from wild strain KSA2 produced pupal lethality, accompanied by the presence of melanotic nodules in L3 larvae. KSA2 mtDNA, which carries a substitution at a conserved residue of cytochrome b that is predicted to be involved in subunit interactions within respiratory complex III, conferred drastically decreased respiratory capacity and complex III activity in the tko(25t) but not a wild-type nuclear background. The complex III inhibitor antimycin A was able to phenocopy effects of the tko(25t) mutation in the KSA2 mtDNA background. This is the first report of a lethal, nuclear-mitochondrial interaction within a metazoan species, representing a paradigm for understanding genetic interactions between nuclear and mitochondrial genotype relevant to human health and disease.Peer reviewe