Stochastic modeling of cargo transport by teams of molecular motors

Many different types of cellular cargos are transported bidirectionally along microtubules by teams of molecular motors. The motion of this cargo-motors system has been experimentally characterized in vivo as processive with rather persistent directionality. Different theoretical approaches have been suggested in order to explore the origin of this kind of motion. An effective theoretical approach, introduced by M\"uller et al., describes the cargo dynamics as a tug-of-war between different kinds of motors. An alternative approach has been suggested recently by Kunwar et al., who considered the coupling between motor and cargo in more detail. Based on this framework we introduce a model considering single motor positions which we propagate in continuous time. Furthermore, we analyze the possible influence of the discrete time update schemes used in previous publications on the system's dynamic.Comment: Cenference proceedings - Traffic and Granular Flow 1

Oncogenic Foxl2 is a chromatin-remodeling pioneer transcription factor in adult-type ovarian granulosa cell tumors

View full abstracthttps://openworks.mdanderson.org/leading-edge/1008/thumbnail.jp

Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia

BACKGROUND. In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction pathways for granulocyte colony-stimulating factor (G-CSF) may play a part in the progression to acute myeloid leukemia. METHODS. We isolated genomic DNA and RNA from hematopoietic cells obtained from two patients with acute myeloid leukemia and histories of severe congenital neutropenia. The nucleotide sequences encoding the cytoplasmic domain of the G-CSF receptor were amplified by means of the polymerase chain reaction and sequenced. Murine myeloid 32D.C10 cells were transfected with complementary DNA encoding the wild-type or mutant G-CSF receptors and tested for their responses to G-CSF. RESULTS. Point mutations in the gene for the G-CSF receptor were identified in both patients. The mutations, a substitution of thymine for cytosine at the codon for glutamine at position 718 (Gln718) in one patient and at the codon for glutamine at position 731(Gln731) in the other, caused a truncation of the C-terminal cytoplasmic region of the receptor. Both mutant and wild-type genes for the G-CSF receptor were present in leukemic cells from the two patients. In one patient, the mutation was also found in the neutropenic stage, before the progression to acute myeloid leukemia. The 32D.C10 cells expressing mutant receptors had abnormally high proliferative responses but failed to mature when cultured in G-CSF. The mutant G-CSF receptors also interfered with terminal maturation mediated by the wild-type G-CSF receptor in the 32D.C10 cells that coexpressed the wild-type and mutant receptors. CONCLUSIONS. Mutations in the gene for the G-CSF receptor that interrupt signals required for the maturation of myeloid cells are involved in the pathogenesis of severe congenital neutropenia and associated with the progression to acute myeloid leukemia

Comparison of the pharmacodynamic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial

Further to the patent expiry of Neupogen® (Amgen filgrastim), Hospira has developed a biosimilar filgrastim (Nivestim™) that may offer a clinically effective alternative for multiple hematologic and oncologic indications. Here results are reported from a phase I trial, primarily designed to compare the pharmacodynamic profiles of Hospira filgrastim and Amgen filgrastim. A phase I, single-center, double-blind, randomized trial was undertaken to demonstrate equivalence of the pharmacodynamic characteristics of Hospira filgrastim and Amgen filgrastim. Fifty healthy volunteers were randomized to receive 5 or 10 µg/kg dosing, before further randomization to treatment sequence. All volunteers received five daily subcutaneous doses of Hospira filgrastim or Neupogen, with subsequent crossover to the alternative treatment. Bioequivalence was evaluated by analysis of variance; if the estimated 90% confidence intervals (CIs) for the ratio of ‘test’ to ‘reference’ treatment means were within the conventional equivalence limits of 0.80–1.25, then bioequivalence was concluded. Forty-eight volunteers completed the study. Geometric mean absolute neutrophil count area under the curve from time 0 to the last time point at day 5 (primary endpoint) was comparable in volunteers given Hospira filgrastim or Amgen filgrastim at 5 µg/kg (ratio of means, 0.98; 90% CI, 0.92–1.05) or 10 µg/kg (ratio, 0.97; 90% CI, 0.93–1.01); 90% CIs were within the predefined range necessary to demonstrate bioequivalence. Hospira filgrastim was well tolerated with no additional safety concerns over Amgen filgrastim. Hospira filgrastim is bioequivalent with Amgen filgrastim with regard to its pharmacodynamic characteristics

Compound-Specific Radiocarbon Analysis by Elemental Analyzer–Accelerator Mass Spectrometry: Precision and Limitations

[EN]We examine instrumental and methodological capabilities for microscale (10−50μg of C) radiocarbon analysisof individual compounds in the context of paleoclimate and paleoceanography applications, for which relatively high-precisionmeasurements are required. An extensive suite of data for14C-free and modern reference materials processed using differentmethods and acquired using an elemental-analyzer−accelerator-mass-spectrometry (EA-AMS) instrumental setup at ETHZurich was compiled to assess the reproducibility of specific isolation procedures. In order to determine the precision, accuracy,and reproducibility of measurements on processed compounds, we explore the results of both reference materials and threeclasses of compounds (fatty acids, alkenones, and amino acids) extracted from sediment samples. We utilize a MATLAB codedeveloped to systematically evaluate constant-contamination-model parameters, which in turn can be applied to measurementsof unknown process samples. This approach is computationally reliable and can be used for any blank assessment of small-sizeradiocarbon samples. Our results show that a conservative lower estimate of the sample sizes required to produce relativelyhigh-precision14C data (i.e., with acceptable errors of 0.5, a precision of 2% can be achieved for alkenone and fatty acid samples containing≥15 and 10μg of C, respectivel

Modeling traffic jams in intracellular transport in axons

Irregularities in intracellular traffic in axons caused by mutations of molecular motors may lead to “traffic jams”, which often result in swelling of axons causing various neurodegenerative diseases. The purpose of this paper is to suggest a model of the formation of traffic jams in axons during molecular-motor-assisted transport of intracellular organelles utilizing transport equations developed in Smith and Simmons [1], which describe the motion of intracellular particles under the combined action of diffusion and motor-driven transport. According to this model, large intracellular organelles are transported in the cytoplasm by a combined action of diffusion and motor-driven transport. In an axon, organelles are transported away from the neuron’s body toward the axon’s terminal by kinesin-family molecular motors running on tracks composed by microtubules; old and used components are carried back toward neuron’s body by dynein-family molecular motors. Binding/detachment kinetic processes between the organelles and microtubules are specified by first rate reaction constants; these lead to coupling between the three organelle concentrations

Single spontaneous photon as a coherent beamsplitter for an atomic matterwave

In spontaneous emission an atom in an excited state undergoes a transition to the ground state and emits a single photon. Associated with the emission is a change of the atomic momentum due to photon recoil. Photon emission can be modified close to surfaces and in cavities. For an ion, localized in front of a mirror, coherence of the emitted resonance fluorescence has been reported. In free space experiments demonstrated that spontaneous emission destroys motional coherence. Here we report on motional coherence created by a single spontaneous emission event close to a mirror surface. The coherence in the free atomic motion is verified by atom interferometry. The photon can be regarded as a beamsplitter for an atomic matterwave and consequently our experiment extends the original recoiling slit Gedanken experiment by Einstein to the case where the slit is in a robust coherent superposition of the two recoils associated with the two paths of the quanta.Comment: main text: 5 pages, 4 figure; supplementary information: 8 pages, 1 figur

A three dimensional model of the photosynthetic membranes of Ectothiorhodospira halochloris

The three dimensional organization of the complete photosynthetic apparatus of the extremely halophilic, bacteriochlorophyll b containing Ectothiorhodospira halochloris has been elaborated by several techniques of electron microscopy. Essentially all thylakoidal sacs are disc shaped and connected to the cytoplasmic membrane by small membraneous ldquobridgesrdquo. In sum, the lumina of all thylakoids (intrathylakoidal space) form one common periplasmic space. Thin sections confirm a paracrystalline arrangement of the photosynthetic complexes in situ. The ontogenic development of the photosynthetic apparatus is discussed based on a structural model derived from serial thin sections