Understanding Mechanochemical Coupling in Kinesins Using First-Passage Time Processes

Kinesins are processive motor proteins that move along microtubules in a stepwise manner, and their motion is powered by the hydrolysis of ATP. Recent experiments have investigated the coupling between the individual steps of single kinesin molecules and ATP hydrolysis, taking explicitly into account forward steps, backward steps and detachments. A theoretical study of mechanochemical coupling in kinesins, which extends the approach used successfully to describe the dynamics of conventional motor proteins, is presented. The possibility of irreversible detachments of kinesins from the microtubules is also explicitly taken into account. Using the method of first- passage times, experimental data on the mechanochemical coupling in kinesins are fully described using the simplest two-state model. It is shown that the dwell times for the kinesin to move one step forward or backward, or to dissociate irreversibly are the same, although the probabilities of these events are different. It is concluded that the current theoretical view, that only the forward motion of the motor protein molecule is coupled to ATP hydrolysis, is consistent with all available experimental observations for kinesins.Comment: Submitted to Biophysical Journa

The hot core towards the intermediate mass protostar NGC7129 FIRS 2: Chemical similarities with Orion KL

NGC 7129 FIRS 2 (hereafter FIRS 2) is an intermediate-mass (2 to 8 Msun) protostar located at a distance of 1250 pc. High spatial resolution observations are required to resolve the hot core at its center. We present a molecular survey from 218200 MHz to 221800 MHz carried out with the IRAM Plateau de Bure Interferometer. These observations were complemented with a long integration single-dish spectrum taken with the IRAM 30m telescope. We used a Local Thermodynamic Equilibrium (LTE) single temperature code to model the whole dataset. The interferometric spectrum is crowded with a total of ~300 lines from which a few dozens remain unidentified yet. The spectrum has been modeled with a total of 20 species and their isomers, isotopologues and deuterated compounds. Complex molecules like methyl formate (CH3OCHO), ethanol (CH3CH2OH), glycolaldehyde (CH2OHCHO), acetone (CH3COCH3), dimethyl ether (CH3OCH3), ethyl cyanide (CH3CH2CN) and the aGg' conformer of ethylene glycol (aGg'-(CH2OH)_2) are among the detected species. The detection of vibrationally excited lines of CH3CN, CH3OCHO, CH3OH, OCS, HC3N and CH3CHO proves the existence of gas and dust at high temperatures. In fact, the gas kinetic temperature estimated from the vibrational lines of CH3CN, ~405 K, is similar to that measured in massive hot cores. Our data allow an extensive comparison of the chemistry in FIRS~2 and the Orion hot core. We find a quite similar chemistry in FIRS 2 and Orion. Most of the studied fractional molecular abundances agree within a factor of 5. Larger differences are only found for the deuterated compounds D2CO and CH2DOH and a few molecules (CH3CH2CN, SO2, HNCO and CH3CHO). Since the physical conditions are similar in both hot cores, only different initial conditions (warmer pre-collapse phase in the case of Orion) and/or different crossing time of the gas in the hot core can explain this behavior.Comment: 30 pages, 9 figure

Interaction Between Motor Domains Can Explain the Complex Dynamics of Heterodimeric Kinesins

Motor proteins are active enzyme molecules that play a crucial role in many biological processes. They transform the chemical energy into the mechanical work and move unidirectionally along rigid cytoskeleton filaments. Single-molecule experiments suggest that motor proteins, consisting of two motor domains, move in a hand-over-hand mechanism when each subunit changes between trailing and leading positions in alternating steps, and these subunits do not interact with each other. However, recent experiments on heterodimeric kinesins suggest that the motion of motor domains is not independent, but rather strongly coupled and coordinated, although the mechanism of these interactions are not known. We propose a simple discrete stochastic model to describe the dynamics of homodimeric and heterodimeric two-headed motor proteins. It is argued that interactions between motor domains modify free energy landscapes of each motor subunit, and motor proteins still move via the hand-over-hand mechanism but with different transitions rates. Our calculations of biophysical properties agree with experimental observations. Several ways to test the theoretical model are proposed.Comment: To appear in New J. Phy

Comparison of serious inhaler technique errors made by device-naïve patients using three different dry powder inhalers: a randomised, crossover, open-label study

Background: Serious inhaler technique errors can impair drug delivery to the lungs. This randomised, crossover, open-label study evaluated the proportion of patients making predefined serious errors with Pulmojet compared with Diskus and Turbohaler dry powder inhalers. Methods: Patients ≥18 years old with asthma and/or COPD who were current users of an inhaler but naïve to the study devices were assigned to inhaler technique assessment on Pulmojet and either Diskus or Turbohaler in a randomised order. Patients inhaled through empty devices after reading the patient information leaflet. If serious errors potentially affecting dose delivery were recorded, they repeated the inhalations after watching a training video. Inhaler technique was assessed by a trained nurse observer and an electronic inhalation profile recorder. Results: Baseline patient characteristics were similar between randomisation arms for the Pulmojet-Diskus (n = 277) and Pulmojet-Turbohaler (n = 144) comparisons. Non-inferiority in the proportions of patients recording no nurse-observed serious errors was demonstrated for both Pulmojet versus Diskus, and Pulmojet versus Turbohaler; therefore, superiority was tested. Patients were significantly less likely to make ≥1 nurse-observed serious errors using Pulmojet compared with Diskus (odds ratio, 0.31; 95 % CI, 0.19–0.51) or Pulmojet compared with Turbohaler (0.23; 0.12–0.44) after reading the patient information leaflet with additional video instruction, if required. Conclusions These results suggest Pulmojet is easier to learn to use correctly than the Turbohaler or Diskus for current inhaler users switching to a new dry powder inhaler

Water in Star-Forming Regions with the Herschel Space Observatory (WISH): Overview of key program and first results

`Water In Star-forming regions with Herschel' (WISH) is a key program on the Herschel Space Observatory designed to probe the physical and chemical structure of young stellar objects using water and related molecules and to follow the water abundance from collapsing clouds to planet-forming disks. About 80 sources are targeted covering a wide range of luminosities and evolutionary stages, from cold pre-stellar cores to warm protostellar envelopes and outflows to disks around young stars. Both the HIFI and PACS instruments are used to observe a variety of lines of H2O, H218O and chemically related species. An overview of the scientific motivation and observational strategy of the program is given together with the modeling approach and analysis tools that have been developed. Initial science results are presented. These include a lack of water in cold gas at abundances that are lower than most predictions, strong water emission from shocks in protostellar environments, the importance of UV radiation in heating the gas along outflow walls across the full range of luminosities, and surprisingly widespread detection of the chemically related hydrides OH+ and H2O+ in outflows and foreground gas. Quantitative estimates of the energy budget indicate that H2O is generally not the dominant coolant in the warm dense gas associated with protostars. Very deep limits on the cold gaseous water reservoir in the outer regions of protoplanetary disks are obtained which have profound implications for our understanding of grain growth and mixing in disks.Comment: 71 pages, 10 figures, PASP, in pres

Sensitive limits on the abundance of cold water vapor in the DM Tau protoplanetary disk

We performed a sensitive search for the ground-state emission lines of ortho- and para-water vapor in the DM Tau protoplanetary disk using the Herschel/HIFI instrument. No strong lines are detected down to 3sigma levels in 0.5 km/s channels of 4.2 mK for the 1_{10}--1_{01} line and 12.6 mK for the 1_{11}--0_{00} line. We report a very tentative detection, however, of the 1_{10}--1_{01} line in the Wide Band Spectrometer, with a strength of T_{mb}=2.7 mK, a width of 5.6 km/s and an integrated intensity of 16.0 mK km/s. The latter constitutes a 6sigma detection. Regardless of the reality of this tentative detection, model calculations indicate that our sensitive limits on the line strengths preclude efficient desorption of water in the UV illuminated regions of the disk. We hypothesize that more than 95-99% of the water ice is locked up in coagulated grains that have settled to the midplane.Comment: 5 pages, 3 figures. Accepted for publication in the Herschel HIFI special issue of A&

Hydrides in Young Stellar Objects: Radiation tracers in a protostar-disk-outflow system

Context: Hydrides of the most abundant heavier elements are fundamental molecules in cosmic chemistry. Some of them trace gas irradiated by UV or X-rays. Aims: We explore the abundances of major hydrides in W3 IRS5, a prototypical region of high-mass star formation. Methods: W3 IRS5 was observed by HIFI on the Herschel Space Observatory with deep integration (about 2500 s) in 8 spectral regions. Results: The target lines including CH, NH, H3O+, and the new molecules SH+, H2O+, and OH+ are detected. The H2O+ and OH+ J=1-0 lines are found mostly in absorption, but also appear to exhibit weak emission (P-Cyg-like). Emission requires high density, thus originates most likely near the protostar. This is corroborated by the absence of line shifts relative to the young stellar object (YSO). In addition, H2O+ and OH+ also contain strong absorption components at a velocity shifted relative to W3 IRS5, which are attributed to foreground clouds. Conclusions: The molecular column densities derived from observations correlate well with the predictions of a model that assumes the main emission region is in outflow walls, heated and irradiated by protostellar UV radiation.Comment: Astronomy and Astrophysics Letters, in pres

Self-assembly of the general membrane-remodeling protein PVAP into sevenfold virus-associated pyramids

This is the final version of the article. Available from National Academy of Sciences via the DOI in this record.Viruses have developed a wide range of strategies to escape from the host cells in which they replicate. For egress some archaeal viruses use a pyramidal structure with sevenfold rotational symmetry. Virus-associated pyramids (VAPs) assemble in the host cell membrane from the virus-encoded protein PVAP and open at the end of the infection cycle. We characterize this unusual supramolecular assembly using a combination of genetic, biochemical, and electron microscopic techniques. By whole-cell electron cryotomography, we monitored morphological changes in virus-infected host cells. Subtomogram averaging reveals the VAP structure. By heterologous expression of PVAP in cells from all three domains of life, we demonstrate that the protein integrates indiscriminately into virtually any biological membrane, where it forms sevenfold pyramids. We identify the protein domains essential for VAP formation in PVAP truncation mutants by their ability to remodel the cell membrane. Self-assembly of PVAP into pyramids requires at least two different, in-plane and out-of-plane, protein interactions. Our findings allow us to propose a model describing how PVAP arranges to form sevenfold pyramids and suggest how this small, robust protein may be used as a general membrane-remodeling system.D.P. and T.E.F.Q. received financial support from L’Agence Nationale de la Recherche. W.K. and B.D. received financial support from the Max Planck Society

Color Reflection Invariance and Monopole Condensation in QCD

We review the quantum instability of the Savvidy-Nielsen-Olesen (SNO) vacuum of the one-loop effective action of SU(2) QCD, and point out a critical defect in the calculation of the functional determinant of the gluon loop in the SNO effective action. We prove that the gauge invariance, in particular the color reflection invariance, exclude the unstable tachyonic modes from the gluon loop integral. This guarantees the stability of the magnetic condensation in QCD.Comment: 28 pages, 3 figures, JHEP styl

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13