Detachment, Futile Cycling and Nucleotide Pocket Collapse in Myosin-V Stepping

Myosin-V is a highly processive dimeric protein that walks with 36nm steps along actin tracks, powered by coordinated ATP hydrolysis reactions in the two myosin heads. No previous theoretical models of the myosin-V walk reproduce all the observed trends of velocity and run-length with [ADP], [ATP] and external forcing. In particular, a result that has eluded all theoretical studies based upon rigorous physical chemistry is that run length decreases with both increasing [ADP] and [ATP]. We systematically analyse which mechanisms in existing models reproduce which experimental trends and use this information to guide the development of models that can reproduce them all. We formulate models as reaction networks between distinct mechanochemical states with energetically determined transition rates. For each network architecture, we compare predictions for velocity and run length to a subset of experimentally measured values, and fit unknown parameters using a bespoke MCSA optimization routine. Finally we determine which experimental trends are replicated by the best-fit model for each architecture. Only two models capture them all: one involving [ADP]-dependent mechanical detachment, and another including [ADP]-dependent futile cycling and nucleotide pocket collapse. Comparing model-predicted and experimentally observed kinetic transition rates favors the latter.Comment: 11 pages, 5 figures, 6 table

Closed-Flux Solutions to the Constraints for Plane Gravity Waves

The metric for plane gravitational waves is quantized within the Hamiltonian framework, using a Dirac constraint quantization and the self-dual field variables proposed by Ashtekar. The z axis (direction of travel of the waves) is taken to be the entire real line rather than the torus (manifold coordinatized by (z,t) is RxR rather than $S_1$ x R). Solutions to the constraints proposed in a previous paper involve open-ended flux lines running along the entire z axis, rather than closed loops of flux; consequently, these solutions are annihilated by the Gauss constraint at interior points of the z axis, but not at the two boundary points. The solutions studied in the present paper are based on closed flux loops and satisfy the Gauss constraint for all z.Comment: 18 pages; LaTe

GIS habitat analysis for lesser prairie-chickens in southeastern New Mexico

BACKGROUND: We conducted Geographic Information System (GIS) habitat analyses for lesser prairie-chicken (LPCH, Tympanuchus pallidicinctus) conservation planning. The 876,799 ha study area included most of the occupied habitat for the LPCH in New Mexico. The objectives were to identify and quantify: 1. suitable LPCH habitat in New Mexico, 2. conversion of native habitats, 3. potential for habitat restoration, and 4. unsuitable habitat available for oil and gas activities. RESULTS: We found 16% of suitable habitat (6% of the study area) distributed in 13 patches of at least 3,200 ha and 11% of suitable habitat (4% of the study area) distributed in four patches over 7,238 ha. The area converted from native vegetation types comprised 17% of the study area. Ninety-five percent of agricultural conversion occurred on private lands in the northeastern corner of the study area. Most known herbicide-related conversions (82%) occurred in rangelands in the western part of the study area, on lands managed primarily by the US Bureau of Land Management (BLM). We identified 88,190 ha (10% of the study area) of habitats with reasonable restoration potential. Sixty-two percent of the primary population area (PPA) contained occupied, suitable, or potentially suitable habitat, leaving 38% that could be considered for oil and gas development. CONCLUSION: Although suitable LPCH habitat appears at first glance to be abundant in southeastern New Mexico, only a fraction of apparently suitable vegetation types constitute quality habitat. However, we identified habitat patches that could be restored through mesquite control or shin-oak reintroduction. The analysis also identified areas of unsuitable habitat with low restoration potential that could be targeted for oil and gas exploration, in lieu of occupied, high-quality habitats. Used in combination with GIS analysis and current LPCH population data, the habitat map represents a powerful conservation and management tool

The β-lactam antibiotic ceftriaxone as a treatment for the symptoms of Parkinson’s disease and L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopamine (DA) neurons in the substantia nigra. The most effective treatment is DA replacement therapy using the DA precursor L-DOPA, which can unfortunately often result in L-DOPA-induced dyskinesia (LID). Animal studies in hemi-Parkinsonian rats have shown glutamatergic NMDA receptor antagonists to be effective in treating both PD symptoms and LID, however, the cognitive side effects prevent these drugs from passing clinical trials. Upregulation of GLT-1, the primary glutamate transporter that removes glutamate from the synapse, could be an alternative to direct receptor antagonism. The β-lactam antibiotic ceftriaxone has been shown to substantially increase GLT-1 protein expression and activity in the brain without side effects. In Experiment 1 it was found that sub-chronic injections of 100 mg/kg ceftriaxone in unilaterally 6-OHDA-lesioned rats caused a 44% increase in impaired forepaw stepping, a measure of bradykinesia, that lasted at least 30 days after the last ceftriaxone injection. In Experiment 2, sub-chronic injections of 50 mg/kg ceftriaxone resulted in a 41% increase in impaired forepaw stepping that was found to be equivalent to that produced by 10 mg/kg L-DOPA. However unlike ceftriaxone, treatment with L-DOPA resulted in the development of L-DOPA-induced dyskinesia. Ceftriaxone was able to slow the development of LID, but not decrease the expression of pre-established LID. Indicating that the effects of ceftriaxone on forepaw stepping were due to enhanced GLT-1 function, injections of the selective GLT-1 inhibitor, dihydrokainate (DHK) reduced the improvement in stepping produced by ceftriaxone. Collectively, these data indicate that ceftriaxone may be a superior treatment for Parkinson’s disease than L-DOPA

Side effects of phenobarbital and carbamazepine in childhood epilepsy: randomised controlled trial

Objective: To compare the behavioural side effects associated with two commonly used antiepilepsy drugs--phenobarbital and carbamazepine--in children in Bangladesh. Design: Prospective randomised controlled single centre trial. Setting: Specialist children's hospital in Dhaka, Bangladesh. Participants: 108 children aged 2-15 with generalised tonic-clonic (n=51) or partial and secondary generalised seizures (n=57). Main outcome measures: Seizure control and behavioural side effects. Results: 91 children were followed up for 12 months. Six required a change of antiepilepsy drug. Side effects were compared in 85 children. In the last quarter of the 12 month follow-up, 71 children were seizure free after one year's treatment. Thirty two in the phenobarbital group and 39 in the carbamazepine group had no seizures in 74 and 102 days after randomisation, respectively. Ten children had increased behavioural problems, which were unacceptable in four (one in the phenobarbital group and three in the carbamazepine group). Independent t tests, however, showed no difference between the two trial drugs. Conclusion: There was no excess in behavioural side effects with phenobarbital in children with epilepsy in a country with limited resources