Translation of hepatitis C virus RNA

The 341-nucleotide 5' non-translated region is the most conserved part of the hepatitis C virus (HCV) genome. It contains a highly structured internal ribosomal entry site (IRES) that mediates cap-independent initiation of translation of the viral polyprotein by a mechanism that is unprecedented in eukaryotes. The first step in translation initiation is assembly of eukaryotic initiation factor (eIF) 3, eIF2, GTP, initiator tRNA and a 40S ribosomal subunit into a 43S preinitiation complex. The HCV IRES recruits this complex and directs its precise attachment at the initiation codon to form a 48S complex in a process that does not involve eIFs 4A, 4B or 4F. The IRES contains sites that bind independently with the eIF3 and 40S subunit components of 43S complexes, and structural determinants that ensure the correct spatial orientation of these binding sites so that the 48S complex assembles precisely at the initiation codon.     

Association between energy cost of walking,muscle activation,and biomechanical parameters in older female fallers and non-fallers

Objective

To determine the nervous activation, muscle strength, and biomechanical parameters that influence the cost of walking in older fallers and non-fallers.

Methods

Maximal voluntary isokinetic torque was measured for the hip, knee and ankle of older women. Oxygen consumption was measured at rest and during 8 min of walking at self-selected speed. An additional minute of walking was performed to collect kinematic variables and the electromyographic signal of trunk, hip, knee, and ankle muscles, which was analyzed by the linear envelope. Cost of walking was calculated by subtracting resting body mass-normalized oxygen consumption from walking body mass-normalized oxygen consumption. Stride time and length, and ankle and hip range of motion were calculated from kinematic data.

Findings

Older adult fallers had 28% lower knee extensor strength (p = 0.02), 47% lower internal oblique activation at heel contact (p = 0.03), and higher coactivation between tibialis anterior and gastrocnemius lateralis in each of the gait phases (p < 0.05). For fallers, a higher activation of gluteus maximus was associated with a higher cost of walking (r = 0.55, p < 0.05 and r = 0.71, p < 0.01, before and after heel contact, respectively). For non-fallers, an association between cost of walking and age (r = 0.60, p = 0.01) and cost of walking and thigh muscle coactivation (r = 0.53, p = 0.01) existed.

Interpretation

This study demonstrated that there may be links between lower-extremity muscle weakness, muscle activation patterns, altered gait, and increased cost of walking in older fallers.     

Symptom reporting during voluntary hyperventilation and mental load: Implications for diagnosing hyperventilation syndrome

Hyperventilation is considered an important factor in the production of a variety of somatic symptoms. This complex of symptoms is called the Hyperventilation Syndrome (HVS). Recognition of symptoms during the hyperventilation provocation test (HVPT) is a widely used criterion for diagnosing HVS. The validity of this criterion is tested in the present study.

Twenty-three patients suspected of HVS performed a HVPT (hyperventilation during 3 min) and a mental load task (Stroop Color Word Test; CWT). It appeared that about the same number of patients (61%) recognized symptoms during the HVPT as during the CWT (52%), despite severe hypocapnia in the first test and normocapnia in the second. Reporting of symptoms was significantly related to psychological state and trait measures (SCL-90 and STAI scores) and unrelated to the degree of hypocapnia. These data have far reaching consequences, as they not only undermine the validity of the HVPT, but also question the tenability of the concept of HVS.     

Rheological properties of three component creams containing sorbitan monoesters as surfactants

The objectives of the present study were (1) to evaluate the effect of formulation ingredients on the release rate of Ubiquinone from its adsorbing solid compact; and (2) to prepare and evaluate an optimized self-nanoemulsified tablet formulation. A three factor, three-level Box–Behnken design was used for the optimization procedure, with the amounts of copolyvidone (X₁), maltodextrin (X₂) and microcrystalline cellulose (X₃) as the independent variables. The response variable was cumulative percent of Ubiquinone emulsified in 45 min with constraints on weight, flowability index, tensile strength, friability and disintegration time of the dry powdered emulsion and the resultant compact. Based on the experimental design, different Ubiquinone release rates and profiles were obtained. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the cumulative percent emulsified in 45 min was Y₆=64.10−12.32X₁−4.36X₂−25.53X₃+6.99X₁X₂+3.97X₁X₃+9.70X₂X₃−8.98X₁²−16.22X₂²+17.10X₃². The optimization model predicted an 85.4% release with X₁, X₂ and X₃ levels of 66.6, 560.1 and 100, respectively. A new formulation was prepared according to these levels. The observed responses were in close agreement with the predicted values of the optimized formulation.     

Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma

Studies in mice and humans have revealed that the T cell, immunoglobulin, mucin (TIM) genes are associated with several atopic diseases. TIM-1 is a type I membrane protein that is expressed on T cells upon stimulation and has been shown to modulate their activation. In addition to a recently described interaction with dendritic cells, TIM-1 has also been identified as a phosphatidylserine recognition molecule, and several protein ligands have been proposed. Our understanding of its activity is complicated by the possibility that TIM-1 possesses multiple and diverse binding partners. In order to delineate the function of TIM-1, we generated monoclonal antibodies directed to a cleft formed within the IgV domain of TIM-1. We have shown here that antibodies that bind to this defined cleft antagonize TIM-1 binding to specific ligands and cells. Notably, these antibodies exhibited therapeutic activity in a humanized SCID model of experimental asthma, ameliorating inflammation, and airway hyperresponsiveness. Further experiments demonstrated that the effects of the TIM-1–specific antibodies were mediated via suppression of Th2 cell proliferation and cytokine production. These results demonstrate that modulation of the TIM-1 pathway can critically influence activated T cells in a humanized disease model, suggesting that TIM-1 antagonists may provide potent therapeutic benefit in asthma and other immune-mediated disorders.