Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous.

Mice deficient for the expression of CTLA-4 develop a lethal lymphoproliferative syndrome and multiorgan inflammation leading to death at about 4 wk of age. Here we show that RAG2-deficient mice reconstituted with CTLA-4-deficient bone marrow do not develop a lymphoproliferative syndrome despite lymphocyte infiltration mainly into pericardium and liver. Moreover, RAG2-deficient mice reconstituted with a mixture of normal and CTLA-4-deficient bone marrow remain healthy and do not develop any disease. Thus, the lethal disease observed in CTLA-4-deficient mice is not T cell autonomous and can be prevented by factors produced by normal T cells.     

Feasibility of using EMG driven neuromusculoskeletal model for prediction of dynamic movement of the elbow.

Neuromusculoskeletal (NMS) modeling is a valuable tool in orthopaedic biomechanics and motor control research. To evaluate the feasibility of using electromyographic (EMG) signals with NMS modeling to estimate individual muscle force during dynamic movement, an EMG driven NMS model of the elbow was developed. The model incorporates dynamical equation of motion of the forearm, musculoskeletal geometry and musculotendon modeling of four prime elbow flexors and three prime elbow extensors. It was first calibrated to two normal subjects by determining the subject-specific musculotendon parameters using computational optimization to minimize the root mean square difference between the predicted and measured maximum isometric flexion and extension torque at nine elbow positions (0-120 degrees of flexion with an increment of 15 degrees ). Once calibrated, the model was used to predict the elbow joint trajectories for three flexion/extension tasks by processing the EMG signals picked up by both surface and fine electrodes using two different EMG-to-activation processing schemes reported in the literature without involving any trajectory fitting procedures. It appeared that both schemes interpreted the EMG somewhat consistently but their prediction accuracy varied among testing protocols. In general, the model succeeded in predicting the elbow flexion trajectory in the moderate loading condition but over-drove the flexion trajectory under unloaded condition. The predicted trajectories of the elbow extension were noted to be continuous but the general shape did not fit very well with the measured one. Estimation of muscle activation based on EMG was believed to be the major source of uncertainty within the EMG driven model. It was especially so apparently when fine wire EMG signal is involved primarily. In spite of such limitation, we demonstrated the potential of using EMG driven neuromusculoskeletal modeling for non-invasive prediction of individual muscle forces during dynamic movement under certain conditions.     

Genomes of Pleistocene Siberian Wolves Uncover Multiple Extinct Wolf Lineages

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Androgen-dependent fibrinolytic activity in a murine mammary carcinoma (Shionogi SC-115 cells) in vitro.

Physiological concentrations of dihydrotestosterone (DHT) can specifically induce the release of fibrinolysin from androgen-dependent mammary carcinoma (Shionogi SC-115) cells in vitro. No fibrinolytic activity was observed in cells cultured either in the absence of DHT or presence of pharmacological concentrations of estrogen. Furthermore, an autonomous tumor derived from the Shionogi SC-115 cells produced fibrinolytic activity independent of added DHT or estrogen. These observations suggest a close correlation between fibrinolytic activity of a tumor and its ability to grow in vivo.     

Single-Channel Kinetics,Inactivation, and Spatial Distribution of Inositol Trisphosphate (IP3) Receptors in Xenopus Oocyte Nucleus

Single-channel properties of the Xenopus inositol trisphosphate receptor (IP₃R) ion channel were examined by patch clamp electrophysiology of the outer nuclear membrane of isolated oocyte nuclei. With 140 mM K⁺ as the charge carrier (cytoplasmic [IP₃] = 10 μM, free [Ca²⁺] = 200 nM), the IP₃R exhibited four and possibly five conductance states. The conductance of the most-frequently observed state M was 113 pS around 0 mV and ∼300 pS at 60 mV. The channel was frequently observed with high open probability (mean P _o = 0.4 at 20 mV). Dwell time distribution analysis revealed at least two kinetic states of M with time constants τ < 5 ms and ∼20 ms; and at least three closed states with τ ∼1 ms, ∼10 ms, and >1 s. Higher cytoplasmic potential increased the relative frequency and τ of the longest closed state. A novel “flicker” kinetic mode was observed, in which the channel alternated rapidly between two new conductance states: F₁ and F₂. The relative occupation probability of the flicker states exhibited voltage dependence described by a Boltzmann distribution corresponding to 1.33 electron charges moving across the entire electric field during F₁ to F₂ transitions. Channel run-down or inactivation (τ ∼ 30 s) was consistently observed in the continuous presence of IP₃ and the absence of change in [Ca²⁺]. Some (∼10%) channel disappearances could be reversed by an increase in voltage before irreversible inactivation. A model for voltage-dependent channel gating is proposed in which one mechanism controls channel opening in both the normal and flicker modes, whereas a separate independent mechanism generates flicker activity and voltage- reversible inactivation. Mapping of functional channels indicates that the IP₃R tends to aggregate into microscopic (<1 μm) as well as macroscopic (∼10 μm) clusters. Ca²⁺-independent inactivation of IP₃R and channel clustering may contribute to complex [Ca²⁺] signals in cells.     

The New Rga Locus Encodes a Negative Regulator of Gibberellin Response in Arabidopsis Thaliana

We have identified a new locus involved in gibberellin (GA) signal transduction by screening for suppressors of the Arabidopsis thaliana GA biosynthetic mutant ga1-3. The locus is named RGA for repressor of ga1-3. Based on the recessive phenotype of the digenic rga/ga1-3 mutant, the wild-type gene product of RGA is probably a negative regulator of GA responses. Our screen for suppressors of ga1-3 identified 17 mutant alleles of RGA as well as 10 new mutant alleles at the previously identified SPY locus. The digenic (double homozygous) rga/ga1-3 mutants are able to partially repress several defects of ga1-3 including stem growth, leaf abaxial trichome initiation, flowering time, and apical dominance. The phenotype of the trigenic mutant (triple homozygous) rga/spy/ga1-3 shows that rga and spy have additive effects regulating flowering time, abaxial leaf trichome initiation and apical dominance. This trigenic mutant is similar to wild type with respect to each of these developmental events. Because rga/spy/ga1-3 is almost insensitive to GA for hypocotyl growth and its bolting stem is taller than the wild-type plant, the combined effects of the rga and spy mutations appear to allow GA-independent stem growth. Our studies indicate that RGA lies on a separate branch of the GA signal transduction pathway from SPY, which leads us to propose a modified model of the GA response pathway.