Impaired myelopoiesis in mice lacking the repressors of translation initiation, 4E-BP1 and 4E-BP2.

We investigated the role of two repressors of translation initiation in granulocytic differentiation using mice with a null mutation in the 4E-BP1 gene or with a null mutation in the 4E-BP2 gene. We show that 4E-BP1(-/-) and 4E-BP2(-/-) mice exhibit an increased number of immature granulocytic precursors, associated with a decreased number of mature granulocytic elements compared with wild-type mice, which is suggestive of an impaired granulocytic differentiation. Clonogenetic analyses revealed a reduced number of granulocytic colonies and concomitant increase in granulo-monocytic colonies in 4E-BP(-/-) mice. Finally, a slight expansion of monocytic cells was observed in the 4E-BP2(-/-) mice. In contrast, we did not observe any significant difference in thymocyte maturation in these mice. These results, together with the fact that 4E-BPs are markedly induced during granulo-monocytic differentiation of myeloid cells in vitro, highlight the pivotal role of 4E-BP1 and 4E-BP2 in the early phases of myelopoiesis. These results represent the first in vivo evidence of the involvement of translation in the early phases of granulo-monocytic differentiation and further extend the role of translation in haematopoietic differentiation.

Effect of acute fatigue of the hip abductors on control of balance in young and older women.

OBJECTIVE: To examine the effects of acute fatigue of the hip abductors on the control of balance in young and older women. DESIGN: Pretest-posttest. SETTING: University research laboratory. PARTICIPANTS: Healthy young women (n=20; age, 23.0+/-1.5y; height, 166.52+/-4.5 cm; mass, 65.33+/-10.5 kg) and community-dwelling older women (n=20; age, 71.65+/-7.2y; height, 162.31+/-3.8 cm; mass, 71.16+/-11.6 kg) without a fall history. INTERVENTION: Measurements of control of single-limb balance before and after fatiguing the hip abductors of the dominant leg. MAIN OUTCOME MEASURE: Performance on 3 clinical assessments of control of balance: the modified Functional Reach Test in the forward, left, and right directions; the Lower-Extremity Reach Test in forward and lateral directions; and the Single-Limb Stance Time Test (SLSTT). RESULTS: Although the younger subjects showed a significantly greater control of balance than the older women in most tests, control of balance after acute fatigue failed to show a significant decline in either age group. The only exception to this was the SLSTT in the younger women in whom a significant 26% decline was noted (P<.05). CONCLUSIONS: Acute fatigue of the hip abductors did not result in a decreased control of balance in healthy young or older women without fall history. Despite considerable changes in movement strategies used to complete the postfatigue tests of balance, quantitative measures of balance did not decrease.

Secondary structure and dynamics of an intrinsically unstructured linker domain.

The transient secondary structure and dynamics of an intrinsically unstructured linker domain from the 70 kDa subunit of human replication protein A was investigated using solution state NMR. Stable secondary structure, inferred from large secondary chemical shifts, was observed for a segment of the intrinsically unstructured linker domain when it is attached to an N-terminal protein interaction domain. Results from NMR relaxation experiments showed the rotational diffusion for this segment of the intrinsically unstructured linker domain to be correlated with the N-terminal protein interaction domain. When the N-terminal domain is removed, the stable secondary structure is lost and faster rotational diffusion is observed. The large secondary chemical shifts were used to calculate phi and psi dihedral angles and these dihedral angles were used to build a backbone structural model. Restrained molecular dynamics were performed on this new structure using the chemical shift based dihedral angles and a single NOE distance as restraints. In the resulting family of structures a large, solvent exposed loop was observed for the segment of the intrinsically unstructured linker domain that had large secondary chemical shifts.