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An aged immune system undergoes substantial changes where myelopoiesis dominates within the bone marrow. Monocytic‐MDSCs (M‐MDSCs) have been found to play an important role in osteoclastogenesis and bone resorption. In this study, we sought to provide a more comprehensive understanding of the osteoclastogenic potential of bone marrow M‐MDSCs during normal aging through transcriptomic and metabolic changes. Using young mature and aged mice, detailed immunophenotypic analyses of myeloid cells revealed that the M‐MDSCs were not increased in bone marrow, however M‐MDSCS were significantly expanded in peripheral tissues. Although aged mice exhibited a similar number of M‐MDSCs in bone marrow, these M‐MDSCs had significantly higher osteoclastogenic potential and greater demineralization activity. Intriguingly, osteoclast progenitors from aged bone marrow M‐MDSCs exhibited greater mitochondrial respiration rate and glucose metabolism. Further, transcriptomic analyses revealed the upregulation of mitochondrial oxidative phosphorylation and glucose metabolism genes. Interestingly, there was 8‐fold increase in Cd38 mRNA gene expression, consistent with the Mouse Aging Cell Atlas transcriptomic database, and confirmed by qRT‐PCR. CD38 regulates NAD+ availability, and 78c, a small molecule inhibitor of CD38, reduced the mitochondrial oxygen consumption rate and glucose metabolism and inhibited the osteoclastogenic potential of aged mice bone marrow‐derived M‐MDSCs. These results indicate that the age‐related increase in Cd38 expression in M‐MDSCs bias the transcriptome of M‐MDSCs towards osteoclastogenesis. This enhanced understanding of the mechanistic underpinnings of M‐MDSCs and their osteoclastogenesis during aging could lead to new therapeutic approaches for age‐related bone loss and promote healthy aging. [ABSTRACT FROM AUTHOR]

This report summarizes the presentations and recommendations of the eleventh annual American Geriatrics Society and National Institute on Aging research conference, "Osteoporosis and Soft Tissue (Muscle/Fat) Disorders," on March 11‐12, 2019, in Bethesda, Maryland. Falls, fractures, and sarcopenia have a major impact on health in older adults, and they are interconnected by known risk factors. The link between osteoporosis, which is common in older adults, and the risk of falls is well known. Sarcopenia, the age‐related decline in skeletal muscle mass and function, is also associated with an increased risk of falls and fractures because it reduces strength and leads to functional limitations. In addition to increasing the risk of falls, sarcopenia and osteoporosis can lead to frailty, reduced quality of life, morbidity, and mortality. The conference highlighted the impact of bone and soft tissue disorders on quality of life, morbidity, and mortality in older adults. Presenters described factors that contribute to these disorders; health disparities experienced by various subpopulations; and promising biological, pharmacologic, and behavioral interventions to prevent or treat these disorders. The workshop identified many research gaps and questions along with research recommendations that have the potential to enhance the prospect of healthy aging and improved quality of life for older adults. J Am Geriatr Soc 68:31–38, 2019 [ABSTRACT FROM AUTHOR]

Isothermal titration calorimetry (ITC) is used in conjunction with macromolecular modeling (MM) to provide evidence for the binding of the ER[alpha] nuclear receptor to its DNA response element which is coupled to proton uptake by two ionizable residues, H196 and E203, located at the protein-DNA interface. The findings uncovered an unexpected but critical step in the molecular action of nuclear receptors that might act as sensors of intracellular pH.

Isothermal titration calorimetry in combination with circular dichroism was applied to study the effect of introducing single nucleotide variations within the TGACGTCA canonical motif on the binding of bZIP domains of Jun-Fos heterodimer to DNA. The obtained results provide better insight into the role of DNA sequence and conformation on protein-DNA interactions in thermodynamic terms.

The isothermal titration calorimetry is used to demonstrate the binding affinities of the nSH3 domain in the physiological range to all four sites containing PX[psi]PXR motifs, designated S1, S2, S3, and S4, and the cSH3 domain binding at the S1 site. The results obtained from site-directed mutagenesis suggested that the two additional arginine residues flanking the PX[psi]PXR motif at the S1 site contributed to free energy of binding via the formation of salt bridges with specific acidic residues in SH3 domains.

The isothermal titration calorimetry approach is employed to explain the thermodynamics of the Jun-Fos heterodimeric transcription factor to the synthetic dsDNA oligos containing TGACTCA element. The TGACTCA cis motif is shown to play an extremely significant role in the modulation of energetics and orientation of the binding process.

The article discusses a study on the protein-protein interaction involved in a diverse array of signaling cascades believed to happen through the binding of C-terminal (cSH3) domain of growth factor receptor binder 2 (Grb2) to an atypical RXXK motif within the PR domain of Gab1. It indicates the cloning of pET102 bacterial expression plasmids for wild-type and mutant cSH3 domains of human Grb2 in Escherichia coli Rosetta2 (DE3) strain. The study provided insights into a protein-protein interaction relevant to cellular signaling and cancer.