Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

Mechanoadaptation maintains bone mass and architecture; its failure underlies age-related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone’s loading response can be partially recovered, non-invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones’ age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation

The Role of Body Size and Shape in Understanding Competitive Interactions within a Community of Neotropical Dung Beetles

Geometric morphometrics is helpful for understanding how body size and body shape influence the strength of inter-specific competitive interactions in a community. Dung beetles, characterized by their use of decomposing organic material, provide a useful model for understanding the structuring of ecological communities and the role of competition based on their size and morphology. The relationship between body size and shape in a dung beetle community from the Atlantic Forest in Serra do Japi, Brazil was analyzed for 39 species. Fifteen anatomical landmarks on three-dimensional Cartesian coordinates were used to describe both the shape and the size of the body of each species on the basis of the centroid located along homologous points in all of the species. The first vector of a principal components analysis explained 38.5% of the morphological variation among species, and represents a gradient of body shape from elongated, flattened bodies with narrow abdomen to rounded or convex bodies. The second component explained 17.8% of the remaining variation in body shape, which goes from species with an abdomen that is larger than the elytra to species with constricted abdomens and large elytra. The relationship between body size and shape was analyzed separately for diurnal and nocturnal species. In both guilds not only were there differences in body size, but also in body shape, suggesting a reduction in their level of competition

Hydroimidazolone Modification of the Conserved Arg12 in Small Heat Shock Proteins: Studies on the Structure and Chaperone Function Using Mutant Mimics

Methylglyoxal (MGO) is an α-dicarbonyl compound present ubiquitously in the human body. MGO reacts with arginine residues in proteins and forms adducts such as hydroimidazolone and argpyrimidine in vivo. Previously, we showed that MGO-mediated modification of αA-crystallin increased its chaperone function. We identified MGO-modified arginine residues in αA-crystallin and found that replacing such arginine residues with alanine residues mimicked the effects of MGO on the chaperone function. Arginine 12 (R12) is a conserved amino acid residue in Hsp27 as well as αA- and αB-crystallin. When treated with MGO at or near physiological concentrations (2–10 µM), R12 was modified to hydroimidazolone in all three small heat shock proteins. In this study, we determined the effect of arginine substitution with alanine at position 12 (R12A to mimic MGO modification) on the structure and chaperone function of these proteins. Among the three proteins, the R12A mutation improved the chaperone function of only αA-crystallin. This enhancement in the chaperone function was accompanied by subtle changes in the tertiary structure, which increased the thermodynamic stability of αA-crystallin. This mutation induced the exposure of additional client protein binding sites on αA-crystallin. Altogether, our data suggest that MGO-modification of the conserved R12 in αA-crystallin to hydroimidazolone may play an important role in reducing protein aggregation in the lens during aging and cataract formation

Efficacy and Safety of a New 20% Immunoglobulin Preparation for Subcutaneous Administration, IgPro20, in Patients With Primary Immunodeficiency

Subcutaneous human IgG (SCIG) therapy in primary immunodeficiency (PID) offers sustained IgG levels throughout the dosing cycle and fewer adverse events (AEs) compared to intravenous immunoglobulin (IVIG). A phase I study showed good local tolerability of IgPro20, a new 20% liquid SCIG stabilized with L-proline. A prospective, open-label, multicenter, single-arm, phase III study evaluated the efficacy and safety of IgPro20 in patients with PID over 15 months. Forty-nine patients (5–72 years) previously treated with IVIG received weekly subcutaneous infusions of IgPro20. The mean serum IgG level was 12.5 g/L. No serious bacterial infections were reported. There were 96 nonserious infections (rate 2.76/patient per year). The rate of days missed from work/school was 2.06/patient per year, and the rate of hospitalization was 0.2/patient per year. Ninety-nine percent of AEs were mild or moderate. No serious, IgPro20-related AEs were reported. IgPro20 effectively protected patients with PID against infections and maintained serum IgG levels without causing unexpected AEs

Epigenetic Regulation of Histone H3 Serine 10 Phosphorylation Status by HCF-1 Proteins in C. elegans and Mammalian Cells

BACKGROUND: The human herpes simplex virus (HSV) host cell factor HCF-1 is a transcriptional coregulator that associates with both histone methyl- and acetyltransferases, and a histone deacetylase and regulates cell proliferation and division. In HSV-infected cells, HCF-1 associates with the viral protein VP16 to promote formation of a multiprotein-DNA transcriptional activator complex. The ability of HCF proteins to stabilize this VP16-induced complex has been conserved in diverse animal species including Drosophila melanogaster and Caenorhabditis elegans suggesting that VP16 targets a conserved cellular function of HCF-1. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the role of HCF proteins in animal development, we have characterized the effects of loss of the HCF-1 homolog in C. elegans, called Ce HCF-1. Two large hcf-1 deletion mutants (pk924 and ok559) are viable but display reduced fertility. Loss of Ce HCF-1 protein at reduced temperatures (e.g., 12 degrees C), however, leads to a high incidence of embryonic lethality and early embryonic mitotic and cytokinetic defects reminiscent of mammalian cell-division defects upon loss of HCF-1 function. Even when viable, however, at normal temperature, mutant embryos display reduced levels of phospho-histone H3 serine 10 (H3S10P), a modification implicated in both transcriptional and mitotic regulation. Mammalian cells with defective HCF-1 also display defects in mitotic H3S10P status. CONCLUSIONS/SIGNIFICANCE: These results suggest that HCF-1 proteins possess conserved roles in the regulation of cell division and mitotic histone phosphorylation

Electrophysiological dynamics of Chinese phonology during visual word recognition in Chinese-English bilinguals

Silent word reading leads to the activation of orthographic (spelling), meaning, as well as phonological (sound) information. For bilinguals, native language information can also be activated automatically when they read words in their second language. For example, when Chinese-English bilinguals read words in their second language (English), the phonology of the Chinese translations is automatically activated. Chinese phonology, however, consists of consonants and vowels (segmental) and tonal information. To what extent these two aspects of Chinese phonology are activated is yet unclear. Here, we used behavioural measures, event-related potentials and oscillatory EEG to investigate Chinese segmental and tonal activation during word recognition. Evidence of Chinese segmental activation was found when bilinguals read English words (faster responses, reduced N400, gamma-band power reduction) and when they read Chinese words (increased LPC, gamma-band power reduction). In contrast, evidence for Chinese tonal activation was only found when bilinguals read Chinese words (gamma-band power increase). Together, our converging behavioural and electrophysiological evidence indicates that Chinese segmental information is activated during English word reading, whereas both segmental and tonal information are activated during Chinese word reading. Importantly, gamma-band oscillations are modulated differently by tonal and segmental activation, suggesting independent processing of Chinese tones and segments

Gefitinib Induces Epidermal Growth Factor Receptor Dimers Which Alters the Interaction Characteristics with 125I-EGF

The tyrosine kinase inhibitor gefitinib inhibits growth in some tumor types by targeting the epidermal growth factor receptor (EGFR). Previous studies show that the affinity of the EGF-EGFR interaction varies between hosting cell line, and that gefitinib increases the affinity for some cell lines. In this paper, we investigate possible mechanisms behind these observations. Real-time interaction analysis in LigandTracer® Grey revealed that the HER2 dimerization preventing antibody pertuzumab clearly modified the binding of 125I-EGF to EGFR on HER2 overexpressing SKOV3 cells in the presence of gefitinib. Pertuzumab did not affect the binding on A431 cells, which express low levels of HER2. Cross-linking measurements showed that gefitinib increased the amount of EGFR dimers 3.0–3.8 times in A431 cells in the absence of EGF. In EGF stimulated SKOV3 cells the amount of EGFR dimers increased 1.8–2.2 times by gefitinib, but this effect was cancelled by pertuzumab. Gefitinib treatment did not alter the number of EGFR or HER2 expressed in tumor cell lines A431, U343, SKOV3 and SKBR3. Real-time binding traces were further analyzed in a novel tool, Interaction Map, which deciphered the different components of the measured interaction and supports EGF binding to multiple binding sites. EGFR and HER2 expression affect the levels of EGFR monomers, homodimers and heterodimers and EGF binds to the various monomeric/dimeric forms of EGFR with unique binding properties. Taken together, we conclude that dimerization explains the varying affinity of EGF – EGFR in different cells, and we propose that gefitinib induces EGFR dimmers, which alters the interaction characteristics with 125I-EGF