A Candidate Therapeutic Monoclonal Antibody Inhibits Both HRSV and HMPV Replication in Mice.

Human metapneumovirus (HMPV) and human respiratory virus (HRSV) are two leading causes of acute respiratory tract infection in young children. While there is no licensed drug against HMPV, the monoclonal antibody (mAb) Palivizumab is approved against HRSV for prophylaxis use only. Novel therapeutics against both viruses are therefore needed. Here, we describe the identification of human mAbs targeting these viruses by using flow cytometry-based cell sorting. One hundred and two antibodies were initially identified from flow cytometry-based cell sorting as binding to the fusion protein from HRSV, HMPV or both. Of those, 95 were successfully produced in plants, purified and characterized for binding activity by ELISA and neutralization assays as well as by inhibition of virus replication in mice. Twenty-two highly reactive mAbs targeting either HRSV or HMPV were isolated. Of these, three mAbs inhibited replication in vivo of a single virus while one mAb could reduce both HRSV and HMPV titers in the lung. Overall, this study identifies several human mAbs with virus-specific therapeutic potential and a unique mAb with inhibitory activities against both HRSV and HMPV.

Dynamic relocation of poly(ADP-ribose) glycohydrolase isoforms during radiation-induced DNA damage.

Poly(ADP-ribosyl)ation is a very early cellular response to DNA damage. Poly(ADP-ribose) (PAR) accumulation is transient since PAR is rapidly hydrolyzed by poly(ADP-ribose) glycohydrolase (PARG). PARG may play a prominent role in DNA damage response and repair by removing PAR from modified proteins including PARP-1. Using living cells, we provide evidence that in response to DNA damage induced by gamma-irradiation the cytoplasmic 103 kDa PARG isoform translocates into the nucleus. We further observed that the nuclear GFP-hPARG110 enzyme relocalizes to the cytoplasm in response to DNA damage. Using different GFP-PARG fusion proteins specific for the nuclear and cytoplasmic forms, we demonstrate their dynamic distribution between cytoplasm and nucleoplasm and a high mobility of major PARG isoforms by fluorescence recovery after photobleaching (FRAP). The dynamic relocation of all PARG isoforms presented in this report reveals a novel biological mechanism by which PARG could be involved in DNA damage response.

Poly(ADP-ribose) glycohydrolase is a component of the FMRP-associated messenger ribonucleoparticles.

PARG [poly(ADP-ribose) glycohydrolase] is the only known enzyme that catalyses the hydrolysis of poly(ADP-ribose), a branched polymer that is synthesized by the poly(ADP-ribose) polymerase family of enzymes. Poly(ADP-ribosyl)ation is a transient post-translational modification that alters the functions of the acceptor proteins. It has mostly been studied in the context of DNA-damage signalling or DNA transaction events, such as replication and transcription reactions. Growing evidence now suggests that poly(ADP-ribosyl)ation could have a much broader impact on cellular functions. To elucidate the roles that could be played by PARG, we performed a proteomic identification of PARG-interacting proteins by mass spectrometric analysis of PARG pulled-down proteins. In the present paper, we report that PARG is resident in FMRP (Fragile-X mental retardation protein)-associated messenger ribonucleoparticles complexes. The localization of PARG in these complexes, which are components of the translation machinery, was confirmed by sedimentation and microscopy analysis. A functional link between poly(ADP-ribosyl)ation modulation and FMRP-associated ribonucleoparticle complexes are discussed in a context of translational regulation.

Gender-specific associations between functional autonomy and physical capacities in independent older adults: results from the NuAge study.

BACKGROUND: Even with healthy and active aging, many older adults will experience a decrease in physical capacities. This decrease might be associated with diminished functional autonomy. However, little is known about the physical capacities associated with functional autonomy in older women and men. OBJECTIVE: This study aimed to examine gender-specific associations between functional autonomy and physical capacities in independent older women and men. METHODS: Secondary analyses were carried out using cross-sectional data from 652 women and 613 men who participated in the NuAge longitudinal study. The "functional autonomy measurement system" (SMAF) was used to evaluate functional autonomy. The physical capacities measured (tests used) were: biceps and quadriceps strength (Microfet dynamometer), grip strength (Martin vigorimeter), unipodal balance, changing position & walking (timed up and go), normal & fast walking (four-meter walking speed) and changing position (chair stand). Correlation and multiple linear regression analyses adjusted for age, depressive symptoms and body composition were performed. RESULTS: On average, participants were aged 73 years and had mild to moderate functional autonomy loss. In women, after controlling for age, depressive symptoms and body composition, greater functional autonomy was best explained by faster changing position & walking skills and superior biceps strength (R(2)=0.46; p<0.001). After controlling for depressive symptoms, faster changing position & walking skills and better unipodal balance best explained greater functional autonomy in men (R(2)=0.21; p<0.001). CONCLUSION: According to these results, physical capacities are moderately associated with functional autonomy among independent older adults, especially women.