NbALY916 is involved in potato virus X P25-triggered cell death in Nicotiana benthamiana

Systemic necrosis often occurs during viral infection of plants and is thought mainly to be the result of long-term stress induced by viral infection. Potato virus X (PVX) encodes the P25 pathogenicity factor that triggers a necrotic reaction during PVX-potato virus Ysynergistic coinfection. In this study, we discovered that NbALY916, a multifunctional nuclear protein, could interact with P25. When NbALY916 expression was reduced by tobacco rattle virus (TRV)-based virus-induced gene silencing, the accumulation of P25 was increased, which would be expected to cause more severe necrosis. However, silencing of NbALY916 reduced the extent of cell death caused by P25. Furthermore, we found that overexpression of NbALY916 increased the accumulation of H₂O₂ and triggered more extensive cell death when coexpressed with P25, even though accumulation of P25 was itself reduced by the increased expression of NbALY916. Furthermore, transient expression of P25 specifically induced the expression of NbALY916 mRNA, but not the mRNAs of three other ALYs in Nicotiana benthamiana. In addition, we showed that silencing of NbALY916 or transient overexpression of NbALY916 affected the infection of PVX in N. benthamiana. Our results reveal that NbALY916 has an antiviral role that, in the case of PVX, operates by inducing the accumulation of H₂O₂ and mediating the degradation of P25.     

Developmental aspects of the tympanic membrane: Shedding light on function and disease

The ear drum, or tympanic membrane (TM), is a key component in the intricate relay that transmits air‐borne sound to our fluid‐filled inner ear. Despite early belief that the mammalian ear drum evolved as a transformation of a reptilian drum, newer fossil data suggests a parallel and independent evolution of this structure in mammals. The term “drum” belies what is in fact a complex three‐dimensional structure formed from multiple embryonic cell lineages. Intriguingly, disease affects the ear drum differently in its different parts, with the superior and posterior parts being much more frequently affected. This suggests a key role for the developmental details of TM formation in its final form and function, both in homeostasis and regeneration. Here we review recent studies in rodent models and humans that are beginning to address large knowledge gaps in TM cell dynamics from a developmental biologist's point of view. We outline the biological and clinical uncertainties that remain, with a view to guiding the indispensable contribution that developmental biology will be able to make to better understanding the TM.     

Base excision repair but not DNA double‐strand break repair is impaired in aged human adipose‐derived stem cells

The decline in DNA repair capacity contributes to the age‐associated decrease in genome integrity in somatic cells of different species. However, due to the lack of clinical samples and appropriate tools for studying DNA repair, whether and how age‐associated changes in DNA repair result in a loss of genome integrity of human adult stem cells remains incompletely characterized. Here, we isolated 20 eyelid adipose‐derived stem cell (ADSC) lines from healthy individuals (young: 10 donors with ages ranging 17–25 years; old: 10 donors with ages ranging 50–59 years). Using these cell lines, we systematically compared the efficiency of base excision repair (BER) and two DNA double‐strand break (DSB) repair pathways—nonhomologous end joining (NHEJ) and homologous recombination (HR)—between the young and old groups. Surprisingly, we found that the efficiency of BER but not NHEJ or HR is impaired in aged human ADSCs, which is in contrast to previous findings that DSB repair declines with age in human fibroblasts. We also demonstrated that BER efficiency is negatively associated with tail moment, which reflects a loss of genome integrity in human ADSCs. Mechanistic studies indicated that at the protein level XRCC1, but not other BER factors, exhibited age‐associated decline. Overexpression of XRCC1 reversed the decline of BER efficiency and genome integrity, indicating that XRCC1 is a potential therapeutic target for stabilizing genomes in aged ADSCs.     

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR‐34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR‐34c in AD remain to be investigated. The expression of miR‐34c was detected by RT–qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR‐34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR‐34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR‐34c was mediated by ROS‐JNK‐p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′‐untranslated region (3′‐UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR‐34c in the HT‐22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR‐34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR‐34c mediated synaptic and memory deficits by targeting SYT1 through ROS‐JNK‐p53 pathway and the miR‐34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD.