Concerted action of ataxin-2 and PABPC1-bound mRNA poly(A) tail in the formation of stress granules.

Stress induces global stabilization of the mRNA poly(A) tail (PAT) and the assembly of untranslated poly(A)-tailed mRNA into mRNPs that accumulate in stress granules (SGs). While the mechanism behind stress-induced global PAT stabilization has recently emerged, the biological significance of PAT stabilization under stress remains elusive. Here, we demonstrate that stress-induced PAT stabilization is a prerequisite for SG formation. Perturbations in PAT length impact SG formation; PAT shortening, achieved by overexpressing mRNA deadenylases, inhibits SG formation, whereas PAT lengthening, achieved by overexpressing their dominant negative mutants or downregulating deadenylases, promotes it. PABPC1, which specifically binds to the PAT, is crucial for SG formation. Complementation analyses reveal that the PABC/MLLE domain of PABPC1, responsible for binding PAM2 motif-containing proteins, plays a key role. Among them, ataxin-2 is a known SG component. A dominant-negative approach reveals that the PAM2 motif of ataxin-2 is essential for SG formation. Notably, ataxin-2 increases stress sensitivity, lowering the threshold for SG formation, probably by promoting the aggregation of PABPC1-bound mRNA. The C-terminal region is responsible for the self-aggregation of ataxin-2. These findings underscore the critical roles of mRNA PAT, PABPC1 and ataxin-2 in SG formation and provide mechanistic insights into this process.

A method for screening the suppressor genes of siRNA and piRNA pathways using cultured silkworm cells.

The BmN-4 cell line originates from the ovaries of silkworm, Bombyx mori , and possesses endogenous small interfering RNA (siRNA) and PIWI-interacting RNA (piRNA) pathways. BmN-4 cells are latently infected with Bombyx mori latent virus (BmLV), an RNA virus whose replication is strictly controlled by both siRNA and piRNA pathways. Knockdown or knockout of the core factors of these two small RNA pathways increases BmLV RNA amount, which in turn inhibits cell growth. Here, we used the known RNAi suppressor CrPV-1A to assess whether the BmN-4 cell line can be used for screening the suppressors of siRNA and piRNA pathways.

Prevalence and risk factors for post-traumatic stress disorder in Japanese relatives of out-of-hospital cardiac arrest patients after receiving a pamphlet concerning the grieving process.

AIM: To investigate the prospective frequency of post-traumatic stress disorder (PTSD) among relatives of sudden death patients following provision of a pamphlet explaining the stages of the complicated grief process and self-regulating techniques. METHODS: From May 2017 to February 2018, we prospectively and consecutively provided a pamphlet to relatives of out-of-hospital sudden cardiac arrest victims who failed to obtain spontaneous circulation. We investigated the psychiatric status of the bereaved relatives using the Impact of Event Scale - Revised (IES-R). An IES-R score over 24 was defined as PTSD. RESULTS: Fifty-four relatives of the 54 dead patients (victims) provided permission of entry to this research. All subjects and victims were Japanese. Among them, 24 subjects had an IES-R score of 0 and 5 (9.3%) had PTSD approximately 1 month after their bereavement. There were no relatives who received spontaneous psychiatric treatment. The IES-R scores for non-medical cardiac arrest, death inquests, and parent variables were significantly higher compared with medical cardiac arrest, no inquest, and no parent, respectively. The IES-R scores in those who were a child of the victim were significantly lower than in those who were not. CONCLUSION: The present study showed that the frequency of PTSD was 9.3% at 1 month following bereavement among Japanese relatives of sudden death victims after an intervention. This frequency was minimal compared with previous reports.

Effects of Sesaminol Feeding on Brain Aß Accumulation in a Senescence-Accelerated Mouse-Prone 8.

Alzheimer's disease (AD) is characterized by the progressive accumulation of extracellular ß-amyloid (Aß) aggregates. Recently, the senescence-accelerated mouse-prone 8 (SAMP8) model was highlighted as a useful model of age-related AD. Therefore, we used the SAMP8 mouse to investigate the preventive effects of sesame lignans on the onset of AD-like pathology. In preliminary in vitro studies, sesaminol showed the greatest inhibitory effect on Aß oligomerization and fibril formation relative to sesamin, sesamolin, and sesaminol triglucoside. Hence, sesaminol was selected for further evaluation in vivo. In SAMP8 mice, feed-through sesaminol (0.05%, w/w, in standard chow) administered over a 16 week period reduced brain Aß accumulation and decreased serum 8-hydroxydeoxyguanosine, an indicator of oxidative stress. Furthermore, sesaminol administration increased the gene and protein expression of ADAM10, which is a protease centrally involved in the non-amyloidogenic processing of amyloid precursor protein. Taken together, these data suggest that long-term consumption of sesaminol may inhibit the accumulation of pathogenic Aß in the brain.

Boron-mediated sequential alkyne insertion and C-C coupling reactions affording extended π-conjugated molecules.

C-C bond coupling reactions illustrate the wealth of organic transformations, which are usually mediated by organotransition metal complexes. Here, we show that a borafluorene with a B-Cl moiety can mediate sequential alkyne insertion (1,2-carboboration) and deborylation/Csp(2)-Csp(2) coupling reactions, leading to aromatic molecules. The first step, which affords a borepin derivative, proceeds very efficiently between the borafluorene and various alkynes by simply mixing these two components. The second step is triggered by a one-electron oxidation of the borepin derivative, which results in the formation of a phenanthrene framework. When an excess amount of oxidant is used in the second step, the phenanthrene derivatives can be further transformed in situ to afford dibenzo[g,p]chrysene derivatives. The results presented herein will substantially expand the understanding of main group chemistry and provide a powerful synthetic tool for the construction of a wide variety of extended π-conjugated systems.

Enhanced antiamyloidal activity of hydroxy cinnamic acids by enzymatic esterification with alkyl alcohols.

Lipophilic derivatives of hydroxyl cinnamic acids (HCAs) including caffeic acid (CA), ferulic acid, sinapic acid (SA), and chlorogenic acid were synthesized by esterification with butanol, octanol, or hexadecanol catalyzed by the lipase from Candida antarctica to investigate the effect of lipophilicity on their antiamyloidal activity assessed by the inhibitory activities toward fibrillization of amyloid ß (Aß) peptide. Among them, CA showed the highest activity at 50 µM, reducing the amyloid fibril formation of Aß to 34.4 ± 6.8%. The antiamyloidal effects of HCAs were enhanced by esterification with alkyl alcohols, and the longer alkyl chain tended to be more effective except for SA. Aß fibril formation was suppressed by the hexadecyl ester of CA, which was reduced to 8.8 ± 2.3%. In contrast, those of octyl and butyl esters were 19.3 ± 2.3% and 41.6 ± 6.1%, respectively. These results show that lipophilicity plays an important role in the antiamyloidal activities of esterified phenolic compounds.

Oral administration of soy peptides suppresses cognitive decline by induction of neurotrophic factors in SAMP8 mice.

SAMP8 mice have a shorter lifespan and show the dysfunction of the central nervous system. We here investigated whether soy peptides (SP) composed mainly of di- and tripeptides has the potential to prevent age-dependent cognitive impairment. SAMP8 and normal aging mice, SAMR1, were fed a diet supplemented with SP or a control diet for 26 weeks to investigate the preventive effects on the progression of cognitive decline using the Morris water maze. The SP-fed groups in SAMP8 and SAMR1 prevented the decline of cognitive ability compared to their controls. Increased expression of neurotrophic factors such as BDNF and NT-3 at mRNA and protein levels were observed in the brain of SP-fed mice, especially SAMP8. Further, the phosphorylated CREB protein level of SAMP8 was markedly up-regulated by SP feeding. These suggest that SPs have the potential for prevention of cognitive impairment via neurotrophic effects.