STAU1 exhibits a dual function by promoting amyloidogenesis and tau phosphorylation in cultured cells.

Staufen-1 (STAU1) is a double-stranded RNA-binding protein (RBP) involved in a variety of pathological conditions. In this study, we investigated the potential role of STAU1 in Alzheimer's disease (AD), in which two hallmarks are well-established as cerebral ß-amyloid protein (Aß) deposition and Tau-centered neurofibrillary tangles. We found that STAU1 protein level was significantly increased in cells that stably express full-length APP and the brain of APP/PS1 mice, an animal model of AD. STAU1 knockdown, as opposed to overexpression, significantly decreased the protein levels of ß-amyloid converting enzyme 1 (BACE1) and Aß. We further found that STAU1 extended the half-life of the BACE1 mRNA through binding to the 3' untranslated region (3'UTR). Transcriptome analysis revealed that STAU1 enhanced the expression of growth arrest and DNA damage 45 ß (GADD45B) upstream of P38 MAPK signaling, which contributed to STAU1-induced regulation of Tau phosphorylation at Ser396 and Thr181. Together, STAU1 promoted amyloidogenesis by inhibiting BACE1 mRNA decay, and augmented Tau phosphorylation through activating GADD45B in relation to P38 MAPK. Targeting STAU1 that acts on both amyloidogenesis and tauopathy may serve as an optimistic approach for AD treatment.

Short-term regulation of TSFM level does not alter amyloidogenesis and mitochondrial function in type-specific cells.

BACKGROUND: Mitochondrial Ts translation elongation factor (TSFM) is an enzyme that catalyzes exchange of guanine nucleotides. By forming a complex with mitochondrial Tu translation elongation factor (TUFM), TSFM participates in mitochondrial protein translation. We have previously reported that TUFM regulates translation of beta-site APP cleaving enzyme 1 (BACE1) via ROS (reactive oxygen species)-dependent mechanism, suggesting a potential role in amyloid precursor protein (APP) processing associated with Alzheimer's disease (AD), which led to the speculation that TSFM may regulate APP processing in a similar way to TUFM. METHODS AND RESULTS: Here, we report that in cultured cells, knockdown or overexpression TSFM did not change protein levels in BACE1 and APP. Besides, the levels of cytoplasmic ROS and mitochondrial superoxide, in addition to ATP level, cell viability and mitochondrial membrane potential were not significantly altered by TSFM knockdown in the short term. Further transcriptome analysis revealed that expression of majority of mitochondrial genes were not remarkably changed by TSFM silencing. The possibility of TSFM involved in cardiomyopathy and cancer development was uncovered using bioinformatics analysis. CONCLUSIONS: Collectively, short-term regulation of TSFM level in cultured cells does not cause a significant change in proteins involved in APP processing, levels in ROS and ATP associated with mitochondrial function. Whereas our study could contribute to comprehend certain clinical features of TSFM mutations, the roles of TSFM in cardiomyopathy and cancer development might deserve further investigation.

[Characteristics，Sources，and Ozone-sensitive Species of VOCs in Four Seasons in Yuncheng].

Based on the one-year observational data of volatile organic compounds （VOCs） in an urban area of Yuncheng in 2021， the concentration， composition， sources， and ozone-sensitive species of VOCs in four seasons were analyzed. The results showed that the average annual concentration of VOCs was （32.1 ±24.2）×10-9， i.e.， at the national middle level. The seasonal concentrations of VOCs were in the order of： winter （46.3×10-9）> autumn （35.5×10-9）> spring （25.6×10-9）> summer （21.2×10-9）. Alkanes and OVOCs were the most dominant VOCs compounds， accounting for 69.0%-80.4% of TVOCs in Yuncheng. Affected by changes in source emissions， the proportion of OVOCs was higher in spring and summer （41%-43%）， whereas the proportion of alkanes was higher in autumn and winter （42%-43%）. Vehicle exhaust， LPG/NG， industrial production， and combustion sources were identified as the main sources of VOCs in Yuncheng. The largest contributors in the four seasons were vehicle exhaust （28.5% in spring）， secondary + combustion sources （29.0% in summer）， LPG/NG sources （30.4% in autumn）， and coal combustion （27.3% in winter）. The ozone formation was located in the transitional regime in summer and in the VOC-limited regime in other seasons. Ozone production was more sensitive to alkenes （isoprene， ethylene， and propene）， OVOCs （acetaldehyde and propanal）， and aromatics （xylene， toluene， and benzene）. Winter was more sensitive to ethylene， and the other seasons were more sensitive to isoprene. The primary emission sources related to these sensitive species should be reduced to achieve the goal of air quality improvement.

The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity.

Discovery of new small molecules that can activate distinct programmed cell death pathway is of significant interest as a research tool and for the development of novel therapeutics for pathological conditions such as cancer and infectious diseases. The small molecule raptinal was discovered as a pro-apoptotic compound that can rapidly trigger apoptosis by promoting the release of cytochrome c from the mitochondria and subsequently activating the intrinsic apoptotic pathway. As raptinal is very effective at inducing apoptosis in a variety of different cell types in vitro and in vivo, it has been used in many studies investigating cell death as well as the clearance of dying cells. While examining raptinal as an apoptosis inducer, we unexpectedly identified that in addition to its pro-apoptotic activities, raptinal can also inhibit the activity of caspase-activated Pannexin 1 (PANX1), a ubiquitously expressed transmembrane channel that regulates many cell death-associated processes. By implementing numerous biochemical, cell biological and electrophysiological approaches, we discovered that raptinal can simultaneously induce apoptosis and inhibit PANX1 activity. Surprisingly, raptinal was found to inhibit cleavage-activated PANX1 via a mechanism distinct to other well-described PANX1 inhibitors such as carbenoxolone and trovafloxacin. Furthermore, raptinal also interfered with PANX1-regulated apoptotic processes including the release of the 'find-me' signal ATP, the formation of apoptotic cell-derived extracellular vesicles, as well as NLRP3 inflammasome activation. Taken together, these data identify raptinal as the first compound that can simultaneously induce apoptosis and inhibit PANX1 channels. This has broad implications for the use of raptinal in cell death studies as well as in the development new PANX1 inhibitors.

[Electroacupuncture at "Baihui"（GV20） and "Yongquan"（KI1） improves learning-memory ability of APP/PS1 double transgenic mice by regulating endosomal-lysosomal system].

OBJECTIVE: To explore the mechanism of electroacupuncture（EA） in improving learning-memory ability in Alzheimer's disease （AD） mice from the perspective of endosomal-lysosomal system. METHODS: Male APP/PS1 transgenic mice were randomly divided into model group and EA group （n=10 in each group） and 10 male C57BL/6 wild mice were taken as the normal group. EA （1 Hz/50 Hz, 1 mA） was applied at bilateral "Yongquan"（KI1） and acupuncture was applied at "Baihui" （GV20） for 15 min. The mice of the model and normal groups were subjected to restriction with the same method as those of the EA group for 15 min. The treatment was conducted once every other day for 6 weeks. The spatial learning-memory ability （shown by escape latency of place navigation test and the time of crossing the target platform and total swimming distance in the target quadrant in 1 min of spatial probe test ） was detected by Morris water maze test. The immunoactivity of senile plaques （SP） in the hippocampus tissue was detected by immunohistochemistry. The ultrastructural characters of hippocampal neurons were observed by transmission electron microscope, and the expression levels of Ras-related protein 5 （Rab5）, Ras-related protein 7 （Rab7） and cathepsin D （CTSD） in the hippocampus were detected by Western blot, separately. RESULTS: Compared with the normal group, the escape latency, SP immunoactivity, and protein expression levels of Rab5, Rab7 and CTSD were significantly increased （P<0.05, P<0.01）, while the number of crossing the original platform and the total swimming distance in the platform quadrant were considerably reduced （P<0.05） in the model group. In contrast to the model group, the EA group had a marked decrease in the escape latency, SP immunoactivity, and protein expression levels of Rab5, Rab7 and CTSD （P<0.05, P<0.01）, and a striking increase in the number of crossing the original platform and the swimming distance in the platform quadrant （P<0.05）. Results of transmission electron microscope showed an accumulation of endosome, lysosome, and endolysosomes in the hippocampal neurons in the model group, which was evidently milder in the EA group. CONCLUSION: EA of GV20 and KI1 can improve the learning-memory ability of AD mice, which may be related to its function in reducing hippocampal Aß deposition and down-regulating endosomal-lysosomal system activity.

TNIP2 inhibits amyloidogenesis by regulating the 3'UTR of BACE1: An in vitro study.

TNFAIP3-interacting protein 2 (TNIP2) is known as a negative regulator of NF-κB signaling and inhibit inflammatory response and apoptosis, and is also involved in RNA metabolism. In this study, we investigated the potential role of TNIP2 in amyloidogenesis critically associated with Alzheimer's disease (AD). We found a significant decline of TNIP2 protein level in both mouse and cell model of AD. In SH-SY5Y and HEK cells that stably express human full-length APP695 (SY5Y-APP and HEK-APP), TNIP2 overexpression decreased the protein levels of ß-secretase (BACE1) and C99, as well as Aß peptides (including Aß40 and Aß42), while those of α-secretase (ADAM10) and the related C83 remained unchanged. We further found that TNIP2 promoted the degradation of BACE1 mRNA and was able to bound to the 3' untranslated region (3'UTR) with the reduced luciferase activity. These results indicated that TNIP2 effectively inhibited amyloidogenic processing by regulating the 3'UTR-associated mRNA decay of BACE1.

[Effects of electroacupuncture on the expression of ß-amyloid and autophagy-related proteins in hippocampal cells of mice with Alzheimer's disease].

OBJECTIVE: To investigate the effect of electroacupuncture (EA) on the expression of ß-amyloid (Aß) and autophagy-related proteins in hippocampal cells of Alzheimer's disease (AD) model mice, so as to explore its underlying mechanisms. METHODS: Eighteen male APP/PS1 transgenic mice (6 months old) were randomly divided into model and EA groups, with 9 mice in each group. Nine male C57BL/6 wild-type mice of the same age were chosen as the normal group. Mice in the EA group were treated with acupuncture on "Baihui" (GV20) and EA (1 Hz/50 Hz, 1 mA) on bilateral "Yongquan" (KI1), once every other day, 20 min each time for a total of 21 times. After the interventions, the spatial learning and memory ability were observed by Morris water maze test. The autophagy-related pathological changes in hippocampus were observed by transmission electron microscopy. The expressions of microtublue associated protein 1 light chain 3 (LC3) and Aß in hippocampus were observed by immunofluorescence and the expression levels of LC3 and p62 proteins were detected by Western blot. RESULTS: Compared with the normal group, the escape latency was prolonged (P<0.01), the residence time in the original quadrant platform was shor-tened (P<0.05), the positive expressions of LC3 and Aß, the expression levels of LC3Ⅱ and p62 proteins, and the ratio of LC3Ⅱ/LC3Ⅰ proteins in hippocampus were increased (P<0.01, P<0.05) in the model group. Compared with the model group, the escape latency was shortened (P<0.05), the residence time in the original quadrant platform was prolonged (P<0.05), the positive expressions of LC3 and Aß, the expression levels of LC3Ⅱ and p62 proteins, and the ratio of LC3Ⅱ/LC3Ⅰ proteins in hippocampus were decreased (P<0.05) in the EA group. The transmission electron microscopy showed that the structure of neurons was normal in the normal group, a large number of autolysosomes and autophagosomes existed in hip-pocampal nerve cells in the model group, and only a small number of autophagosomes were observed in the EA group. CONCLUSION: EA can reduce the expression levels of autophagy-related proteins LC3 and p62 in APP/PS1 transgenic mice, improve the hip-pocampal autophagy state, reduce intracellular Aß aggregation, and thus improve the learning and memory ability.

[Spatial distribution patterns and intraspecific and interspecific associations of dominant shrub species Lonicera fragrantissima var. lancifolia in Huangguan of Qinling Mountains, China]. / ç§¦å²­çš‡å† ä¼˜åŠ¿çŒæœ¨è‹¦ç³–æžœçš„ç©ºé—´åˆ†å¸ƒæ ¼å±€åŠç§å† ç§é—´å ³è”.

In this study, the spatial distribution patterns of individuals with different diameter classes of dominant shrub Lonicera fragrantissima var. lancifolia and the intraspecific and interspecific relationships were analyzed in Qinling Huangguan Plot. The results showed that the diameter class structure of L. fragrantissima var. lancifolia showed a pyramid shape, with a wide bottom and a narrow top. The number of small-diameter class individuals was the largest, showing a good state of renewal and a stable growth, which was conducive to community renewal and succession. Based on Ripley's K function, using univariate and bivariate paired correlation functions, under complete spatial randomness model, heterogeneous Poisson model and antecedent condition model, all individual of the species and their diameter-dividing classes were mainly aggregated, and the aggregation degree decreased with the increases of research scale, and gradually tended to random distribution. Affected by habitat heterogeneity, diffusion restriction and negative density dependence, there was a positive correlation among different intraspecific dia-meter classes, and also a certain degree of no correlation, but without negative correlation. The interspecific relationship was complex. All types of association (no, positive and negative) were observed, but negative association and no association were dominated.

[Spatial distribution pattern and intraspecific association of dominant species Quercus aliena var. acu-tiserrata in Qinling Mountains, China]. / ç§¦å²­ä¼˜åŠ¿ä¹”æœ¨é”é½¿æ§²æ Žçš„ç©ºé—´åˆ†å¸ƒæ ¼å±€åŠç§å† å ³è”.

To explore the spatial distribution and intraspecific correlation of Quercus aliena var. acutiserrata, a domi-nant tree species in a 25 hm2 plot of warm temperate deciduous broadleaved forest in Qinling Mountains, the pair-correlation function g(r) was used to study the spatial pattern and intraspecific association. The results showed that the diameter class structure of Q. aliena var. acutiserrata was bimodal, with a large proportion of young trees (1 cm≤DBH＜5 cm), indicating an increase population structure with good capability of regeneration. The abundance of middle trees (15 cm≤DBH＜25 cm) was slightly more than that of big trees (25 cm≤DBH＜35 cm) and old trees (DBH≥35 cm), but far less than that of young trees and small trees. The spatial distribution of Q. aliena var. acuteserrata was obviously altitude dependent, which mainly distributed in the middle and high altitude areas. Results of complete spatial randomness (CSR) model analysis showed that young trees, small trees, adult trees, big trees, and old trees were aggregated in the large scale (＜60 m). Heterogeneous Poisson (HP) model was used to eliminate habitat heterogeneity. The results of HP model showed that the individual aggregation degree of each diameter class decreased, indicating that the distribution was affected by habitat heterogeneity. At the small scale (＜40 m), spatial correlation was positively correlated between individuals with small diameter gap, whereas the spatial correlation was negative correlation and no correlation between individuals with large diameter gap. At large scale (>40 m), the spatial correlation was positively correlated between large-diameter individuals, but negatively correlated and unrelated between saplings and other diameter individuals. Our results indicated that biological cha-racteristics of Q. aliena var. acutiserrata and habitat heterogeneity were important drivers for the formation of population spatial pattern.