Alpha‐fetoprotein accelerates the progression of hepatocellular carcinoma by promoting Bcl‐2 gene expression through an RA‐RAR signalling pathway

Previous studies have found that alpha‐fetoprotein (AFP) can promote the proliferation of hepatoma cells and accelerate the progression of hepatocellular carcinoma (HCC). However, the exact mechanism of action remains unclear. Recent bioinformatics studies have predicted the possible interaction between AFP and retinoic acid receptors (RARs). Thus, the purpose of this study was to investigate the molecular mechanism through which AFP promotes tumour cell proliferation by interfering with the RA‐RAR signal pathway. Our data indicated that AFP could significantly promote the proliferation and weaken ATRA‐induced apoptosis of hepatoma cells. Besides, cytoplasmic AFP interacts with RAR, disrupting its entrance into the nucleus, which in turn affects the expression of the Bcl‐2 gene. In addition, knockdown of AFP in HepG2 cells was synchronously associated with an incremental increase of RAR binding to DNA, as well as down‐regulation of Bcl‐2; the opposite effect was observed in AFP gene‐transfected HLE cells. Moreover, a similar effect of AFP was detected in tumour tissues with high serum AFP, but not in adjacent non‐cancerous liver tissues, or HCC tissues with low serum AFP levels. These results indicate that AFP acts as signalling molecule and prevents RAR from entering into the nucleus by interacting with RAR, thereby promoting the expression of Bcl‐2. Our data reveal a novel mechanism through which AFP regulates Bcl‐2 expression and further suggest that AFP may be used as a novel target for treating HCC.     

神经递质和调质参与导水管周围灰质痛觉调控的研究进展

导水管周围灰质(periaqueductal gray,PAG)在疼痛的调控过程中处于一个不可或缺的位置.其不仅是痛觉信息上行传递的重要部位,还是疼痛抑制系统的重要组成部分.在PAG,包括γ-氨基丁酸(γ-aminobutyric acid,GABA)、5-羟色胺(5-hydroxytryptamine,5-HT)和谷氨酸(glutamate,Glu)在内的神经递质以及内源性阿片肽(endogenous opioid peptides,EOP)和内源性大麻素(endocannabinoid,e CB)为代表的神经调质都参与了PAG对疼痛的信息传递以及调节.本文重点综述GABA、5-HT、Glu、EOP和eCB在PAG参与疼痛生理调控机制的研究进展,以期为中枢神经系统的镇痛研究提供一定的理论基础.     

α‐ketoglutarate delays age‐related fertility decline in mammals

The fecundity reduction with aging is referred as the reproductive aging which comes earlier than that of chronological aging. Since humans have postponed their childbearing age, to prolong the reproductive age becomes urgent agenda for reproductive biologists. In the current study, we examined the potential associations of α‐ketoglutarate (α‐KG) and reproductive aging in mammals including mice, swine, and humans. There is a clear tendency of reduced α‐KG level with aging in the follicle fluids of human. To explore the mechanisms, mice were selected as the convenient animal model. It is observed that a long term of α‐KG administration preserves the ovarian function, the quality and quantity of oocytes as well as the telomere maintaining system in mice. α‐KG suppresses ATP synthase and alterations of the energy metabolism trigger the nutritional sensors to down‐regulate mTOR pathway. These events not only benefit the general aging process but also maintain ovarian function and delay the reproductive decline. Considering the safety of the α‐KG as a naturally occurring molecule in energy metabolism, its utility in reproduction of large mammals including humans deserves further investigation.     

Electrically-Evoked Frequency-Following Response (EFFR) in the Auditory Brainstem of Guinea Pigs

It is still a difficult clinical issue to decide whether a patient is a suitable candidate for a cochlear implant and to plan postoperative rehabilitation, especially for some special cases, such as auditory neuropathy. A partial solution to these problems is to preoperatively evaluate the functional integrity of the auditory neural pathways. For evaluating the strength of phase-locking of auditory neurons, which was not reflected in previous methods using electrically evoked auditory brainstem response (EABR), a new method for recording phase-locking related auditory responses to electrical stimulation, called the electrically evoked frequency-following response (EFFR), was developed and evaluated using guinea pigs. The main objective was to assess feasibility of the method by testing whether the recorded signals reflected auditory neural responses or artifacts. The results showed the following: 1) the recorded signals were evoked by neuron responses rather than by artifact; 2) responses evoked by periodic signals were significantly higher than those evoked by the white noise; 3) the latency of the responses fell in the expected range; 4) the responses decreased significantly after death of the guinea pigs; and 5) the responses decreased significantly when the animal was replaced by an electrical resistance. All of these results suggest the method was valid. Recording obtained using complex tones with a missing fundamental component and using pure tones with various frequencies were consistent with those obtained using acoustic stimulation in previous studies.     

Effects of SARA on Oxygen–Glucose Deprivation in PC12 Cell Line

Ischemic stroke is a major composition of cerebrovascular disease, seriously threatening to human health in the world. Activin A (ActA), belonging to transforming growth factor-beta (TGF-β) super family, plays an important role in the hypoxic-ischemic brain injury through ActA/Smads pathway. While as an essential phosphorylation assistor in TGF-β signaling, the functions and mechanisms of smad anchor for receptor activation (SARA) in ischemic brain injury remain poorly understood. To solve this problem and explore the pathological processes of ischemic stroke, we used an Oxygen–Glucose deprivation (OGD) model in nerve growth factor-induced differentiated rattus PC12 pheochromocytoma cells and down regulated the expressions of SARA by RNA interference technology. Our results showed that the repression of SARA before OGD exposure reduced the expressions of Smad2, 3, 4 mRNA and the phosphorylation rate of Smad2 protein, but it did not affect the mRNA expressions of Smad7. After OGD treatment, ActA/Smads pathway was activated and the expression of SARA in the SARA pre-repression group was significantly up-regulated. The pre-repression of SARA increased the sensitivities of nerve-like cells to OGD damage. Moreover, the mRNA expression of Smad7 which was supposed to participate in the negative feedback of ActA/Smads pathway was also elevated due to OGD injury. Taken together, these results suggest a positive role of SARA in assisting the phosphorylation of Smad2 and maintaining the neuron protective effect of ActA/Smads pathway.     

Yaks and sheep trigger different changes in the grasshopper assemblages of the Qilian Mountains via differentially altering plant assemblages

1. The Qilian Mountains represent one of the key livestock‐raising grasslands in China. The two main herbivore species raised in this area – yaks and sheep – are of critical economical value. Grasshoppers compete with these animals for available nutrients, creating multifaceted relationships between livestock, grasshoppers and plants. A clear understanding of such relationships is lacking and is urgently needed to guide conservation efforts. 2. This study aims to document the effects of yak and sheep grazing on grasshopper assemblages and to elucidate the underlying mechanisms of such effects. 3. It is shown here that yaks and sheep impact grasshopper assemblages differently. Grasshopper assemblages exhibited lower density, biodiversity, richness, and evenness of distribution in yak‐grazed pastures than in grazing‐free grasslands. Sheep‐grazed pastures exhibited a dramatically divergent picture, with elevated density, biodiversity and richness, and a slightly decreased evenness of distribution. Grasshoppers were generally larger in grazed pastures than in grazing‐free grasslands, especially in yak‐grazed plots. 4. The present study suggests that differences between yak and sheep pastures in plant assemblage structure and plant traits are probably the underlying forces driving the differences in grasshopper assemblage structure and grasshopper traits, respectively. 5. The study shows that the grasshopper habitat indicator species differ between yak and sheep pastures, raising the possibility that such indicators can be used to monitor grassland usage and degradation in the Qilian Mountains. 6. These results provide novel insights into the dynamic interactions of common domesticated herbivore species, grasshoppers and plants in Qilian Mountains, which augment current knowledge and may ultimately lead to better conservation practices.     

Intravenous injection of the oncolytic virus M1 awakens antitumor T cells and overcomes resistance to checkpoint blockade

Reversing the highly immunosuppressive tumor microenvironment (TME) is essential to achieve long-term efficacy with cancer immunotherapy. Despite the impressive clinical response to checkpoint blockade in multiple types of cancer, only a minority of patients benefit from this approach. Here, we report that the oncolytic virus M1 induces immunogenic tumor cell death and subsequently restores the ability of dendritic cells to prime antitumor T cells. Intravenous injection of M1 disrupts immune tolerance in the privileged TME, reprogramming immune-silent (cold) tumors into immune-inflamed (hot) tumors. M1 elicits potent CD8⁺ T cell-dependent therapeutic effects and establishes long-term antitumor immune memory in poorly immunogenic tumor models. Pretreatment with M1 sensitizes refractory tumors to subsequent checkpoint blockade by boosting T-cell recruitment and upregulating the expression of PD-L1. These findings reveal the antitumor immunological mechanism of the M1 virus and indicated that oncolytic viruses are ideal cotreatments for checkpoint blockade immunotherapy.Subject terms: Cancer microenvironment, Targeted therapies     

Survivorship of geographic Pomacea canaliculata populations in responses to cold acclimation

1. Pomacea canaliculata, a freshwater snail from South America, has rapidly established natural populations from south to north subtropical region in China, since its original introductions in the 1980s. Low temperature in winter is a limiting factor in the geographic expansion and successfully establishment for apple snail populations. There have been some studies on population level of low temperature tolerance for P. canaliculata, yet little is quantified about its life‐history traits in responses to cold temperatures. Whether these responses vary with the acclimation location is also unclear. We investigated the survivorship and longevity of P. canaliculata in responses to cold temperatures and examine whether these responses vary with the location and snail size. We hypothesized that survival of the snails depends on their shell height and the level of low temperature, and P. canaliculata population from the mid-subtropical zone may exhibit the highest viability over the cold thermal range.
2. We sampled P. canaliculata populations from five latitude and longitude ranges of subtropical China: Guangzhou population in southernmost (SM‐GZ), three populations of Yingtan (MR‐YT), Ningbo (MR‐NB), Ya'an (MR‐YA) in midrange, and Huanggang population in northernmost (NM‐HG) subtropical zone. For each P. canaliculata population, survival and longevity at six cold acclimation temperature levels (12, 9, 6, 3, 0, and ?3°C) were quantified, and the effects of location and shell height were examined.
3. The MR‐YA population from mid-subtropical zone of China exhibited the highest survival rate and prolonged survival time regardless of the temperature acclimation treatments, whereas the SM‐GZ population from southern subtropical was the most sensitive to cold temperatures, particular temperatures below 9°C. No individuals of the SM‐GZ population could survive after stressed for 30 days (3°C), 5 days (0°C) and 2 days (?3°C), respectively. For each experimental P. canaliculata population held at 3, 0, and ?3°C, individuals with intermediate shell height of 15.0–25.0 mm had significantly higher survivals.
4. The results highlight a request of a more thorough investigation on acclimation responses in each of the life table demographic parameters for P. canaliculata, and pose the question of whether natural selection or some genetic changes may have facilitated adaptation in invasive locations.