Distinct basolateral amygdala excitatory inputs mediate the somatosensory and aversive-affective components of pain

Pain is a multidimensional perception that includes unpleasant somatosensory and affective experiences; however, the underlying neural circuits that mediate different components of pain remain elusive. Although hyperactivity of basolateral amygdala glutamatergic (BLA^Glu) neurons is required for the somatosensory and emotional processing of pain, the precise excitatory inputs to BLA^Glu neurons and their roles in mediating different aspects of pain are unclear. Here, we identified two discrete glutamatergic neuronal circuits in male mice: a projection from the insular cortex glutamatergic (IC^Glu) to BLA^Glu neurons, which modulates both the somatosensory and affective components of pain, and a projection from the mediodorsal thalamic nucleus (MD^Glu) to BLA^Glu neurons, which modulates only the aversive-affective component of pain. Using whole-cell recording and fiber photometry, we found that neurons within the IC→BLA and MD→BLA pathways were activated in mice upon inflammatory pain induced by injection of complete Freund’s adjuvant (CFA) into their paws. Optical inhibition of the IC^Glu→BLA pathway increased the nociceptive threshold and induced behavioral place preference in CFA mice. In contrast, optical inhibition of the MD^Glu→BLA pathway did not affect the nociceptive threshold but still induced place preference in CFA mice. In normal mice, optical activation of the IC^Glu→BLA pathway decreased the nociceptive threshold and induced place aversion, while optical activation of the MD^Glu→BLA pathway only evoked aversion. Taken together, our results demonstrate that discrete IC^Glu→BLA and MD^Glu→BLA pathways are involved in modulating different components of pain, provide insights into its circuit basis, and better our understanding of pain perception.     

Age‐related memory vulnerability to interfering stimuli is caused by gradual loss of MAPK‐dependent protection in Drosophila

Age‐related memory impairment (AMI) is a common phenomenon across species. Vulnerability to interfering stimuli has been proposed to be an important cause of AMI. However, the molecular mechanisms underlying this vulnerability‐related AMI remain unknown. Here we show that learning‐activated MAPK signals are gradually lost with age, leading to vulnerability‐related AMI in Drosophila. Young flies (2‐ or 3‐day‐old) exhibited a significant increase in phosphorylated MAPK levels within 15 min after learning, whereas aged flies (25‐day‐old) did not. Compared to 3‐day‐old flies, significant 1 h memory impairments were observed in 15‐, 20‐, and 30‐day‐old flies, but not in 10‐day‐old flies. However, with post‐learning interfering stimuli such as cooling or electric stimuli, 10‐day‐old flies had worse memory performance at 1 h than 3‐day‐old flies, showing a premature AMI phenomenon. Increasing learning‐activated MAPK signals through acute transgene expression in mushroom body (MB) neurons restored physiological trace of 1 h memory in a pair of MB output neurons in aged flies. Decreasing such signals in young flies mimicked the impairment of 1 h memory trace in aged flies. Restoring learning‐activated MAPK signals in MB neurons in aged flies significantly suppressed AMI even with interfering stimuli. Thus, our data suggest that age‐related loss of learning‐activated neuronal MAPK signals causes memory vulnerability to interfering stimuli, thereby leading to AMI.     

LRG‐1 promotes fat graft survival through the RAB31‐mediated inhibition of hypoxia‐induced apoptosis

Autologous adipose tissue is an ideal soft tissue filling material, and its biocompatibility is better than that of artificial tissue substitutes, foreign bodies and heterogeneous materials. Although autologous fat transplantation has many advantages, the low retention rate of adipose tissue limits its clinical application. Here, we identified a secretory glycoprotein, leucine‐rich‐alpha‐2‐glycoprotein 1 (LRG‐1), that could promote fat graft survival through RAB31‐mediated inhibition of hypoxia‐induced apoptosis. We showed that LRG‐1 injection significantly increased the maintenance of fat volume and weight compared with the control. In addition, higher fat integrity, more viable adipocytes and fewer apoptotic cells were observed in the LRG‐1‐treated groups. Furthermore, we discovered that LRG‐1 could reduce the ADSC apoptosis induced by hypoxic conditions. The mechanism underlying the LRG‐1‐mediated suppression of the ADSC apoptosis induced by hypoxia was mediated by the upregulation of RAB31 expression. Using LRG‐1 for fat grafts may prove to be clinically successful for increasing the retention rate of transplanted fat.     

Design,synthesis, and biological evaluation of novel carbazole derivatives as potent DNMT1 inhibitors with reasonable PK properties

The DNA methyltransferases (DNMTs) were found in mammals to maintain DNA methylation. Among them, DNMT1 was the first identified, and it is an attractive target for tumour chemotherapy. DC_05 and DC_517 have been reported in our previous work, which is non-nucleoside DNMT1 inhibitor with low micromolar IC₅₀ values and significant selectivity towards other S-adenosyl-_L-methionine (SAM)-dependent protein methyltransferases. In this study, through a process of similarity-based analog searching, a series of DNMT1 inhibitors were designed, synthesized, and evaluated as anticancer agents. SAR studies were conducted based on enzymatic assays. And most of the compounds showed strong inhibitory activity on human DNMT1, especially WK-23 displayed a good inhibitory effect on human DNMT1 with an IC₅₀ value of 5.0 µM. Importantly, the pharmacokinetic (PK) profile of WK-23 was obtained with quite satisfying oral bioavailability and elimination half-life. Taken together, WK-23 is worth developing as DNMT1-selective therapy for the treatment of malignant tumour.     

Rhabdomyolysis happened after the start of dabigatran etexilate treatment: A case report

There are few reports of rhabdomyolysis caused by anticoagulants, and it is extremely rare for it to be caused by dabigatran etexilate. An 86-year-old female experienced sudden muscle weakness and pain, a significant increase in Creatine kinase, and renal impairment after oral administration of dabigatran etexilate for 3 weeks. The enhanced thigh MRI showed abnormal signal in multiple thigh muscle groups, indicating that the lesions should be considered inflammatory diseases. In conclusion, the possibility of rhabdomyolysis should be ruled out when muscle weakness and myalgia occur at the beginning of dabigatran etexilate treatment.     

谭清苏铁性别相关的RAPD标记研究

以谭清苏铁(Cycas tanqingii D.Y.Wang)雌雄植株半年生羽叶为材料,用优化的CTAB法分别提取其全基因组DNA,进行RAPD单因子梯度实验和正交实验以优化扩增条件。应用160个RAPD随机引物检测基因组DNA,雌雄植株均扩增出1450多条带,其中引物S0465扩增出与谭清苏铁雌株高度相关的RAPD标记,其大小约为500bp,该标记与雄株没有关联。     

泛素化修饰与植物免疫应答

植物暴露在细菌、病毒和真菌等病原微生物环境中,病虫害是限制农作物产量和品质的主要因素,而植物病虫害的防治依赖于对植物抗病机制的深入认识。近年来的研究表明,蛋白质泛素化广泛地参与植物防御调节。蛋白质泛素化是真核生物中重要的翻译后修饰方式之一,在植物中,泛素化修饰在多种信号传导途径中发挥作用,如激素、光、糖应答,发育调节和病原菌防御信号途径等。综述了蛋白质泛素化修饰在植物免疫应答中的调控作用。     

Mechanisms of the acute ischemia-induced arrhythmogenesis--a simulation study

The underlying ionic mechanisms of ischemic-induced arrhythmia were studied by the computer simulation method. To approximate the real situation, ischemic cells were simulated by considering the three major component conditions of acute ischemia (elevated extracellular K(+) concentration, acidosis and anoxia) at the level of ionic currents and ionic concentrations, and a round ischemic zone was introduced into a homogeneous healthy sheet to avoid sharp angle of the ischemic tissue. The constructed models were solved using the operator splitting and adaptive time step methods, and the perturbation finite difference (PFD) scheme was first used to integrate the partial differential equations (PDEs) in the model. The numerical experiments showed that the action potential durations (APDs) of ischemic cells did not exhibited rate adaptation characteristic, resulting in flattening of the APD restitution curve. With reduction of sodium channel availability and long recovery of excitability, refractory period of the ischemic tissue was significantly prolonged, and could no longer be considered as same as APD. Slope of the conduction velocity (CV) restitution curve increased both in normal and ischemic region when pacing cycle length (PCL) was short, and refractory period dispersion increased with shortening of PCL as well. Therefore, dynamic changes of CV and dispersion of refractory period rather than APD were suggested to be the fundamental mechanisms of arrhythmia in regional ischemic myocardium.     

无花果曲霉发酵生产β-葡萄糖苷酶的动力学分析

在7L生物反应器的分批发酵中,通过对无花果曲霉UV-29液态发酵茵丝体的生长、基质消耗（以总糖计）及β-葡萄糖苷酶产生的特性研究,发现总糖是无花果曲霉生长的限制性基质;β-葡萄糖苷酶的增长趋势明显滞后于细胞生长的增长趋势,其发酵过程属于部分相关模型,即Ga—den提出的Ⅱ型发酵;基于logistic方程,建立了发酵动力学模型,同时对实验数据与模型进行了验证比较,模型计算值与实验数据拟合良好。在7L生物反应器的最大茵体生物量（干重）达到1．17g／100mL,β-葡萄糖苷酶最高酶活达到22．25IU／mL。