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An increase in protein synthesis following learning is a fundamental and evolutionarily conserved mechanism of long-term memory. To maintain homeostasis, this protein synthesis must be counterbalanced by mechanisms such as protein degradation. Recent studies reported that macroautophagy/autophagy, a major protein degradation mechanism, is required for long-term memory formation. However, how learning regulates autophagy and recruits it into long-term memory formation remains to be established. Here, we show that inhibitory avoidance in rats significantly increases the levels of autophagy and lysosomal degradation proteins, including BECN1/beclin 1, LC3-II, SQSTM1/p62 and LAMP1, as well as autophagic flux in the hippocampus. Moreover, pharmacological inhibition or targeted molecular disruption of the learning-induced autophagy impairs long-term memory, leaving short-term memory intact. The increase in autophagy proteins results from active translation of their mRNA and not from changes in their total mRNA levels. Additionally, the induction of autophagy requires the immediate early gene Arc/Arg3.1. Finally, in contrast to classical regulation of autophagy in other systems, we found that the increase in autophagy upon learning is dispensable for the increase in protein synthesis. We conclude that coupling between learning-induced translation and autophagy, rather than translation per se, is an essential mechanism of long-term memory. Abbreviations: AAV: adeno-associated virus; ARC/ARG3.1: activity regulated cytoskeletal-associated protein; ATG: autophagy related; DG: dentate gyrus; GFP: green fluorescent protein; IA: inhibitory avoidance; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; ODN: oligodeoxynucleotide; qPCR: quantitative polymerase chain reaction; SBI: SBI0206965; SQSTM1/p62: sequestosome 1; SUnSET: surface sensing of translation; TRAP: translating ribosome affinity purification; ULK1: unc-51 like kinase 1

Cation-independent mannose-6-phosphate receptor, also called insulin-like growth factor two receptor (CIM6P/IGF2R), plays important roles in growth and development, but is also extensively expressed in the mature nervous system, particularly in the hippocampus, where its functions are largely unknown. One of its major ligands, IGF2, is critical for long-term memory formation and strengthening. Using CIM6P/IGF2R inhibition in rats and neuron-specific knockdown in mice, here we show that hippocampal CIM6P/IGF2R is necessary for hippocampus-dependent memory consolidation, but dispensable for learning, memory retrieval, and reconsolidation. CIM6P/IGF2R controls the training-induced upregulation of de novo protein synthesis, including increase of Arc, Egr1, and c-Fos proteins, without affecting their mRNA induction. Hippocampal or systemic administration of mannose-6-phosphate, like IGF2, significantly enhances memory retention and persistence in a CIM6P/IGF2R-dependent manner. Thus, hippocampal CIM6P/IGF2R plays a critical role in memory consolidation by controlling the rate of training-regulated protein metabolism and is also a target mechanism for memory enhancement.

// Zheng-Shui Xu 1, * , Fa-Peng Zhang 2, * , Yin Zhang 3 , Yong-Peng Ou-Yang 3 , Xiao-Wen Yu 3 , Wen-Long Wang 3 , Wen-Ji Xu 3 and Zhi-Qiang Luo 3 1 Department of General Surgery, GuangRen Hospital of Xi’an Jiaotong University, 710000, Xi’an, Shaanxi, China 2 Department of General Surgery, The Second Affiliated Hospital of Sun Yat-Sen University, 510120, Guangzhou, Guangdong, China 3 Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 330006, Nanchang, Jiangxi, China * These authors contributed equally to this study and share first authorship Correspondence to: Zhi-Qiang Luo, email: Zqluo999@163.com Wen-Ji Xu, email: 972903941@qq.com Keywords: PLR, pancreatic cancer, overall survival, meta-analysis Received: December 20, 2016 Accepted: September 03, 2017 Published: September 14, 2017 ABSTRACT Background and Aims: Recently, the pre-treatment platelet-lymphocyte ratio (PLR), which is based on blood parameters, was accepted as a prognostic factor for patients with various cancers. Numerous studies have investigated the prognostic role of the PLR in pancreatic cancer; however, it remains unclear. Therefore, we conducted this meta-analysis to evaluate the relationship between the pre-treatment PLR and overall survival (OS) in pancreatic cancer. Materials and Methods: We performed a systematic literature search of the PubMed, Embase and Web of Science databases for relevant studies that explored the prognostic role of the pre-treatment PLR in pancreatic cancer. The hazard ratios (HRs) and 95% confidence intervals (CIs) related to OS were pooled using a random effects model. Results: Fourteen retrospective cohort studies involving 2,260 patients were included in this meta-analysis. Compared with low PLR, high PLR was a predictor of shorter OS (HR = 1.24, 95% CI: 1.10–1.39, I 2 = 74%). Conclusions: In this meta-analysis, high pre-treatment PLR was a bio-predictor of short OS in patients with pancreatic cancer, suggesting that PLR could be used to predict prognosis of patients with pancreatic cancer before treatment. However, additional well-designed and large-scale studies are necessary.

Humans and laboratory animals display cognitive deficits as they age. However, there are currently no effective therapies available to treat these deficits, as the underlying mechanisms are poorly understood. Studies using pharmacological compounds have found a link between cognitive performance and the intrinsic cellular excitability of CA1 hippocampal neurons. Therefore, it is of great interest to identify molecular regulators that may be influencing both cognition and neuronal excitability, which could be changed with age. One possible regulator is the transcription factor cAMP response element binding-protein (CREB). In young adult animals, manipulation of CREB activity has resulted in modulation of both cognitive performance on behavioral tasks, and neuronal excitability. While evidence is sparse, studies also point to a dysfunction in CREB signaling with aging. We propose that CREB may be a viable therapeutic target for the treatment of age-related cognitive deficits, along with potential experiments to test this hypothesis.

Findings reveal a novel basis for protecting CNS neurons against Aβ oligomers (AβOs), neurotoxins believed to instigate neural damage leading to Alzheimer’s dementia. Results with spatially separated cocultures of astrocytes and hippocampal neurons show an exosome-like mechanism by which insulin/IGF1 from astrocytes clear bound AβOs from neuronal surfaces., Synaptopathy underlying memory deficits in Alzheimer’s disease (AD) is increasingly thought to be instigated by toxic oligomers of the amyloid beta peptide (AβOs). Given the long latency and incomplete penetrance of AD dementia with respect to Aβ pathology, we hypothesized that factors present in the CNS may physiologically protect neurons from the deleterious impact of AβOs. Here we employed physically separated neuron–astrocyte cocultures to investigate potential non–cell autonomous neuroprotective factors influencing AβO toxicity. Neurons cultivated in the absence of an astrocyte feeder layer showed abundant AβO binding to dendritic processes and associated synapse deterioration. In contrast, neurons in the presence of astrocytes showed markedly reduced AβO binding and synaptopathy. Results identified the protective factors released by astrocytes as insulin and insulin-like growth factor-1 (IGF1). The protective mechanism involved release of newly bound AβOs into the extracellular medium dependent upon trafficking that was sensitive to exosome pathway inhibitors. Delaying insulin treatment led to AβO binding that was no longer releasable. The neuroprotective potential of astrocytes was itself sensitive to chronic AβO exposure, which reduced insulin/IGF1 expression. Our findings support the idea that physiological protection against synaptotoxic AβOs can be mediated by astrocyte-derived insulin/IGF1, but that this protection itself is vulnerable to AβO buildup.

The molecular mechanisms underlying age-related cognitive deficits are not yet fully elucidated. In aged animals, a decrease in the intrinsic excitability of CA1 pyramidal neurons is believed to contribute to age-related cognitive impairments. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents facilitates cognition, and increases intrinsic excitability. However, it has yet to be tested if increasing CREB expression also ameliorates age-related behavioral and biophysical deficits. To test this hypothesis, we virally overexpressed CREB in CA1 of dorsal hippocampus. Rats received CREB or control virus, before undergoing water maze training. CREB overexpression in aged animals ameliorated the long-term memory deficits observed in control animals. Concurrently, cells overexpressing CREB in aged animals had reduced post-burst afterhyperpolarizations, indicative of increased intrinsic excitability. These results identify CREB modulation as a potential therapy to treat age-related cognitive decline. DOI: http://dx.doi.org/10.7554/eLife.19358.001

We investigate the cross-correlation between price returns and trading volumes for the China Securities Index 300 (CSI300) index futures, which are the only stock index futures traded on the China Financial Futures Exchange (CFFEX). The basic statistics suggest that distributions of these two time series are not normal but exhibit fat tails. Based on the detrended cross-correlation analysis (DCCA), we obtain that returns and trading volumes are long-range cross-correlated. The existence of multifractality in the cross-correlation between returns and trading volumes has been proven with the multifractal detrended cross-correlation analysis (MFDCCA) algorithm. The multifractal analysis also confirms that returns and trading volumes have different degrees of multifractality. We further perform a cross-correlation statistic to verify whether the cross-correlation significantly exists between returns and trading volumes for CSI300 index futures. In addition, results of the test for lead-lag effect demonstrate that contemporaneous cross-correlation of return and trading volume series is stronger than cross-correlations of leaded or lagged series.

We choice the yuan exchange rate index based on a basket of currencies as the effective exchange rate of the yuan and investigate the statistical properties of the yuan exchange rate index after China’s exchange rate system reform on the 21st July 2005. After dividing the time series into two parts according to the change in the yuan exchange rate regime in July 2008, we compare the statistical properties of the yuan exchange rate index during these two periods. We find that the distribution of the two return series has the exponential form. We also perform the detrending moving average analysis (DMA) and the multifractal detrending moving average analysis (MFDMA). The two periods possess different degrees of long-range correlations, and the multifractal nature is also unveiled in these two time series. Significant difference is found in the scaling exponents τ ( q ) and singularity spectra f ( α ) of the two periods obtained from the MFDMA analysis. Besides, in order to detect the sources of multifractality, shuffling and phase randomization procedures are applied to destroy the long-range temporal correlation and fat-tailed distribution of the yuan exchange rate index respectively. We find that the fat-tailedness plays a critical role in the sources of multifractality in the first period, while the long memory is the major cause in the second period. The results suggest that the change in China’s exchange rate regime in July 2008 gives rise to the different multifractal properties of the yuan exchange rate index in these two periods, and thus has an effect on the effective exchange rate of the yuan after the exchange rate reform on the 21st July 2005.

Introduction. Laparoscopic and robot-assisted laparoscopic surgery are widely performed in urology field, so Hem-o-Lok clips are thus extensively used in the laparoscopic procedures. We describe the first case of Hem-o-Lok clip which migrated into the neobladder with calculus formation 26 months after laparoscopic orthotopic neobladder cystectomy, which causes symptoms of gross hematuria and frequent urination. Case Presentation. A 57-year-old man with T2a muscle invasive bladder cancer underwent laparoscopic orthotopic sigmoid neobladder reconstruction after cystectomy which was complicated by intestinal anastomosis leak and peritoneal abscess requiring transverse colostomy and drainage 15 days postoperatively. Twenty-six months after cystectomy, he complained of gross hematuria and frequent urination. Computerized tomography and plain pelvic X-ray revealed a stone measuring approximately 2.8 cm in diameter in the neobladder. During cystoscopy, a closed whitish Hem-o-Lok clip was seen in the center of the calculi. No anastomotic leak or neoplasm was found during cystoscopy. Conclusion. Hem-o-Lok clip migration into the bladder after laparoscopic orthotopic neobladder cystectomy is a rare complication; the first reported case in the literature. To prevent Hem-o-Lok clip migration, it is recommended to avoid extensive use of Hem-o-Lok clip close to anastomosis site, and any loose Hem-o-Lok clip should be retrieved before closure.

Background: Hospitals have expressed no knowledge of patients’ opinions regarding diversified appointment registration systems, despite efforts to develop novel appointment registration systems that assist patients and increase hospital efficiency. Therefore, the aim of this study was to investigate the use of diversified appointment registration systems and explore the factors influencing patients’ registration system choices. Methods: A survey study using a questionnaire was conducted in West China Hospital in February 2012. Outpatients were randomly selected from different hospital departments and the questionnaire was distributed and collected on-site. Results: Data from 1,009 patients were available for analysis. Of these, 63.4% used appointment systems to register while others chose a traditional queuing method to register. 114 telephone (30.4%) and on-site (22.9%) appointments were made, whereas other systems were less used by patients. Between the non-appointment and appointment groups there were significant differences in gender, educational degree, and residence location (P < 0.05), but no significant difference in age (P > 0.05). While the clinical appointment system had the greatest number of appointment days (25.75), the bank's self-service terminal appointment had the least number of appointment days (5.05). Leaflets sent from the hospital (50.70%) and the recommendations of friends or families (40.77%) were the two main ways of knowing about the appointment registration systems. With the exception of those who felt no need to make an appointment (30.12%), not having the capability to use the appointment systems (24.10%) and the lack of a registered health card (34.53%) were the two main reasons for not using appointment registration systems. Conclusions: Convenience was a major motivation for patients’ use of appointment registration systems. Personal knowledge and capability were the two important factors that influenced patients’ appointment system choices. Hospitals must improve the design and promotion of appointment registration systems to better facilitate their use.

Breast cancer stem cells (BCSCs) initiate and sustain breast cancers, and several putative markers have been proposed to prospectively isolate BCSC from the non-cancer stem cell population. The candidate BCSC marker Sca-1 is a GPI-linked membrane protein expressed on activated lymphocytes, hematopoietic stem cells and mammary stem cells. Sca-1+ cells were purified from the murine mammary tumour cell line 4T1. However, this did not enrich for a stem-like, tumour initiating or metastatic cell population in vitro or in vivo. Sphere formation, which induced high levels of Sca-1, reduced BCSC gene expression with near complete loss of spontaneous metastasis from sphere-derived tumours. This was associated with decreased expression of TGFB2 and reduced activation of the TGFβ signalling pathway in spheres. Both TGFB2 expression in vitro and spontaneous metastasis in vivo could be restored upon re-differentiation of sphere cells by exposure to serum, and this occurred with retention of the majority of Sca-1 expression. We conclude that while putative BCSC, including spheres, can have high Sca-1 expression, Sca-1 itself is not a marker of BCSC in established 4T1 tumours or the cell line.

Purpose: To examine international technology development of fibrates based on a cross-database quantitative patent review and to describe the evolution pathway for fibrates by means of a technology roadmap. Methods: The patent data were collected in March 2013 from United States Patent and Trademark Office (USPTO), European Patent Office (EPO) and China Intellectual Property Right Net (CNIPR) to broadly represent global patent activities. Results: This study selected and examined 84 patents from USPTO, 41 patents from EPO and 39 patents from CNIPR. It showed that most of the fibrate patents were fenofibrate patents (41.67 % at USPTO, 46.34 % at EPO and 33.33 % at CNIPR). The number of preparation patents (44 at USPTO, 24 at EPO and 17 at CNIPR) and combination patents (23 at USPTO, 11 at EPO and 15 at CNIPR) was obviously larger than other types of fibrate patents. The technology roadmap shows that new monomersor derivatives of fibrates can drive fibrate evolution into a new cycle of application-synthesiscombination- preparation. Conclusion: This study provides a comprehensive picture of fibrate development. It will aid researchers, entrepreneurs, investors and policymakers to identify foci for fibrate research and ensure better decision-making.

To evaluate the clinical effect of repair of massive bone defect in tibia by vascularized fibula grafting of either sides.Twenty-four cases of massive bone defect in tibia, among which 14 case were repaired by vascularized fibula grafting of the other side and another 10 cases were repaired by those of the same side, from 1987 to 1997 were followed up for 3 to 13 years; the functions of the operated limbs were evaluated according to Enneking Score System, and the outcome of the fibula grafts were assessed by radiographic examination with reference to the standard established by International Symposium on Limb Salvage.The average recover rate of the operated limbs in those repaired by the other side grafting was 80.7%, and the average healing period of the fibula graft was 14 weeks with fracture of the graft in one case which made the operated lower limb shorten for about 2.5 cm; the fibula grafts were observed thickened in 43 weeks, on average, and the patients could walk independently without a crutch. While in those repaired by the same side grafting, the average recover rate of the operated limbs was 68.3%, the average healing period of the fibula graft was 17 weeks with fracture of the graft in 3 cases, in 2 of which the lower limbs were shortened for 2 cm and 4 cm respectively, and in the third one infection occurred and amputation was performed finally; the fibula grafts were observed thickened in 49 weeks, on average, which made it available for the patients to walk without a crutch. All of the data showed that there was a significant difference statistically between the differently treated cases.It's a good choice to repair massive bone defect in tibia by vascularized fibula grafting, and the vascularized fibula graft from the other side could promote the bone healing and accelerate the recover of the function of the operated lower limb.