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The function and number of muscle stem cells (satellite cells, SCs) decline with muscle aging. Although SCs are heterogeneous and different subpopulations have been identified, it remains unknown whether a specific subpopulation of muscle SCs selectively decreases during aging. Here, we find that the number of SCs expressing high level of transcription factor Pax7 (Pax7(Hi)) is dramatically reduced in aged mice. Myofiber‐secreted granulocyte colony‐stimulating factor (G‐CSF) regulates age‐dependent loss of Pax7(Hi) cells, as the Pax7(Hi) SCs are replenished by exercise‐induced G‐CSF in aged mice. Mechanistically, we show that transcription of G‐CSF (Csf3) gene in myofibers is regulated by MyoD in a metabolism‐dependent manner. Furthermore, myofiber‐secreted G‐CSF acts as a metabolic niche factor required for establishing and maintaining the Pax7(Hi) SC subpopulation in adult and physiological aged mice by promoting the asymmetric division of Pax7(Hi) and Pax7(Mi) SCs. Together, our findings uncover that muscles provide a metabolic niche regulating Pax7 SC heterogeneity in mice.

The long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) has been shown to play an important role in tumourigenesis. The aim of this study was to investigate the role of MALAT1 in pancreatic ductal adenocarcinoma. MALAT1 is expressed at higher levels in pancreatic ductal adenocarcinoma (PDAC) tissues than in nontumour tissues and in metastatic PDAC than in localized tumours. Patients with PDAC and high MALAT1 expression levels have shorter overall survival than patients with PDAC and low MALAT1 expression levels. Knocking down MALAT1 reduces pancreatic tumour cell growth and proliferation both in vitro and in vivo. Moreover, MALAT1 knockdown inhibits cell cycle progression and impairs tumour cell migration and invasion. We found that miR-217 can bind MALAT1 and regulate its expression in PDAC cell lines. We also found MALAT1 knockdown attenuates the protein expression of KRAS, a known target of miR-217. After MALAT1 knockdown, KRAS protein expression levels can be rescued through inhibition of miR-217 expression. More importantly, MALAT1 knockdown does not directly affect cellular miR-217 expression but decreases the miR-217 nucleus/cytoplasm ratio, suggesting that MALAT1 inhibits the translocation of miR-217 from the nucleus to the cytoplasm.

Tumor-infiltrating immune cells and their prognostic value have been analyzed in various malignancies. Although tissue microarray (TMA) has been used in some of these studies, it is still questionable whether this technique can represent the results of infiltrating CD8+ cells obtained from whole-tissue sections (WTS). The aim of this study was to assess and compare the density of tumor-infiltrating CD8+ cells in ovarian cancer using TMA and WTS. CD8+ lymphocytes were immunohistochemically stained on WTS and TMA cores from 37 ovarian cancer patients and quantified using the image analysis software HistoQuest. Four different areas were selected on the WTS, namely (i) tumor; (ii) stroma; (iii) mixed; and (iv) dense, whereby dense represented areas of most abundant CD8+ cells. On the TMA, (i) the whole TMA cores and (ii) areas containing only epithelial tumor tissue were analyzed. The Pearson correlation and principal component analysis was used to estimate the correlation of results from different techniques. CD8+ lymphocytes showed highly correlated measurements between tumor, mixed, and dense areas. Moderate correlations were found between each of these 3 measurements and stroma. CD8+ cell counts from WTS showed moderate correlation with TMA cell counts. Consistently, principal component analysis showed 3 clusters (i) tumor, dense, mixed; (ii) stroma; and (iii) TMA areas. Taken together, when the prognostic impact of tumor-infiltrating CD8+ cells in ovarian cancer is investigated with TMA technique, a moderate correlation with WTS results has to be considered.

To identify novel lncRNAs involved in cerebellar neurogenesis using neuronal specific Nbs1-deficient (Nbs1(CNS-del)) mouse model.Microarray analysis was performed to identify differentially expressed lncRNAs between Nbs1(CNS-ctr) and Nbs1(CNS-del) mice. Expression profiles of lncRNA Gm15577 and coding gene Negr1 in mice, primary cerebellar culture and cell lines were measured using RT-qPCR. Subcellular fractionation was performed to determine the subcellular localization of Gm15577.Gm15577 was specifically expressed in mice cerebellum in a developmentally regulated manner, which could be abolished upon Nbs1-deficiency. Gm15577 was located in the intronic region of Negr1 in a reversed orientation. Gm15577 modulated the RNA expression of Negr1, Shh and β-catenin. NEGR1 had a distinct expression pattern between normal and medulloblastoma patients.Gm15577 may modulate cerebellar granule cell proliferation and differentiation by targeting Negr1, and their dysfunctions or abnormal expression may be related to tumorigenesis of medulloblastoma.

Analogues of the hypertensive octapeptide angiotensin II, comprising novel constrained 5,8-bicyclic and 5,9-bicyclic tripeptide units adopting nonclassical beta-turn geometries, as deduced from theoretical conformational analysis, have been synthesized. Spontanous bicyclization upon acid-catalyzed deprotection of a model peptide, encompassing a protected omega-formyl alpha-amino acid in position 5 and cysteine residues in positions 3 and 7, revealed a strong preference for bicyclization toward the C-terminus. The bicyclic thiazolidine related angiotensin II analogues synthesized exhibited no affinity for the angiotensin II AT1 receptor.

This study investigates intraday price discovery between the Chinese stock index market and the CSI 300 index futures market, and examines the relation between index futures intraday price discovery and exchanges regulations using Granger Causality Method, Johansen cointegration analysis and Vector Error Correction Model (VECM). The research on price discovery has divided into three stages according to China Financial Futures Exchanges' regulations. Minute by minute data showing that the movements of the two markets are interrelated. The CSI300 index futures was not dominant in the price discovery process in its infancy stage after futures market launched, but the futures market plays a more and more important role after an effective control on over-speculation by CFFEX. The supervision measures give a significant effect on market maturing.

The conformational characteristics of abasic 1-deoxy sugars 1,2, and 3 and pentofuranose moieties in 2',3'- dideoxy-(ddA (6), ddG (7), ddC (S)), 2'-deoxy-(dA (9), dG (lo), dC (ll)), and ribo-@-D-nucleosides (Ade (12), Gua (13), Cyt (14)) were established through the analysis of vicinal proton-proton coupling constants extracted from their 500-MHz lH-NMR spectra recorded at 20 K intervals in the temperature range from 278 to 358 K in D20 solution. Two novel deuterated analogues of (S)-tetrahydrofurfuryl alcohol (l), 2-(S)-(hydroxymethyl)-4-(R)-deuteriotetrahy- drofuran (4) and 2-(S)-(hydroxymethyl)-3-(S)-deuteriotetrahydrofuran (5), have enabled unequivocal assignment of the complex nine-spin system in its 'H-NMR spectrum. The van't Hoff plots of (In(&/&)) as a function of 1 / Tgave AH' and AS' values of pseudorotational equilibrium in pentofuranoses 1-3 and pentofuranose moieties in nucleosides 614. The values of AH' were dissected into various stereoelectronic effects (gauche versus anomeric effects) of exocyclic substituents on the pentofuranose moiety. Clearly, the gauche effect of the 04'-C4'-C3'-03' fragment drives the pseudorotational equilibrium to the S-type conformations, while the gauche effect of the 04'-Cl'-C2'-02' fragment pushes the pseudorotational equilibrium to the N. These gauche effects are the strongest factors responsible for driving the N e S pseudorotational equilibrium. The strength of the gauche effect of the 04'-C4'-C3'-03' fragment in abasic sugars 1-3 is further tuned by the presence of a heterocyclic base at C1' in nucleosides 6-14. The relatively weaker anomeric effect of the heterocyclic base drives the N e S equilibrium to the N. The assessment of the relative strengths of the anomeric effects in 2',3'-dideoxy, 2'-deoxy-, and ribo-@-D-nucleosides has shown that the anomeric effect of the cytosine base is stronger than the anomeric effect of the adenine or guanine base. The experimental data suggest that the anomeric effect is considerably reduced as 04' experiences the electron-withdrawing effect(s) of 2'(3')-hydroxyls. The differences in the conformational preferences found in purine and pyrimidine ribonucleosides were additionally attributed to the distinct relative strength of the gauche effect of the N-C1'-C2'-02' fragment. The preference for the gauche orientation of the N-C1'-C2'-02' fragment and therefore S-type sugar conformation is affected by the nature of the purine or pyrimidine glycosyl nitrogen atom.

Background Formation of an HIV-1 particle with a conical core structure is a prerequisite for the subsequent infectivity of the virus particle. We have previously described that glycineamide (G-NH2) when added to the culture medium of infected cells induces non-infectious HIV-1 particles with aberrant core structures. Results Here we demonstrate that it is not G-NH2 itself but a metabolite thereof that displays antiviral activity. We show that conversion of G-NH2 to its antiviral metabolite is catalyzed by an enzyme present in bovine and porcine but surprisingly not in human serum. Structure determination by NMR suggested that the active G-NH2 metabolite was α-hydroxy-glycineamide (α-HGA). Chemically synthesized α-HGA inhibited HIV-1 replication to the same degree as G-NH2, unlike a number of other synthesized analogues of G-NH2 which had no effect on HIV-1 replication. Comparisons by capillary electrophoresis and HPLC of the metabolite with the chemically synthesized α-HGA further confirmed that the antiviral G-NH2-metabolite indeed was α-HGA. Conclusion α-HGA has an unusually simple structure and a novel mechanism of antiviral action. Thus, α-HGA could be a lead for new antiviral substances belonging to a new class of anti-HIV drugs, i.e. capsid assembly inhibitors.

This paper presents wavelet method for time series in business-field forecasting. An autoregressive moving average (ARMA) model is used, it can model the near-periodicity, nonstationarity and nonlinearity existed in business short-term time series. According to the wavelet denoising, wavelet decomposition and wavelet reconstruction, the hidden period and the nonstationarity existed in time series are extracted and separated by wavelet transformation. The characteristic of wavelet decomposition series is applied to BP networks and an autoregressive moving average (ARMA) model. It shows that the proposed method can provide more accurate results than the conventional techniques, like those only using BP networks or autoregressive moving average (ARMA) models.

The business field is one of the important fields where the data mining technology is applied. The study mainly focuses on different attribute object's quantitative prediction and customer structure's qualitative prediction. Aiming at the characteristics of time series in business field, such as near-periodicity, non-stationarity and nonlinearity, the wavelet-neural networks-ARMA method is proposed and its application is examined in this paper. The hidden period and the non-stationarity existed in time series are extracted and separated by wavelet transformation. The characteristic of wavelet decomposition series is applied to BP networks and an autoregressive moving average (ARMA) model. The given example elucidates that the forecasting method mentioned in this paper can be employed to the business field successfully and efficiently.

A simple experimental procedure on solid phase for the construction of new tripeptidic 5,9- and 5,10-fused thiazabicycloalkane scaffolds that adopt beta-turns has been developed. This N-terminal-directed bicyclization, relying on masked aldehyde precursors derived from glutamic acid as key building blocks, provides a complement to the related bicyclization previously reported, where an aspartic acid-derived precursor was employed to induce cyclization toward the C-terminal end of the peptide. Thus, the regioselectivity of the bicyclization can be altered simply by varying the chain length of the incorporated aldehyde precursor. Four analogues of the hypertensive octapeptide angiotensin II, comprising the new scaffolds in the 3-5- and 5-7-positions, were synthesized. One of these conformationally constrained angiotensin II analogues exhibited AT(1) receptor affinity (K(i) = 750 nM). Results from theoretical conformational analysis of model compounds of the bicyclic tripeptide mimetics are presented, and they demonstrate that subtle differences in geometry have a strong impact on the affinity to the AT(1) receptor.

Disulfide cyclization is a powerful method for reducing the conformational space of a peptide. This in turn may enable the study of its bioactive conformation. Several analogues of angiotensin II (Ang II) containing a disulfide bridge between amino acids 3 and 5 have been reported. Among these the cyclic octapeptides c[Hcy3,5]-Ang II, c[Cys3,5]-Ang II, and c[Pen 3,5]-Ang II showed significant activity at Ang II receptors. We have performed conformational analysis studies using theoretical calculations and 1H-NMR spectroscopy on tripeptide model compounds of these cyclic octapeptides which show that the cyclic moieties of c[Cys3,5]-Ang II and c[Pen3,5]-Ang II preferentially assume an inverse gamma-turn conformation. On the basis of these results, we substituted amino acid residues 3-5 in Ang II with two different gamma-turn mimetics giving four diastereomeric Ang II analogues. Interestingly, two of these are equipotent to Ang II in binding to AT1 receptors. In the contractile test using rabbit aorta rings, one of the analogues is an agonist with full contractile activity approximately equipotent to c[Pen3,5]-Ang II but 300-fold less potent than Ang II. This low potency may suggest that Ang II does not adopt a gamma-turn in the 3-5 region when interacting with the receptor.