Telomerase activity and its regulation in malignant hematopoietic cells

Telomerase, a multicomponent ribonucleoprotein, synthesizes TTAGGG telomeric repeats essential for the stability and integrity of chromosomes. Most normal human somatic cells exhibit undetectable telomerase activity. Activation of telomerase is widely observed in both primary malignant tissues and immortal cell lines and has been suggested as a critical step during turnorigenesis. The aim of this thesis was to define clinical and biological implications of telomerase activity in acute myelogenous leukemia (AML) and the regulatory pathways of telomerase expression in malignant hematopoietic cells.Ninety-five leukemic cell samples from 66 patients with AML were analyzed for telomerase activity and for the expression of its subunits telomerase reverse transcriptase (hTERT), telomerase RNA (hTER) and telomerase associated protein (hTEPI). Eighty out of 95 AML samples exhibited elevated telomerase activity, which was in accordance with the upregulation of hTERT expression. Higher levels of enzymatic activity was significantly associated with progressive disease, CD34 expression, and abnormal karyotypes. This data suggests that activation of telomerase may play a role in the development and progression of AML.We found that terminal differentiation led to the repression of telomerase activity in the HL60 promyelocytic leukemic cell line when treated with differentiation-inducing agents. Downregulation of hTERT rnRNA expression at the transcriptional level preceded the reduction of telomerase activity in differentiated HL60 cells. During this process, ongoing protein synthesis was required for the inhibition of hTERT expression. These findings indicate that tumor cells may maintain an intact repression pathway that can be triggered to signal a shut-off of hTERT and telomerase expression, which provides a base for the manipulation of telomerase in human tumors.We demonstrated that either the overexpression of wild type (wt) tumor suppressor p53 in the BL41 Burkitt lymphoma cell line or the activation of endogenous wt p53 in the breast carcinoma MCF-7 cell line transcriptionally downregulated hTERT rnRNA expression. The activation of the hTERT proximal promoter in Drosophila Schneider SL2 cells completely depended on the ectopic expression of the transcription factor Sp1. Sp1-mediated transactivation of the promoter could be abrogated by wt p53. wt p53 repressed Sp1-binding to the hTERT promoter by forming a p53-Sp1 complex. Thus, p53-mediated repression of hTERT/telomerase may reflect yet another anti-tumor mechanism of p53.Interferon-[alpha] (IFN-[alpha]) has acquired use in the treatment of various human malignancies. However, the underlying mechanisms for its action remain unclear. We found that IFN-[alpha] treatment induces a rapid downregulation of hTERT expression followed by a decline in telomerase activity in hematopoietic cell lines Daudi, P3HR1, U266 and H9 and in leukemic cells from patients with acute leukemia. The suppression of hTERT/telomerase mediated by IFN-[alpha] was apparently independent of cell growth arrest and alterations in myc expression. This suppression could not be blocked by inhibition of protein synthesis. The anti-telomerase effect of IFN-[alpha] may represent one of the mechanisms contributing to its action against human tumors.</p

Data for: Up-regulation of TNF Receptor-associated Factor 7 after spinal cord injury in rats may have implication for neuronal apoptosis

Data for: Up-regulation of TNF Receptor-associated Factor 7 after spinal cord injury in rats may have implication for neuronal apoptosi

Image_1_Efficacy of Face-to-Face Delivered Cognitive Behavioral Therapy in Improving Health Status of Patients With Insomnia: A Meta-Analysis.TIFF

Background: Face-to-face cognitive behavioral therapy (CBT) is one of the most widely used non-pharmacological treatment approaches for insomnia. The aim of this study is to assess the efficacy of face-to-face delivered CBT on health outcomes and to evaluate the effect of CBT components as subgroup variables to explain the efficacy of face-to-face delivered CBT on health outcomes in adults over 18 years old with insomnia.Methods: Relevant randomized controlled trial studies published in the past 22 years were searched through the electronic databases. The Physiotherapy Evidence Database (PEDro) scale was used to assess the quality of the 31 included studies. The mean difference and standard deviation of outcome variables and subgroup variables were analyzed using random effect model, and the heterogeneity among the articles was assessed with the Q-test and I2. Egger regression analysis was used to assess publication bias.Results: The meta-analysis showed a significant reduction in Insomnia Severity Index [standardized mean difference (SMD) = −2.56, 95% CI −3.81 to −1.30, p 0.05) and mental health (SMD = 1.09, 95% CI −0.59 to 2.77, p > 0.05) in CBT intervention group compared with control group. Group-delivered studies with larger number of intervention sessions and longer duration of single session provided a larger improvement in sleep quality.Conclusion: Face-to-face delivered CBT is effective in increasing total sleep time, sleep efficiency, and physical health, and reducing Insomnia Severity Index scores, Pittsburgh Sleep Quality Index scores, sleep onset latency, wakening after sleep onset, number of awakenings, depression, anxiety, and fatigue in patients with insomnia. Face-to-face delivered CBT is more effective when delivered through a larger number of sessions with longer duration of each session, and when delivered in groups. Face-to-face CBT is recommended to provide treatment to patients with insomnia in clinical settings.Systematic Review Registration:www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020200091, identifier: CRD4202020009.</p

Image_2_Efficacy of Face-to-Face Delivered Cognitive Behavioral Therapy in Improving Health Status of Patients With Insomnia: A Meta-Analysis.TIFF

Background: Face-to-face cognitive behavioral therapy (CBT) is one of the most widely used non-pharmacological treatment approaches for insomnia. The aim of this study is to assess the efficacy of face-to-face delivered CBT on health outcomes and to evaluate the effect of CBT components as subgroup variables to explain the efficacy of face-to-face delivered CBT on health outcomes in adults over 18 years old with insomnia.Methods: Relevant randomized controlled trial studies published in the past 22 years were searched through the electronic databases. The Physiotherapy Evidence Database (PEDro) scale was used to assess the quality of the 31 included studies. The mean difference and standard deviation of outcome variables and subgroup variables were analyzed using random effect model, and the heterogeneity among the articles was assessed with the Q-test and I2. Egger regression analysis was used to assess publication bias.Results: The meta-analysis showed a significant reduction in Insomnia Severity Index [standardized mean difference (SMD) = −2.56, 95% CI −3.81 to −1.30, p 0.05) and mental health (SMD = 1.09, 95% CI −0.59 to 2.77, p > 0.05) in CBT intervention group compared with control group. Group-delivered studies with larger number of intervention sessions and longer duration of single session provided a larger improvement in sleep quality.Conclusion: Face-to-face delivered CBT is effective in increasing total sleep time, sleep efficiency, and physical health, and reducing Insomnia Severity Index scores, Pittsburgh Sleep Quality Index scores, sleep onset latency, wakening after sleep onset, number of awakenings, depression, anxiety, and fatigue in patients with insomnia. Face-to-face delivered CBT is more effective when delivered through a larger number of sessions with longer duration of each session, and when delivered in groups. Face-to-face CBT is recommended to provide treatment to patients with insomnia in clinical settings.Systematic Review Registration:www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020200091, identifier: CRD4202020009.</p

Wetland Destruction in a Headwater River Leads to Disturbing Decline of In-stream Nitrogen Removal

Wetlands have long been recognized as efficient nitrogen (N) processing systems. While widespread interest is in constructing wetlands to mitigate N pollution, there is a dearth of information about the environmental consequences following wetland dismantlement. This study elucidated the changing trajectories of water quality and N removal capacity in a headwater river that initially contained a series of constructed wetlands but later underwent wetland destruction. An estimated 17% surge in total N concentration has been reported since the wetlands’ destruction. This adverse trend is primarily attributed to a weakened in-stream N removal capacity, which was reduced to a mere 25% of the levels observed when the wetlands were operational. Further analysis confirms that the presence of wetlands actively shapes desirable environmental settings for N processing. In stark contrast, wetland destruction leads to unfavorable environmental conditions, which not only restrain in-stream anaerobic metabolisms but also trigger algal proliferation and biological N fixation. Collectively, this research provides compelling evidence of the detrimental consequences associated with wetland destruction, emphasizing the need for remedial strategies to mitigate these negative effects

Vinyl Benzenes as Dienes in Mild Solid-Phase Diels−Alder Reactions^†

Wang resin-bound intermediates derived from Fmoc-l-phenylalaninal and Fmoc-l-valinal, and a resin supported Horner−Wadsworth−Emmons reaction, were treated with cinnamaldehyde derivatives, acetic acid, and borohydride to give secondary amines which were subsequently benzoylated to afford various derivatives of 3. Heating 3 at 95 °C induced cycloaddition reactions and produced 4 as the major product. Compounds 3 which were derived from 4-methoxycinnamaldehyde were more reactive, but did not give 4 and 4−7g. The direct cleavage of 3b using TFA led to the isolation of cycloaddition−demethylation product 10. The derivative of 3, which contained an electron-withdrawing nitro group on the phenyl ring, produced a single diastereomer of 4. The Diels−Alder cycloaddition between two electron-deficient counterparts showed similar reactivity to that of the reactions which have a normal complementary electron-demand

Additional file 1 of Comprehensive analyses of the cancer-associated fibroblast subtypes and their score system for prediction of outcomes and immunosuppressive microenvironment in prostate cancer

Supplementary Material

Node online rate number percentage chart.

Bitcoin is a decentralized digital cryptocurrency. Its network is a Peer-to-peer(P2P) network consisting of distributed nodes. Some of these nodes are always online and in this article are called Bitcoin backbone nodes. They have a significant impact on the stability and security of the Bitcoin network, so it is meaningful to analyze and discuss them. In this paper, we first continuously collect information about Bitcoin nodes from July 2021 through June 2022 (which is the longest duration of data collection to date). In total, we collect information on 127,613 Bitcoin nodes. At the same time, we conclude that the fluctuation of Bitcoin nodes is directly related to the fluctuation of onion network nodes. Further, we filtered 2694 Bitcoin backbone nodes based on our algorithm. By analyzing the backbone nodes’ attributes such as geographic distribution, client version, operator, node function, and abnormal port number, it is demonstrated that these nodes are centralized and play an important role in the Bitcoin network. Based on this, three unsupervised machine learning algorithms are selected to cluster multiple attributes of backbone nodes in a more scientific way. In this paper, the whole process from data collection to cluster analysis is completed and the best results are obtained by comparison. The experiments proved the existence of centralization of Bitcoin backbone nodes and obtained the number of nodes within each cluster. Finally, cluster nodes are de-anonymized based on the optimal results. Through our experiments, we obtain organizational information about the deployers of 103 nodes, linking the Bitcoin backbone nodes to the real world, thus accurately demonstrating the existence of Bitcoin centrality.</div

Silhouette coefficient curve with the number of clusters (Hierarchical clustering).

Silhouette coefficient curve with the number of clusters (Hierarchical clustering).</p

Bitcoin backbone node function statistics.

The numbers on the right side of the figure represent the different functions of the nodes. As an example: 1101 (Simultaneous functions) = 1024 (NODE NETWORK LIMITED) + 64 (NODE COMPACT FILTERS) +8 (NODE WITNESS) + 4 (NODE BLOOM) + 1 (NODE NETWORK).</p