Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to cancer cell apoptosis and renders synergism to overcome paclitaxel resistance in breast cancer cells.

BACKGROUND: Microtubule polymerization is usually considered as the upstream of apoptotic cell death induced by taxanes, but recently published studies provide more insights into the mechanisms responsible for the antineoplastic effect of taxanes. In this study, we figure out the role of the stress-related PERK/eIF2α axis in tumor cell death upon taxane treatment along with paclitaxel resistance. METHODS: Utilizing immunoblot assay, the activation status of PERK-eIF2α signaling was detected in a panel of cancer cell lines after the treatment of taxanes. The causal role of PERK-eIF2α signaling in the cancer cell apoptosis induced by taxanes was examined via pharmacological and genetic inhibitions of PERK. The relationship between microtubule polymerization and PERK-eIF2α activation was explored by immunofluorescent and immunoblotting assays. Eventaually, the combined therapeutic effect of paclitaxel (PTX) and CCT020312, a PERK agonist, was investigated in PTX-resistant breast cancer cells in vitro and in vivo. RESULTS: PERK-eIF2α axis was dramatically activated by taxanes in several cancer cell types. Pharmacological or genetic inhibition of PERK efficiently impaired taxane-induced apoptotic cell death, independent of the cellular microtubule polymerization status. Moreover, PTX was able to activate the PERK/eIF2α axis in a very low concentration without triggering microtubule polymerization. In PTX-resistant breast cancer cells, the PERK/eIF2α axis was attenuated in comparison with the PTX-sensitive counterparts. Reactivation of the PERK/eIF2α axis in the PTX-resistant breast cancer cells with PERK agonist sensitized them to PTX in vitro. Combination treatment of the xenografted PTX-resistant breast tumors with PERK agonist and PTX validated the synergic effect of PTX and PERK activation in vivo. CONCLUSION: Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to initiate cancer cell apoptosis, which is independent of the well-known microtubule polymerization-dependent manner. Simultaneous activation of PERK-eIF2α signaling would be a promising therapeutic strategy to overcome PTX resistance in breast cancer or other cancers.

UiO-66/PIM-1 Mixed-Matrix Membrane for Hexane Isomer Separation.

The separation of high-octane dibranched alkanes from naphtha is critical in the refining of gasoline. To date, research on the membrane-based separation of alkane isomers has been limited, with a particular paucity of investigations into mixed-matrix membranes. Herein, the continuous and dense UiO-66/PIM-1 mixed-matrix membrane, which was prepared through precise control of the interfacial structure, was first applied to the differentiation of C6 alkane isomers. Due to the synergistic combination of UiO-66 with differential adsorption capabilities for alkanes and PIM-1 that possesses a cross-linkable structure, the resulting UiO-66/PIM-1-(20) membrane demonstrated remarkable separation performance and high stability. Pervaporation measurements showed that the mass fraction of 2,2-dimethylbutane in the feed side was increased from 50.0 to 75.8 wt % while an excellent flux of 1700 g m-2 h-1 was maintained over a continuous 40 h period. The UiO-66/PIM-1-(20) membrane, characterized by its facile replication and processing, shows potential for large-scale fabrication. This study offers a new approach to the membrane separation of alkane isomers.

All-dielectric super-lattice metasurfaces with fivefold spatial resolution enhancement for structured illumination microscopy.

Structured illumination microscopy (SIM) is a promising imaging technique for high-resolution imaging with a wide field of view. Although a periodic nanostructure is a versatile platform for engineering the spatial frequency of structured illumination patterns in SIM, challenges remain, including artifacts from Fourier space gaps. We designed an all-dielectric super-lattice metasurface (ADSLM) to generate structured illumination patterns with enhanced spatial frequency and broadened spatial frequency coverage with no intermediate frequency gaps. Our numerical simulations reveal that ADSLM-based image reconstruction is capable of producing high-contrast, artifact-free images, resulting in enhanced spatial resolution up to 5.7-fold for coherent SIM at 450 nm. Our results show that the ADSLM-SIM technique may facilitate high-resolution imaging using CMOS-compatible substrates, offering potential for compact miniaturized imaging applications.

Activation of the MEK/ERK Pathway Mediates the Inhibitory Effects of Silvestrol on Nasopharyngeal Carcinoma Cells via RAP1A, HK2, and GADD45A.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with Epstein-Barr virus (EBV) infection. Chemoradiotherapy is the mainstream treatment for locally advanced NPC, and chemotherapeutic drugs are an indispensable part of NPC treatment. However, the toxic side-effects of chemotherapy drugs limit their therapeutic value, and new chemotherapy drugs are urgently needed for NPC. Silvestrol, an emerging natural plant anticancer molecule, has shown promising antitumor activity in breast cancer, melanoma, liver cancer, and other tumor types by promoting apoptosis in cancer cells to a greater extent than in normal cells. However, the effects of silvestrol on NPC and its possible molecular mechanisms have yet to be fully explored. METHODS: Cell counting kit-8 (CCK-8), cell scratch, flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU), and Western blot (WB) assays were used to evaluate the effects of silvestrol on the cell viability, cell cycle, apoptosis, and migration of NPC cells. RNA sequencing (RNA-Seq) was used to study the effect of extracellular signal-regulated kinase (ERK) inhibitors on the cell transcriptome, and immunohistochemistry (IHC) to assess protein expression levels in patient specimens. RESULTS: Silvestrol inhibited cell migration and DNA replication of NPC cells, while promoting the expression of cleaved caspase-3, apoptosis, and cell cycle arrest. Furthermore, silvestrol altered the level of ERK phosphorylation. The ERK-targeted inhibitor LY3214996 attenuated silvestrol-mediated inhibition of NPC cell proliferation but not migration. Analysis of RNA-Seq data and WB were used to identify and validate the downstream regulatory targets of silvestrol. Expression of GADD45A, RAP1A, and hexokinase-II (HK2) proteins was inhibited by silvestrol and LY3214996. Finally, IHC revealed that GADD45A, RAP1A, and HK2 protein expression was more abundant in cancer tissues than in non-tumor tissues. CONCLUSIONS: Silvestrol inhibits the proliferation of NPC cells by targeting ERK phosphorylation. However, the inhibition of NPC cell migration by silvestrol was independent of the Raf-MEK-ERK pathway. RAP1A, HK2, and GADD45A may be potential targets for the action of silvestrol.

D-SAT: dual semantic aggregation transformer with dual attention for medical image segmentation.

Objective. Medical image segmentation is significantly essential to assist clinicians in facilitating a quick and accurate diagnoses. However, most of the existing methods are still challenged by the loss of semantic information, blurred boundaries and the huge semantic gap between the encoder and decoder.Approach. To tackle these issues, a dual semantic aggregation transformer with dual attention is proposed for medical image segmentation. Firstly, the dual-semantic feature aggregation module is designed to build a bridge between convolutional neural network (CNN) and Transformer, effectively aggregating CNN's local feature detail ability and Transformer's long-range modeling ability to mitigate semantic information loss. Thereafter, the strip spatial attention mechanism is put forward to alleviate the blurred boundaries during encoding by constructing pixel-level feature relations across CSWin Transformer blocks from different spatial dimensions. Finally, a feature distribution gated attention module is constructed in the skip connection between the encoder and decoder to decrease the large semantic gap by filtering out the noise in low-level semantic information when fusing low-level and high-level semantic features during decoding.Main results. Comprehensive experiments conducted on abdominal multi-organ segmentation, cardiac diagnosis, polyp segmentation and skin lesion segmentation serve to validate the generalization and effectiveness of the proposed dual semantic aggregation transformer with dual attention (D-SAT). The superiority of D-SAT over current state-of-the-art methods is substantiated by both subjective and objective evaluations, revealing its remarkable performance in terms of segmentation accuracy and quality.Significance. The proposed method subtly preserves the local feature details and global context information in medical image segmentation, providing valuable support to improve diagnostic efficiency for clinicians and early disease control for patients. Code is available athttps://github.com/Dxkm/D-SAT.

PEC/Colorimetric Dual-Mode Lab-on-Paper Device via BiVO4/FeOOH Nanocomposite In Situ Modification on Paper Fibers for Sensitive CEA Detection.

A dual-mode lab-on-paper device based on BiVO4/FeOOH nanocomposites as an efficient generating photoelectrochemical (PEC)/colorimetric signal reporter has been successfully constructed by integration of the lab-on-paper sensing platform and PEC/colorimetric detection technologies for sensitive detection of carcinoembryonic antigen (CEA). Concretely, the BiVO4/FeOOH nanocomposites were in situ synthesized onto the paper-working electrode (PWE) through hydrothermal synthesis of the BiVO4 layer on cellulose fibers (paper-based BiVO4) which were initially modified by Au nanoparticles for improving the conductivity of three dimensional PWE, and then the photo-electrodeposition of FeOOH onto the paper-based BiVO4 to construct the paper-based BiVO4/FeOOH for the portable dual-mode lab-on-paper device. The obtained nanocomposites with an FeOOH needle-like structure deposited on the BiVO4 layer exhibits enhanced PEC response activity due to its effective separation of the electron-hole pair which could further accelerate the PEC conversion efficiency during the sensing process. With the introduction of CEA targets onto the surface of nanocomposite-modified PWE assisted by the interaction with the CEA antibody from a specific recognition property, a signal-off PEC signal state with a remarkable photocurrent response decreasing trend can be achieved, realizing the quantitative detection of CEA with the PEC signal readout mode. By means of a smart origami paper folding, the colorimetric signal readout is achieved by catalyzing 3,3',5,5'-tetramethylbenzidine (TMB) to generate blue oxidized TMB in the presence of H2O2 due to the satisfied enzyme-like catalytic activity of the needle-like structure, FeOOH, thereby achieving the dual-mode signal readout system for the proposed lab-on-paper device. Under the optimal conditions, the PEC and colorimetric signals measurement were effectively carried out, and the corresponding linear ranges were 0.001-200 ng·mL-1 and 0.5-100 ng·mL-1 separately, with the limit of detection of 0.0008 and 0.013 ng·mL-1 for each dual-mode. The prepared lab-on-paper device also presented a successful application in serum samples for the detection of CEA, providing a potential pathway for the sensitive detection of target biomarkers in clinical application.

Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer. RNA-binding proteins (RBPs) regulate highly dynamic post-transcriptional processes and perform very important biological functions. Although over 1900 RBPs have been identified, most are considered markers of tumor progression, and further information on their general role in PAAD is not known. Here, we report a bioinformatics analysis that identified five hub RBPs and produced a high-value prognostic model based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Among these, the prognostic signature of the double-stranded RNA binding protein Staufen double-stranded RNA (STAU2) was identified. Firstly, we found that it is a highly expressed critical regulator of PAAD associated with poor clinical outcomes. Accordingly, the knockdown of STAU2 led to a profound decrease in PAAD cell growth, migration, and invasion and induced apoptosis of PAAD cells. Furthermore, through multiple omics analyses, we identified the key target genes of STAU2: Palladin cytoskeletal associated protein (PALLD), Heterogeneous nuclear ribonucleoprotein U (HNRNPU), SERPINE1 mRNA Binding Protein 1 (SERBP1), and DEAD-box polypeptide 3, X-Linked (DDX3X). Finally, we found that a high expression level of STAU2 not only helps PAAD evade the immune response but is also related to chemotherapy drug sensitivity, which implies that STAU2 could serve as a potential target for combinatorial therapy. These findings uncovered a novel role for STAU2 in PAAD aggression and resistance, suggesting that it probably represents a novel therapeutic and drug development target.

Development and clinical advancement of small molecules for ex vivo expansion of hematopoietic stem cell.

Hematopoietic stem cell (HSC) transplantation is the only curative therapy for many diseases. HSCs from umbilical cord blood (UCB) source have many advantages over from bone marrow. However, limited HSC dose in a single CB unit restrict its widespread use. Over the past two decades, ex vivo HSC expansion with small molecules has been an effective approach for obtaining adequate HSCs. Till now, several small-molecule compounds have entered the phase I/II trials, showing safe and favorable pharmacological profiles. As HSC expansion has become a hot topic over recent years, many newly identified small molecules along with novel biological mechanisms for HSC expansion would help solve this challenging issue. Here, we will give an overview of HSC biology, discovery and medicinal chemistry development of small molecules, natural products targeting for HSC expansion, and their recent clinical progresses, as well as potential protein targets for HSC expansion.

A Template Model Explains Jerboa Gait Transitions Across a Broad Range of Speeds.

For cursorial animals that maintain high speeds for extended durations of locomotion, transitions between footfall patterns (gaits) predictably occur at distinct speed ranges. How do transitions among gaits occur for non-cursorial animals? Jerboas (Jaculus) are bipedal hopping rodents that frequently transition between gaits throughout their entire speed range. It has been hypothesized that these non-cursorial bipedal gait transitions are likely to enhance their maneuverability and predator evasion ability. However, it is difficult to use the underlying dynamics of these locomotion patterns to predict gait transitions due to the large number of degrees of freedom expressed by the animals. To this end, we used empirical jerboa kinematics and dynamics to develop a unified spring Loaded Inverted Pendulum model with defined passive swing leg motions. To find periodic solutions of this model, we formulated the gait search as a boundary value problem and described an asymmetrical running gait exhibited by the jerboas that emerged from the numerical search. To understand how jerboas change from one gait to another, we employed an optimization approach and used the proposed model to reproduce observed patterns of jerboa gait transitions. We then ran a detailed numerical study of the structure of gait patterns using a continuation approach in which transitions are represented by bifurcations. We found two primary mechanisms to increase the range of speeds at which gait transitions can occur. Coupled changes in the neutral leg swing angle alter leg dynamics. This mechanism generates changes in gait features (e.g., touchdown leg angle and timings of gait events) that have previously been shown to induce gait transitions. This mechanism slightly alters the speeds at which existing gait transitions occur. The model can also uncouple the left and right neutral leg swing angle, which generates asymmetries between left and right leg dynamics. New gait transitions emerge from uncoupled models across a broad range of speeds. In both the experimental observations and in the model, the majority of the gait transitions involve the skipping and asymmetrical running gaits generated by the uncoupled neutral leg swing angle mechanism. This simulated jerboa model is capable of systematically reproducing all biologically relevant gait transitions at a broad range of speeds.

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer.

Prostate cancer (PCa) is one of the most prevalent cancers in men worldwide, and hormonal therapy plays a key role in the treatment of PCa. However, the drug resistance of hormonal therapy makes it urgent and necessary to identify novel targets for PCa treatment. Herein, dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) is found and confirmed to be highly expressed in the PCa tissues and cells, and knock-down of DYRK2 remarkably reduces PCa burden in vitro and in vivo. On the base of DYRK2 acting as a promising target, we further discover a highly selective DYRK2 inhibitor YK-2-69, which specifically interacts with Lys-231 and Lys-234 in the co-crystal structure. Especially, YK-2-69 exhibits more potent anti-PCa efficacy than the first-line drug enzalutamide in vivo. Meanwhile, YK-2-69 displays favorable safety properties with a maximal tolerable dose of more than 10,000 mg/kg and pharmacokinetic profiles with 56% bioavailability. In summary, we identify DYRK2 as a potential drug target and verify its critical roles in PCa. Meanwhile, we discover a highly selective DYRK2 inhibitor with favorable druggability for the treatment of PCa.

Two complete mitochondrial genomes in Scolopendra and a comparative analysis of tRNA rearrangements in centipedes.

BACKGROUND: Centipedes are one of the oldest terrestrial arthropods belonging to the sub phylum Myriapoda. With the expansion of our understanding of the application of the two centipedes Scolopendra morsitans and Scolopendra hainanum, belonging to the order Scolopendromorpha, an exhaustive classification was required. Although consensus has been reached on the phylogeny of Chilopoda based on morphological traits, recent analyses based on molecular data exhibited differences in results. METHODS AND RESULTS: The mitochondrial genome sequences of S. morsitans and S. hainanum were obtained by next-generation sequencing. S. morsitans contains 13 PCGs, two rRNAs, 11 tRNAs, and one CR. whereas S. hainanum contains 12 PCGs, of which ATP8 remains unpredicted, two rRNAs, 14 tRNAs, and one CR. An obvious tRNA rearrangement was found in the genus Scolopendra. S. morsitans exhibited a loss of trnW, trnC, trnI, trnK, trnD, trnA, trnN, trnQ, trnF, trnT, trnS, trnL, and trnV, and a repeat of trnR and trnL. S. hainanum exhibited a loss of trnQ, trnC, trnW, trnI, trnD, trnQ, trnP, and trnV. Phylogenetic analyses of centipedes based on 12 PCGs supported the sister relationship between the orders Geophilomorpha and Lithobiomorpha and a close relationship between Scolopendra dehaani and S. hainanum. CONCLUSIONS: The new mitogenomes determined in this study provide new genomic resources for gene rearrangements and contribute to the understanding of the evolution of gene rearrangement in Chilopoda.

PTPN2, A Key Predictor of Prognosis for Pancreatic Adenocarcinoma, Significantly Regulates Cell Cycles, Apoptosis, and Metastasis.

Objective: This study conducted a comprehensive analysis of the members of the PTPN family and emphasized the key role of PTPN2 as a potential therapeutic target and diagnostic biomarker in improving the survival rate of PAAD. Method: Oncomine was used to analyze the pan-cancer expression of the PTPN gene family. The Cancer Genome Atlas (TCGA) data as well as Genotype-Tissue Expression (GTEx) data were downloaded to analyze the expression and prognosis of PTPNs. The diagnosis of PTPNs was evaluated by the experimental ROC curve. The protein-protein interaction (PPI) network was constructed by combining STRING and Cytoscape. The genes of 50 proteins most closely related to PTPN2 were screened and analyzed by GO and KEGG enrichment. The differentially expressed genes of PTPN2 were found by RNA sequencing, and GSEA enrichment analysis was carried out to find the downstream pathways and targets, which were verified by online tools and experiments. Finally, the relationship between PTPN2 and immune cell infiltration in PAAD, and the relationship with immune score and immune checkpoint were studied. Result: The expression patterns and the prognostic value of multiple PTPNs in PAAD have been reported through bioinformatic analyzes. Among these members, PTPN2 is the most important prognostic signature that regulates the progression of PAAD by activating JAK-STAT signaling pathway. Comparison of two PAAD cell lines with normal pancreatic epithelial cell lines revealed that PTPN2 expression was up-regulated as a key regulator of PAAD, which was associated with poor prognosis. Knockdown of PTPN2 caused a profound decrease in PAAD cell growth, migration, invasion, and induced PAAD cell cycle and apoptosis. In addition, we conducted a series of enrichment analyses to investigate the PTPN2-binding proteins and the PTPN2 expression-correlated genes. We suggest that STAT1 and EGFR are the key factors to regulate PTPN2, which are involved in the progression of PAAD. Meanwhile, the silencing of PTPN2 induced the repression of STAT1 and EGFR expression. Conclusion: These findings provide a comprehensive analysis of the PTPN family members, and for PAAD, they also demonstrate that PTPN2 is a diagnostic biomarker and a therapeutic target.

The mitochondrial genome and phylogenetic characteristics of the Thick-billed Green-Pigeon, Treron curvirostra: the first sequence for the genus.

Members of the genus Treron (Columbidae) are widely distributed in southern Asia and the Indo-Malayan Region but their relationships are poorly understood. Better knowledge of the systematic status of this genus may help studies of historical biogeography and taxonomy. The complete mitochondrial genome of T. curvirostra was characterized, a first for the genus. It is 17,414 base pairs in length, containing two rRNAs, 22 tRNAs, 13 protein coding genes (PCGs), and one D-loop with a primary structure that is similar to that found in most members of Columbidae. Most PCGs start with the common ATG codon but are terminated by different codons. The highest value of the Ka/Ks ratio within 13 PCGs was found in ATP8 with 0.1937, suggesting that PCGs of the mitochondrial genome tend to be conservative in Columbidae. Moreover, the phylogenetic relationships within Columbidae, which was based on sequences of 13 PCGs, showed that (T. curvirostra + Hemiphaga novaeseelandiae) were clustered in one clade, suggesting a potentially close relationship between Treron and Hemiphaga. However, the monophyly of the subfamilies of Columbidae recognized by the Interagency Taxonomic Information System could not be corroborated. Hence, the position of the genus Treron in the classification of Columbidae may have to be revised.

Upgrading Octane Number of Naphtha by a Robust and Easily Attainable Metal-Organic Framework through Selective Molecular Sieving of Alkane Isomers.

The separation of alkanes, particularly monobranched and dibranched isomers, is of paramount importance in the petrochemical industry for optimizing the feedstock of ethylene production as well as for upgrading the octane number of gasoline. Here, we report the full separation of linear/monobranched alkanes from their dibranched isomers by a robust and easily scalable metal-organic framework material, Co3 (HCOO)6 . The compound completely excludes dibranched alkanes but adsorbs their linear and monobranched isomers, as evidenced by single-component and multicomponent adsorption measurements. More importantly, the material exhibits excellent performance in separating naphtha and is capable of providing high quality feedstock for the production of ethylene and gasoline components with high octane number, making it a promising candidate for naphtha separation in petrochemical industry.

Comparative mitogenomes of three species in Moenkhausia: Rare irregular gene rearrangement within Characidae.

Generally, a teleostean group possesses only one type or a set of similar mitochondrial gene arrangements. However, a new type of gene arrangement has been identified in the mitochondrial genomes (mitogenomes) of Moenkhausia. Here, three newly sequenced complete mitogenomes of tetras (Characidae: Moenkhausia) are presented (M. costae, M. pittieri, and M. sanctaefilomenae). The three mitogenomes had a classical circular structure, with total lengths ranging from 15,811 to 18,435 bp. Base composition analysis indicated that the sequences were biased toward adenine (A) and thymine (T), with A + T content of 54.63% in M. costae, 58.47% in M. pittieri, and 59.98% in M. sanctaefilomenae. The gene order and organization of M. sanctaefilomenae differed from those of typical teleostean mitogenomes. The genes tRNA-Ile, tRNA-Gln, and tRNA-Pro were translocated between tRNA-Trp and tRNA-Asn. One extra tRNA-Met and an extra CR were also discovered in the mitogenome. BI and ML analyses based on sequences of 38 different mitogenomes showed that M. costae and M. pittieri were classified together, and M. sanctaefilomenae was slightly further from other fish of the same genus. These results provide insight into the gene arrangement features of Characidae mitogenomes and lay the foundation for further phylogenetic studies on Characidae.

Interaction mechanism of dissolved Cr(VI) and manganite in the presence of goethite coating.

Hexavalent chromium has aroused a series of environmental concerns due to its high mobility and toxicity. Iron and manganese oxides usually coexist in the environments and influence the speciation and geochemical cycling of chromium. However, the interaction mechanism of iron-manganese oxides with dissolved Cr(VI) remains largely unknown. In this work, the interaction processes of dissolved Cr(VI) and manganite in the presence of goethite coating were investigated, and the effects of pH (2.0-9.0) and iron oxide content were also studied. Manganite-goethite composites were formed with uniform micromorphologies in the system of manganite and Fe(II). In the reaction system of single manganite and Cr(VI), manganite could only adsorb but not reduce Cr(VI), with the adsorption amount decreasing at higher pHs. In the reaction system of manganite-goethite composites and Cr(VI), adsorbed Cr(VI) was reduced to Cr(III) by Fe(II) on composites surface. The generated Cr(III) was then retained as Cr(OH)3 on the mineral surface. Goethite coating suppressed the re-oxidation of newly formed Cr(III) by manganite. The amounts of adsorbed Cr(VI) and generated Cr(III) increased with increasing iron oxide content, and increased first and then decreased with increasing pH. The Cr(III) formation and Cr(VI) adsorption amount reached the maximum at pH 5.0-6.0. The present work highlights the transformation and retention of Cr(VI) by iron-manganese oxides and provides potential implications for the use of such oxides in the remediation of Cr(VI) polluted waters and soils.

Effects of the New Lift-Thrust Operation in Laser Acupuncture Investigated by Thermal Imaging.

Acupuncture manipulation is one of the key factors affecting the performance of acupuncture in Traditional Chinese Medicine. Lift-thrust and twirl-twist are two of the most commonly used manipulation methods for needle acupuncture. We previously have developed a novel laser acupuncture model that emulates lift-thrust operation. In this study, we intend to show the effectiveness of such a model by applying it on the Neiguan acupoint (PC6). Stimulation was reported to be beneficial for improving cardiac output and peripheral circulation. Therefore, we hypothesized that the stimulation of laser acupuncture may increase the temperature of the subjects' fingertip due to increased peripheral blood flow. A thermal imager was used to measure the temperature change of subjects' fingertips. Through regression analysis, it has been shown that while PC6 is stimulated, laser acupuncture with lift-thrust operation caused a more rapid, stable, and lasting temperature rise of fingertip than that without lift-thrust operation. On the contrary, we observe no significant temperature change when a sham point nearby PC6 (a point which is not traditionally defined as the acupoint) was stimulated. Our results suggest the emulation of manipulation methods such as the lift-thrust operation could be a potential direction for the future development of laser acupuncture.

Further Studies on Structure-Cardiac Activity Relationships of Diterpenoid Alkaloids.

The cardiac effect of thirty-eight diterpenoid alkaloids was evaluated on the isolated bullfrog heart model. Among them, twelve compounds exhibited appreciable cardiac activity, with compounds 3 and 35 being more active than the reference drug lanatoside. The structure-cardiac activity relationships of the diterpenoid alkaloids were summarized based on our present and previous studies [2]: i) 1α-OMe or 1α-OH, 8-OH, 14-OH, and NH (or NMe) are key structural features important for the cardiac effect of the aconitine-type C19-diterpenoid alkaloids without any esters. C18-diterpenoid alkaloids, lycoctonine-type C19-diterpenoid alkaloids, and the veatchine- and denudatine-type C20-diterpenoid alkaloids did not show any cardiac activity; ii) the presence of 3α-OH is beneficial to the cardiac activity; iii) the effect on the cardiac action of 6α-OMe, 13-OH, 15α-OH, and 16-demethoxy or a double bond between C-15 and C-16 depends on the substituent pattern on the nitrogen atom.