Fast PI Research Articles

Abstract 522: TP53mutations promote death of breast cancer cells following Kif11 inhibition

Abstract Background: Triple-Negative Breast Cancer (TNBC) comprises 15-20% of breast cancer diagnoses. These aggressive breast cancers are characterized by their lack of expression of the estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and progesterone receptor (PR), resulting in few targeted therapy options for TNBC patients. While 85-90% of TNBCs contain mutations in TP53, mutant p53 is challenging to target directly. Instead, we aim to identify other survival pathways critical for the growth and survival of TP53 mutant cells. Through a combined in vitro and in silico drug screen, we identified the Kif11 inhibitor SB-743921 as more effective in TP53 mutant compared to wild-type breast cancer cells. Hypothesis: We hypothesized that Kif11 inhibition causes TP53 mutant cells to undergo cell death due to failure of activation of p53-mediated cell cycle checkpoints. Methods: Clinical data from the TCGA and METABRIC cohorts was obtained from cBioPortal. Expression and survival analyses were performed using GraphPad Prism. Cell growth assays were conducted by seeding cells, treating under designated conditions, then staining with Hoechst 33342 for cell counting on the ImageXpress Pico. Cell death was determined by staining with Annexin V and PI or DAPI Staining followed by flow cytometry analysis. Cell cycle analysis was conducted following synchronization with Lovastatin and Mevalonate release followed by imaging analysis of cell lines expressing the Fast FUCCI reporter or PI staining and flow cytometry analysis. Immunofluorescence imaging was conducted by staining with anti-alpha-tubulin-AlexaFluor488 and DAPI and imaging on the Nikon TI2 or ImageXPress PICO. In vitro expression experiments were carried out through qPCR and western blotting. Results: KIF11 is most highly expressed in TP53 mutant and triple-negative tumors and high expression of KIF11 is associated with poorer overall survival. In breast cancer cell lines, Kif11 inhibition leads to a cell cycle block in both TP53 mutant and wild-type cells, but TP53 mutant cells then die following this cell cycle block. Furthermore, Kif11 inhibition causes mitotic dysfunction, including monopolar spindle formation and multinucleated cells in TP53 mutants. Introduction of a TP53 mutation into TP53 wild-type cells also induces cell death following Kif11 inhibition. Conclusions: KIF11 is highly expressed in aggressive breast cancers and is associated with poorer prognosis. Using the small molecule inhibitor SB-74321 that has been tested in phase I/II clinical trials with favorable tolerability, we found that Kif11 inhibition results in mitotic dysfunction and death of TP53 mutant breast cancer cells due to mitotic catastrophe. These results suggest that Kif11 is a promising target for the treatment of TP53 mutant TNBCs. Citation Format: Amanda L. Lanier, William Tahaney, Jing Qian, Cassandra Moyer, Yanxia Ma, Banu Arun, Abhijit Mazumdar, Powel H. Brown. TP53mutations promote death of breast cancer cells following Kif11 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 522.

853-P: Effect of Ketogenic Diet with Weight Maintenance in Type 2 Diabetes (T2D)

Aim: To examine the effect of ketogenic diet in T2D patients on glucose tolerance, beta cell function, insulin sensitivity and body fat content. Methods: 29 T2D subjects were randomized to receive for 10 days a weight maintaining diet containing: GROUP I - 30% protein, 50% CHO, 20% fat (n=8); GROUP II - isocaloric ketogenic diet with 15% protein, 5% CHO, 80% fat (n=10); GROUP III - isocaloric ketogenic diet plus ketone ester of β-OH-B, 8 grams every 8h (n=11). Subjects ate breakfast daily in the TDI Metabolic Kitchen and picked up food for lunch and dinner. Results: After 10 days, body weight remained constant: Group I (89.0 vs 89.0 kg), II (93.0 vs 92.5) and III (96.0 vs 97.0), as did body fat content. HbA1c and fructosamine did not change in any of the 3 groups. During OGTT, FPG, 2-h PG, mean PG, fasting PI, mean PI, [Delta]I/[Delta]G, and Matsuda index of insulin sensitivity did not change in Groups I, II, III. Subjects received a 2-step euglycemic insulin clamp (20 and 60 mU/m2.min) with 3-3H-glucose and indirect calorimetry. Before and after 10 days basal HGP and suppression of HGP (step I) were similar in all 3 groups. Insulin-stimulated glucose disposal (step 2) did not change in group I (4.23 vs 4.38 mg/kg.min), II (3.62 vs 3.55), or III (3.26 vs 3.35). After 10 days, basal lipid oxidation increased, while CHO oxidation decreased (both P<0.01) in groups II and III and was unchanged in group I. Disclosure A.Merovci: None. B.Finley: None. A.Chavez: None. A.A.Hansis-diarte: None. S.Neppala: None. D.Tripathy: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk, Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc., Speaker's Bureau; AstraZeneca.

1345-P: Proinsulin–to–C-Peptide Ratio Is Associated with the Time above the Target Glucose Range and the Duration of Type 2 Diabetes

Background: The proinsulin-to-C-peptide (PI:C) ratio is thought to be an index of pancreatic β-cell dysfunction, and in subjects with prediabetes and type 2 diabetes (T2DM), abnormally high PI:C ratios have been identified. In the present study, we investigated the relationships of the duration of diabetes and glucose variability in subjects with T2DM with the PI:C ratio. Methods: We performed a prospective observational study of 272 Japanese outpatients with T2DM who underwent blinded professional continuous glucose monitoring (CGM) and fasting blood sample collection. Their fasting PI:C ratio and CGM-related indices were calculated. After placing all the participants into four groups on the basis of quartile (Q) of diabetes duration (Q1 <8 years, Q2 8-13 years, Q3 14-21 years, Q4 ≥22 years), the characteristics associated with PI:C ratio were identified. All of the statistical tests were two-sided and P<0.05 was considered to indicate statistical significance. Results: The mean age of the cohort was 68.0 years, their mean HbA1c 7.1%, and their mean body mass index (BMI) 24.9 kg/m2. High PI:C ratio was associated with a short duration of diabetes (P<0.001). In each group, there was a positive correlation between PI:C ratio and the time above the target glucose range (TAR; >180 mg/dL) in Q1, Q2, and Q3. The closest correlation between PI:C ratio and TAR was found for Q1 but there was no significant correlation for Q4 (Q1: ρ=0.38, P=0.003; Q2: ρ=0.28, P=0.019; Q3: ρ=0.24, P=0.045; Q4: ρ=0.03, P=0.811). Conclusions: We have shown that the PI:C ratio was positively associated with TAR in subjects with a short duration of T2DM. Given that insufficient pancreatic β-cell function and hyperglycemia is closely related, the PI:C ratio may play a role as the index of pancreatic β-cell dysfunction in subjects with a short duration of T2DM, but not in those with long-standing T2DM. Disclosure A.Miya: None. A.Nakamura: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Daiichi Sankyo, Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma Limited, Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. H.Nomoto: Speaker's Bureau; Novo Nordisk, Sumitomo Pharma, Co., Ltd. H.Kameda: None. T.Atsumi: Speaker's Bureau; Eli Lilly Japan K.K., Kowa Company, Ltd. Funding Japan Society for the Promotion of Science (22K17766)

Tuning the stability and phosphate sorption of novel MnII/IVFeII/III layered double hydroxides

Layered double hydroxides (LDHs) have been intensively studied for phosphate (Pi) removal but suffer from poor stability and low sorption affinity under ambient conditions. In this paper, well crystallized MnIIFeIIFeIII-Cl, MnIIFeIII-CO3 and novel MnIVFeIII-CO3 LDHs were synthesized. The LDHs show fast Pi sorption with 90 % uptake within 20 min, and high Pi sorption capacity of 11 mg P/g at low solution Pi concenrations of 0.1 mg P/L, corresponding to a very high Pi sorption affinity (Kd 1.1 × 105 L/kg). Fast MnII dissolution from the MnIIFeIIFeIII-Cl LDHs and formation of MnFe2O4 at pH 7 were observed in aqueous suspensions of non-oxidized material where up to 70% of total Mn was released within 2 h. However, when interlayer Cl- was exchanged with CO32−, much lower Mn dissolution (5.4%) was observed. Furthermore, after oxidation of MnII to MnIV, the obtained MnIVFeIII-CO3 LDH maintained the layered structure of LDH and the particles were surrounded by birnessite nanorods. The MnIVFeIII-CO3 LDH showed excellent stability but lower Pi sorption capacity. However, a high sorption affinity was maintained which is attributed to more positively charged Fe-centered sorption sites. XPS and ATR-FTIR data together with DFT calculations demonstrated that Pi was mainly sorbed via the formation of mononuclear mono- and bidentate Pi surface complexes on planar LDH particle surfaces.

Proinsulin to C-Peptide Ratio in the First Year After Diagnosis of Type 1 Diabetes.

The proinsulin to C-peptide (PI:C) ratio is reputedly a biomarker of β-cell endoplasmic reticulum (ER) stress. This study examined the natural history of the PI:C ratio and its correlation with residual β-cell function in childhood new-onset type 1 diabetes (T1D). Over the first year of T1D, the temporal trend in fasting and nutrient-stimulated PI data is limited. PI was a secondary pre-planned analysis of our 1-year, randomized, double-blind, placebo-controlled gamma aminobutyric acid (GABA) trial in new-onset T1D. Of the 99 participants in the primary study, aged 4 to 18 years, 30 were placebo. This study only involved the 30 placebo patients; all were enrolled within 5 weeks of T1D diagnosis. A liquid mixed meal tolerance test was administered at baseline and 5 and 12 months for determination of C-peptide, PI, glucose, and hemoglobin A1C. Both the fasting (P = 0.0003) and stimulated (P = 0.00008) PI:C ratios increased from baseline to 12 months, indicating escalating β-cell ER stress. The baseline fasting PI correlated with the fasting change in C-peptide at 12 months (P = 0.004) with a higher PI correlating with greater decline in C-peptide. Patients with an insulin-adjusted A1C >9% (hence, not in remission) had higher fasting PI:C ratios. Younger age at diagnosis correlated with a higher PI:C ratio (P = 0.04). Children with new-onset T1D undergo progressive β-cell ER stress and aberrant proinsulin processing, as evidenced by increasing PI:C ratios. Moreover, the PI:C ratio reflects more aggressive β-cell onslaught with younger age, as well as diminished glycemic control.

Multinuclear MRS at 7T Uncovers Exercise Driven Differences in Skeletal Muscle Energy Metabolism Between Young and Seniors.

Purpose: Aging is associated with changes in muscle energy metabolism. Proton (1H) and phosphorous (31P) magnetic resonance spectroscopy (MRS) has been successfully applied for non-invasive investigation of skeletal muscle metabolism. The aim of this study was to detect differences in adenosine triphosphate (ATP) production in the aging muscle by 31P-MRS and to identify potential changes associated with buffer capacity of muscle carnosine by 1H-MRS.Methods: Fifteen young and nineteen elderly volunteers were examined. 1H and 31P-MRS spectra were acquired at high field (7T). The investigation included carnosine quantification using 1H-MRS and resting and dynamic 31P-MRS, both including saturation transfer measurements of phosphocreatine (PCr), and inorganic phosphate (Pi)-to-ATP metabolic fluxes.Results: Elderly volunteers had higher time constant of PCr recovery (τPCr) in comparison to the young volunteers. Exercise was connected with significant decrease in PCr-to-ATP flux in both groups. Moreover, PCr-to-ATP flux was significantly higher in young compared to elderly both at rest and during exercise. Similarly, an increment of Pi-to-ATP flux with exercise was found in both groups but the intergroup difference was only observed during exercise. Elderly had lower muscle carnosine concentration and lower postexercise pH. A strong increase in phosphomonoester (PME) concentration was observed with exercise in elderly, and a faster Pi:PCr kinetics was found in young volunteers compared to elderly during the recovery period.Conclusion: Observations of a massive increment of PME concentration together with high Pi-to-ATP flux during exercise in seniors refer to decreased ability of the muscle to meet the metabolic requirements of exercise and thus a limited ability of seniors to effectively support the exercise load.

Phosphorus starvation and luxury uptake in green microalgae revisited

Phosphorus (P) is central to storing and transferring energy and information in living cells, including those of microalgae. Many microalgal species dwelling in low P environments are naturally equipped to take up and store P whenever it becomes available through a complex phenomenon known as “luxury P uptake.” Its research is required for better understanding of the nutrient geochemical cycles in aquatic environments but also for biotechnological applications such as sequestration of nutrients from wastewater and production of algal fertilizers. Here, we report on our recent insights into luxury P uptake and polyphosphate formation originating from physiological, ultrastructural, and transcriptomic evidence. The cultures pre-starved of P and re-fed with inorganic phosphate (Pi) exhibited a bi-phasic kinetics of Pi uptake comprising fast (1–2 h after re-feeding) and slow (1–3 d after re-feeding) phases. The rate of Pi uptake in the fast phase was ca. 10 times higher than in the slow phase with an opposite trend shown for the cell division rate. The transient peak of polyphosphate accumulation was determined 2–4 h after re-feeding and coincided with the period of slow cell division and fast Pi uptake. In this phase, the microalgal cells reached the highest P content (up to 5% of dry cell weight). The P re-feeding also reversed the characteristic changes in cell lipids induced by P starvation, namely increase in the major membrane glycolipid (DGDG/MGDG) ratio and betaine lipids. These changes were reversed upon Pi re-feeding of the starved culture. Electron microscopy revealed the ordered organization of vacuolar polyphosphate indicative of the possible involvement of an enzyme (complex) in their synthesis. A candidate gene encoding a protein similar to the vacuolar transport chaperone (VTC) protein, featuring an expression pattern corresponding to polyphosphate accumulation, was revealed. Implications of the findings for efficient biocapture of phosphorus are discussed.

230-LB: Intraindividual Variability of Measures of Beta-Cell Response

Diabetes intervention study designs require knowledge of within-subject variability of outcome measures. We evaluated the variability of measures of β-cell response assessed across 9-12 weeks in 3 nondiabetic adult populations relevant to type 1 diabetes (T1D) research: relatives of individuals with T1D who are single islet autoantibody (Ab) +, first degree relatives (FDR) with TID who are Ab -, and Ab- adults with no family history of T1D. C-peptide and glucose levels were measured in repeated mixed meal tolerance tests (MMTT) and hyperglycemic clamps separated by means of 2.8 months and 3.0 months. The 12 participants (22-49 y; 50% male) included 3 single Ab + FDRs, 5 Ab-FDRs, and 4 with no family history of T1D. Fasting proinsulin:C-peptide (PI:C) ratios were calculated as molar ratios. For MMTTs and clamps, stimulated C-peptide measures were calculated. Between-visit coefficients of variation and intraclass correlations were calculated. Test-retest variability differed between measures (Table). Test-retest correlations were highest for fasting PI:C and first-phase C-peptide response measures. In nondiabetic adults with or without known T1D risk factors, test-retest variability ranged from 10-30% for measures of β-cell response. These observations will inform study design including choice of methodology and sample sizes needed to detect treatment effects using these methods. Disclosure A. Neyman: None. C. Evans-Molina: None. L. DiMeglio: Research Support; Self; Amgen Inc., Caladrius Biosciences, Inc., Janssen Research & Development, Medtronic, Sanofi. Other Relationship; Self; Dexcom, Inc. R. Mirmira: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. E.K. Sims: None. Funding JDRF (2-SRA-2017-498-M-B)

“I’m Niu Voices”: Selina Tusitala Marsh’s Poetic Re-Imagining of Pacific Literature

This article analyzes Selina Tusitala Marsh’s collection of poetry, Fast Talking PI (2009) in the context of the poet’s call for the “Pasifikisation” of New Zealand literature. It focuses on three poetic acts: the naming and unnaming of the Pacific self, the recovering of past and present Pacific female voices, and the remythologizing of figures and places. These acts locate Marsh’s poetry within the decolonizing paradigm of postcolonial literature and exemplify the postcolonial categories of hybridity, syncretism and transnationalism.

Mechanisms of oat (Avena sativa L.) acclimation to phosphate deficiency.

BackgroundDeficiency of available forms of phosphorus is common in most soils and causes reduction of crop plants growth and yield. Recently, model plants responses to phosphate (Pi) deficiency have been intensively studied. However, acclimation mechanisms of cereals like oat (Avena sativa L.), to low Pi stress remains not fully understood. Oat plants have been usually cultured on poor soils, with a low nutrient content, but their responses to such conditions are not well known, therefore the main goal of the study was to investigate the mechanisms that enable oat plants to grow under low Pi conditions.MethodsFour oat cultivars (A. sativa, cv. Arab, Krezus, Rajtar and Szakal) were grown for three weeks in a nutrient media with various P sources: inorganic—KH2PO4 (control), organic—phytate (PA) and with no phosphate (−P). The effects of Pi deficiency on the level of P, oat growth parameters, intensity of photosynthesis, plant productivity, root exudation ability, localization, activity and isoforms of acid phosphatases, enzymes involved in Pi mobilization, were estimated. In addition, the effect of mycorrhization on plant growth was also observed.ResultsAll studied oat cultivars grown on Pi-deficient media had significantly decreased Pi content in the tissues. Pi deficiency caused inhibition of shoot growth, but generally it did not affect root elongation; root diameter was decreased, root/shoot ratios increased, whereas PA plants showed a similar growth to control. Photosynthesis rate and productivity parameters decreased under low Pi nutrition, however, sugar content generally increased. Studied oat cultivars did not respond to low Pi via increased exudation of carboxylates from the roots, as pH changes in the growth media were not observed. Pi starvation significantly increased the activity of extracellular and intracellular acid phosphatases (APases) in comparison to the control plants. Three major APase isoforms were detected in oat tissues and the isoform pattern was similar in all studied conditions, usually with a higher level of one of the isoforms under Pi starvation. Generally no significant effects of mycorrhizal colonization on growth of oat cultivars were observed.DiscussionWe postulated that acid phosphatases played the most important role in oat cultivars acclimation to Pi deficiency, especially extracellular enzymes involved in Pi acquisition from soil organic P esters. These APases are mainly located in the epidermis of young roots, and may be released to the rhizosphere. On the other hand, intracellular APases could be involved in fast Pi remobilization from internal sources. Our study showed that oat, in contrast to other plants, can use phytates as the sole source of P. The studied oat cultivars demonstrated similar acclimation mechanisms to Pi deficiency, however, depending on stress level, they can use different pools of acid phosphatases.

Prediction of Impending Type 1 Diabetes through Automated Dual-Label Measurement of Proinsulin:C-Peptide Ratio.

BackgroundThe hyperglycemic clamp test, the gold standard of beta cell function, predicts impending type 1 diabetes in islet autoantibody-positive individuals, but the latter may benefit from less invasive function tests such as the proinsulin:C-peptide ratio (PI:C). The present study aims to optimize precision of PI:C measurements by automating a dual-label trefoil-type time-resolved fluorescence immunoassay (TT-TRFIA), and to compare its diagnostic performance for predicting type 1 diabetes with that of clamp-derived C-peptide release.MethodsBetween-day imprecision (n = 20) and split-sample analysis (n = 95) were used to compare TT-TRFIA (AutoDelfia, Perkin-Elmer) with separate methods for proinsulin (in-house TRFIA) and C-peptide (Elecsys, Roche). High-risk multiple autoantibody-positive first-degree relatives (n = 49; age 5–39) were tested for fasting PI:C, HOMA2-IR and hyperglycemic clamp and followed for 20–57 months (interquartile range).ResultsTT-TRFIA values for proinsulin, C-peptide and PI:C correlated significantly (r2 = 0.96–0.99; P<0.001) with results obtained with separate methods. TT-TRFIA achieved better between-day %CV for PI:C at three different levels (4.5–7.1 vs 6.7–9.5 for separate methods). In high-risk relatives fasting PI:C was significantly and inversely correlated (rs = -0.596; P<0.001) with first-phase C-peptide release during clamp (also with second phase release, only available for age 12–39 years; n = 31), but only after normalization for HOMA2-IR. In ROC- and Cox regression analysis, HOMA2-IR-corrected PI:C predicted 2-year progression to diabetes equally well as clamp-derived C-peptide release.ConclusionsThe reproducibility of PI:C benefits from the automated simultaneous determination of both hormones. HOMA2-IR-corrected PI:C may serve as a minimally invasive alternative to the more tedious hyperglycemic clamp test.

Fast response Antiwindup PI speed controller of Brushless DC motor drive: Modeling, simulation and implementation on DSP

Most of the Brushless DC (BLDC) motors drive adopts proportional, integral and derivative (PID) controller and pulse width modulation (PWM) scheme for speed control. Hence, BLDC motor drive has strong saturation characteristics. The saturation results in a typical windup phenomenon. The paper presents an Antiwindup drive for BLDC motor. An Antiwindup controller (AWC) has been used in the paper. AWC has been modeled in MATLAB/Simulink and comparison has been done between conventional PI controller and AWC at different starting loads. Dynamic characteristics of the BLDC motor drive have been examined and results are presented and discussed in detail in this paper. Details of DSP based experimental validation of the simulated results are also presented here.

PCR-BasedIn VitroSynthesis of Hepatitis C Virus NS3 Protease for Rapid Phenotypic Resistance Testing of Protease Inhibitors

Protease inhibitors (PIs) targeting the hepatitis C virus (HCV) NS3 protease, such as telaprevir, have significantly improved the sustained virologic response (SVR) rates of HCV genotype 1 antiviral therapy. Given the expanding antiviral therapy regimen, fast HCV PI resistance assays are urgently needed. In this view, we have developed a novel phenotypic resistance test for HCV PIs based on in vitro synthesis of patient-derived HCV NS3 protease and subsequent enzymatic testing in a fluorescent readout. The enzymatically active HCV NS3 proteases were synthesized from PCR-derived templates by an Escherichia coli S30 extract system. Tests of the protease genes with known mutations for telaprevir resistance showed that the phenotypic resistance test was fast, with a total turnaround time of <10 h, and was fully in agreement with the previous resistance results. The initial tests with 38 treatment-naive serum samples showed that the method was significantly less laborious and faster than currently available phenotypic resistance assays of HCV NS3 PIs.

PIP2 Dynamics underlying Muscarinic or Vasopressin Receptor-Activated TRPC3 C6 And C7 Currents

Subfamily of human expressed TRPC channels (TRPC3/6/7) are activated by ‘diacylglycerol' (DAG), a phospholipase C (PLC) hydrolyzed product of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] (Hofmann et al., 1999, Nature). In contrary, we have recently reported that the depletion of PI(4,5)P2 by-itself act as a potent negative regulator to all these channels even in the presence of DAG (Imai et al., 2012, J. of Physiol.). Stimulation upon the vasoconstrictile receptors coupled with PLC theoretically causes inseparable bimodal effect to these TRPC channels, i.e. activation and inhibition by DAG production and coincident PI(4,5)P2 reduction or depletion which is corresponding to the strength of PLC activities. Here, to elucidate such self-limiting regulatory function coupled to PI(4,5)P2-DAG signal, we simultaneously measure TRPC6/7 currents in the whole-cell configuration and PI(4,5)P2 dynamics by FRET using PI(4,5)P2 binding PH-domain sensor proteins in the various strength of muscarinic- or vasopressin-receptor stimulation. Our simultaneous detection approach reveals good kinetics correlation between TRPC activation/fast-inactivation and PI(4,5)P2 depletion. Furthermore, a simple self-limiting regulation model wherein experimentally determined PI(4,5)P2 binding constants incorporated aware an emergence of fast recovery of PI(4,5)P2 to produce slow inactivation (plateau phase) of TRPC currents. We find that such model implicated PI(4,5)P2 enhancement can be reproduced after the fast PI(4,5)P2 depletion under the robust agonist stimulation by the local FRET measurement near the channels. Hence, these data indicates that self-limiting regulation coupled to PI(4,5)P2-DAG signal is the pivotal mechanism to understand the receptor-PLC mediated TRPC3/6/7 channels activity.

3-D Space Modulation With Voltage Balancing Capability for a Cascaded Seven-Level Converter in a Solid-State Transformer

The solid-state transformer (SST) is an alternative for existing power transformer due to its advantage in low volume, bidirectional power flow, power factor control, and fault management capability. In this paper, a three-stage cascaded-type SST, which utilizes the cascaded seven-level rectifier as the interface with a 7.2 kV distribution system, is presented. In the described system, dc voltage balancing of the cascaded seven-level rectifier is a necessity for stable operation. Previous PI-based voltage balancing control has intrinsic disadvantage in compromise between fast regulation and PI saturation. Besides, the addition of a voltage balancing controller may also change the system loop and bring unexpected performance. This paper aims at giving an alternative view of voltage balancing mechanism in a cascaded multilevel converter. A novel 3-D space modulation technique with voltage balancing capability is proposed for a cascaded seven-level rectifier stage of SST. By choosing the most suitable switching pairs for dc voltage balance, this method has a very good voltage balancing capability that can realize fast regulation of dc voltages in all operation modes, including unity power factor operation, capacitive operation, and inductive operation. Simulation and experimental results in a scaled-down system are provided to verify the effectiveness of the proposed method.

Dynamics in miscible blends of polyisoprene and poly(p-tert-butyl styrene): thermo–rheological behavior of components

Viscoelastic and dielectric properties were examined for miscible blends of moderately entangled cis-polyisoprene (PI) and poly(p-tert-butyl styrene) (PtBS). The dielectric response exclusively detected the global motion of PI chains having type-A dipoles. In most of the blends, PI and PtBS were the fast and much slower components, respectively. In those blends, the dielectric response of PI was thermo–rheologically complex because the slow PtBS chains quenched the dynamic frictional heterogeneity in the time scale of the PI relaxation. In contrast, the viscoelastic response of PtBS was thermo–rheologically simple because the fast PI chains smeared the heterogeneity. Nevertheless, PtBS exhibited no ordinary entanglement relaxation but retarded Rouse-like relaxation attributable to pseudo-constraint release activated by the PI motion. A simple model based on this molecular picture well described the viscoelastic data of the blends.

Alpha-1-antitrypsin (Pi) phenotypes in a Finnish population

alpha-1-antitrypsin (Pi) phenotypes of 548 normal Finnish blood donors were determined by isoelectric focusing in polyacrylamide gel. The frequencies obtained (M, 93.3%; FM, 0.4%, GM, 0.2%; MS, 3.5%; MZ, 2.7%) differed from those reported earlier for a more restricted Finnish population but agreed better with the frequencies reported for other Scandinavian populations. The disagreement with the earlier report was attributed to differences in sampling and laboratory techniques. The present study confirms an earlier finding of a sarcity of fast Pi variants in the Finnish population. One M variant was found. The isoelectric focusing technique used in this study has several advantages over the methods previously described for Pi typing.

Single Pion Production in 0.96-Bevπ−−pInteractions

ABS>Photographs of interactions in a hydrogen bubble chamber irradiated by 0.96-Bev pi /sup -/ were analyzed. Measurements revealed 415 events of the reaction pi /sup -/ + p yields n + pi /sup +/ + pi /sup -/ and 267 events of the reaction pi /sup -/+ p yields p + pi /sup o/ + pi /sup -/. It is shown that the angular distributions are quite different and the observed ratio of proton to neutron events with fast pi /sup -/ is 0.9 plus or minus 0.2. Q values for the different nucleon-pion combinations were computed from the observed momenta. The distributions of Q values are plotted for pion-pion combinations in each reaction, with backward-nucleon events and forward-nucleon events plotted separately. No evidence is seen of pcaking for ( pi /sup -/ pi / sup +/), either for forward or backward neutrons or for ( pi /sup -/ pi /sup o/) forward protons. The Q distribution of ( pi /sup -/ pi /sup o/) for backward protons shows a distinct peak at about 325-Mev, which is suggestive of a 600Mev resonant di-pion'' state (T = 1 or 2). This event is being analyzed. (B.O.G.)