Biochemical and transcript level differences between the three human phosphofructokinases show optimisation of each isoform for specific metabolic niches

6-Phosphofructokinase-1-kinase (PFK) tetramers catalyse the phosphorylation of fructose 6-phosphate (F6P) to fructose 1,6-bisphosphate (F16BP). Vertebrates have three PFK isoforms (PFK-M, PFK-L, and PFK-P). This study is the first to compare the kinetics, structures, and transcript levels of recombinant human PFK isoforms. Under the conditions tested PFK-M has the highest affinities for F6P and ATP (K0.5ATP 152 µM; K0.5F6P 147 µM), PFK-P the lowest affinities (K0.5ATP 276 µM; K0.5F6P 1333 µM), and PFK-L demonstrates a mixed picture of high ATP affinity and low F6P affinity (K0.5ATP 160 µM; K0.5F6P 1360 µM). PFK-M is more resistant to ATP inhibition compared with PFK-L and PFK-P (respectively, 23%, 31%, 50% decreases in specificity constants). GTP is an alternate phospho donor. Interface 2, which regulates the inactive dimer to active tetramer equilibrium, differs between isoforms, resulting in varying tetrameric stability. Under the conditions tested PFK-M is less sensitive to fructose 2,6-bisphosphate (F26BP) allosteric modulation than PFK-L or PFK-P (allosteric constants [K0.5ATP+F26BP/K0.5ATP] 1.10, 0.92, 0.54, respectively). Structural analysis of two allosteric sites reveals one may be specialised for AMP/ADP and the other for smaller/flexible regulators (citrate or phosphoenolpyruvate). Correlations between PFK-L and PFK-P transcript levels indicate that simultaneous expression may expand metabolic capacity for F16BP production whilst preserving regulatory capabilities. Analysis of cancer samples reveals intriguing parallels between PFK-P and PKM2 (pyruvate kinase M2), and simultaneous increases in PFK-P and PFKFB3 (responsible for F26BP production) transcript levels, suggesting prioritisation of metabolic flexibility in cancers. Our results describe the kinetic and transcript level differences between the three PFK isoforms, explaining how each isoform may be optimised for distinct roles.

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Tuning Down the Pain – An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200601155451 ◽

2020 ◽

Vol 20 (31) ◽

pp. 2852-2865 ◽

Cited By ~ 1

Author(s):

Damian Bartuzi ◽

Tomasz M. Wróbel ◽

Agnieszka A. Kaczor ◽

Dariusz Matosiuk

Keyword(s):

Side Effects ◽

Opioid Receptors ◽

Pain Perception ◽

Allosteric Modulation ◽

Allosteric Modulators ◽

Signaling Mechanisms ◽

Main Target ◽

Allosteric Sites ◽

Biased Signaling ◽

Opioid Signaling

Opioid signaling plays a central role in pain perception. As such, it remains the main target in the development of antinociceptive agents, despite serious side effects involved. In recent years, hopes for improved opioid painkillers are rising, together with our understanding of allosterism and biased signaling mechanisms. In this review, we focus on recently discovered allosteric modulators of opioid receptors, insights into phenomena underlying their action, as well as on how they extend our understanding of mechanisms of previously known compounds. A brief overlook of their synthesis is also presented.

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Toward an Automatic Quality Assessment of Voice-Based Telemedicine Consultations: A Deep Learning Approach

Sensors ◽

10.3390/s21093279 ◽

2021 ◽

Vol 21 (9) ◽

pp. 3279

Author(s):

Maria Habib ◽

Mohammad Faris ◽

Raneem Qaddoura ◽

Manal Alomari ◽

Alaa Alomari ◽

...

Keyword(s):

Neural Networks ◽

Deep Learning ◽

Quality Assessment ◽

Transcript Level ◽

Assessment Process ◽

Classification Model ◽

Systematic Evaluation ◽

Transcript Levels ◽

Perceptual Evaluation

Maintaining a high quality of conversation between doctors and patients is essential in telehealth services, where efficient and competent communication is important to promote patient health. Assessing the quality of medical conversations is often handled based on a human auditory-perceptual evaluation. Typically, trained experts are needed for such tasks, as they follow systematic evaluation criteria. However, the daily rapid increase of consultations makes the evaluation process inefficient and impractical. This paper investigates the automation of the quality assessment process of patient–doctor voice-based conversations in a telehealth service using a deep-learning-based classification model. For this, the data consist of audio recordings obtained from Altibbi. Altibbi is a digital health platform that provides telemedicine and telehealth services in the Middle East and North Africa (MENA). The objective is to assist Altibbi’s operations team in the evaluation of the provided consultations in an automated manner. The proposed model is developed using three sets of features: features extracted from the signal level, the transcript level, and the signal and transcript levels. At the signal level, various statistical and spectral information is calculated to characterize the spectral envelope of the speech recordings. At the transcript level, a pre-trained embedding model is utilized to encompass the semantic and contextual features of the textual information. Additionally, the hybrid of the signal and transcript levels is explored and analyzed. The designed classification model relies on stacked layers of deep neural networks and convolutional neural networks. Evaluation results show that the model achieved a higher level of precision when compared with the manual evaluation approach followed by Altibbi’s operations team.

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Regulation of Major Cellulosomal Endoglucanases of Clostridium thermocellum Differs from That of a Prominent Cellulosomal Xylanase

Journal of Bacteriology ◽

10.1128/jb.187.7.2261-2266.2005 ◽

2005 ◽

Vol 187 (7) ◽

pp. 2261-2266 ◽

Cited By ~ 37

Author(s):

Tali W. Dror ◽

Adi Rolider ◽

Edward A. Bayer ◽

Raphael Lamed ◽

Yuval Shoham

Keyword(s):

Growth Rate ◽

Clostridium Thermocellum ◽

Transcript Level ◽

Clear Correlation ◽

Transcript Levels ◽

Batch Cultures ◽

Processive Endoglucanase ◽

The Family ◽

Genes Encoding ◽

Family 10 Xylanase

ABSTRACT The expression of scaffoldin-anchoring genes and one of the major processive endoglucanases (CelS) from the cellulosome of Clostridium thermocellum has been shown to be dependent on the growth rate. For the present work, we studied the gene regulation of selected cellulosomal endoglucanases and a major xylanase in order to examine the previously observed substrate-linked alterations in cellulosome composition. For this purpose, the transcript levels of genes encoding endoglucanases CelB, CelG, and CelD and the family 10 xylanase XynC were determined in batch cultures, grown on either cellobiose or cellulose, and in carbon-limited continuous cultures at different dilution rates. Under all conditions tested, the transcript levels of celB and celG were at least 10-fold higher than that of celD. Like the major processive endoglucanase CelS, the transcript levels of these endoglucanase genes were also dependent on the growth rate. Thus, at a rate of 0.04 h−1, the levels of celB, celG, and celD were threefold higher than those obtained in cultures grown at maximal rates (0.35 h−1) on cellobiose. In contrast, no clear correlation was observed between the transcript level of xynC and the growth rate—the levels remained relatively high, fluctuating between 30 and 50 transcripts per cell. The results suggest that the regulation of C. thermocellum endoglucanases is similar to that of the processive endoglucanase celS but differs from that of a major cellulosomal xylanase in that expression of the latter enzyme is independent of the growth rate.

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Proteolytic and Structural Changes in Rye and Triticale Roots under Aluminum Stress

Cells ◽

10.3390/cells10113046 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3046

Author(s):

Joanna Szewińska ◽

Elżbieta Różańska ◽

Ewa Papierowska ◽

Mateusz Labudda

Keyword(s):

Heavy Metals ◽

Structural Changes ◽

Transcript Level ◽

Fine Tuning ◽

Gelatinolytic Activity ◽

Border Cells ◽

Aluminum Stress ◽

Transcript Levels ◽

Root Border Cells ◽

Level Analysis

Proteolysis and structural adjustments are significant for defense against heavy metals. The purpose of this study was to evaluate whether the Al3+ stress alters protease activity and the anatomy of cereale roots. Azocaseinolytic and gelatinolytic measurements, transcript-level analysis of phytocystatins, and observations under microscopes were performed on the roots of Al3+-tolerant rye and tolerant and sensitive triticales exposed to Al3+. In rye and triticales, the azocaseinolytic activity was higher in treated roots. The gelatinolytic activity in the roots of rye was enhanced between 12 and 24 h in treated roots, and decreased at 48 h. The gelatinolytic activity in treated roots of tolerant triticale was the highest at 24 h and the lowest at 12 h, whereas in treated roots of sensitive triticale it was lowest at 12 h but was enhanced at 24 and 48 h. These changes were accompanied by increased transcript levels of phytocystatins in rye and triticale-treated roots. Light microscope analysis of rye roots revealed disintegration of rhizodermis in treated roots at 48 h and indicated the involvement of root border cells in rye defense against Al3+. The ultrastructural analysis showed vacuoles containing electron-dense precipitates. We postulate that proteolytic-antiproteolytic balance and structural acclimation reinforce the fine-tuning to Al3+.

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Nitrogen Supply and Leaf Age Affect the Expression of TaGS1 or TaGS2 Driven by a Constitutive Promoter in Transgenic Tobacco

Genes ◽

10.3390/genes9080406 ◽

2018 ◽

Vol 9 (8) ◽

pp. 406 ◽

Cited By ~ 6

Author(s):

Yihao Wei ◽

Aibo Shi ◽

Xiting Jia ◽

Zhiyong Zhang ◽

Xinming Ma ◽

...

Keyword(s):

Amino Acid ◽

Nitrogen Metabolism ◽

Soluble Protein ◽

Leaf Age ◽

Sufficient Conditions ◽

Transcript Level ◽

Nitrogen Supply ◽

High Accumulation ◽

Transcript Levels ◽

Chlorophyll Contents

Glutamine synthetase (GS) plays a key role in nitrogen metabolism. Here, two types of tobacco transformants, overexpressing Triticum aestivum GS1 (TaGS1) or GS2 (TaGS2), were analysed. Four independent transformed lines, GS1-TR1, GS1-TR2, GS2-TR1 and GS2-TR2, were used for the nitrogen treatment. Under nitrogen-sufficient conditions, the leaves of GS2-TR showed high accumulation of the TaGS2 transcript, while those of GS1-TR showed a low TaGS1 transcript levels. However, compared with nitrogen-sufficient conditions, the TaGS1 transcript level increased in the leaves under nitrogen starvation, but the TaGS2 transcript level decreased. In addition, the TaGS1 and TaGS2 transcript levels were highest in the middle leaves under nitrogen-sufficient and starvation conditions. These results show that nitrogen supply and leaf age regulate TaGS expression, even when they are driven by a super-promoter. Additionally, in regard to nitrogen metabolism level, the lower leaves of the GS1-TR exhibited lower NH4+ and higher amino acid contents, while the upper leaves exhibited higher amino acid, soluble protein and chlorophyll contents. The leaves of the GS2-TR exhibited lower NH4+ but higher amino acid, soluble protein and chlorophyll contents. Given the role that GS isoforms play in nitrogen metabolism, these data suggest that TaGS1 overexpression may improve nitrogen transport, and that TaGS2 overexpression may improve nitrogen assimilation under nitrogen stress.

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Gene expression amplification by nuclear speckle association

The Journal of Cell Biology ◽

10.1083/jcb.201904046 ◽

2019 ◽

pp. jcb.201904046 ◽

Cited By ~ 7

Author(s):

Jiah Kim ◽

Neha Chivukula Venkata ◽

Gabriela Andrea Hernandez Gonzalez ◽

Nimish Khanna ◽

Andrew S. Belmont

Keyword(s):

Gene Expression ◽

Rna Polymerase Ii ◽

Liquid Droplet ◽

Transcript Level ◽

Rna Degradation ◽

Nuclear Speckles ◽

Nascent Transcript ◽

Nuclear Compartment ◽

Transcript Levels ◽

Endogenous Genes

Many active genes reproducibly position near nuclear speckles, but the functional significance of this positioning is unknown. Here we show that HSPA1B BAC transgenes and endogenous Hsp70 genes turn on 2–4 min after heat shock (HS), irrespective of their distance to speckles. However, both total HSPA1B mRNA counts and nascent transcript levels measured adjacent to the transgene are approximately twofold higher for speckle-associated alleles 15 min after HS. Nascent transcript level fold-increases for speckle-associated alleles are 12–56-fold and 3–7-fold higher 1–2 h after HS for HSPA1B transgenes and endogenous genes, respectively. Severalfold higher nascent transcript levels for several Hsp70 flanking genes also correlate with speckle association at 37°C. Live-cell imaging reveals that HSPA1B nascent transcript levels increase/decrease with speckle association/disassociation. Initial investigation reveals that increased nascent transcript levels accompanying speckle association correlate with reduced exosome RNA degradation and larger Ser2p CTD-modified RNA polymerase II foci. Our results demonstrate stochastic gene expression dependent on positioning relative to a liquid-droplet nuclear compartment through “gene expression amplification.”

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Acclimation of nitrifying biomass and its effect on 2-chlorophenol removal

Water Science & Technology ◽

10.2166/wst.2014.508 ◽

2014 ◽

Vol 71 (2) ◽

pp. 277-282 ◽

Cited By ~ 5

Author(s):

J. E. Pérez-Alfaro ◽

G. González-Blanco ◽

E. Sierra-Palacios ◽

J. Marcial-Quino ◽

R. Beristain-Cardoso

Keyword(s):

Gel Electrophoresis ◽

Denaturing Gradient Gel Electrophoresis ◽

The Other ◽

Kinetic Behavior ◽

Metabolic Capacity ◽

Batch Cultures ◽

Ammonium Removal ◽

Halogenated Compound ◽

Gradient Gel Electrophoresis ◽

Consumption Efficiency

The metabolic and kinetic behavior of a nitrifying sludge exposed to 2-chlorophenol (2-CP) was evaluated in batch cultures. Two kinds of nitrifying culture were used; one acclimated to 4-methylphenol (4-mp), and the other unacclimated to 4-mp. The unacclimated culture was affected adversely by the 2-CP's presence, since neither nitrification nor 2-CP oxidation was observed. Nonetheless, the acclimated culture showed metabolic capacity to nitrify and mineralize 2-CP. Ammonium removal was 100%, with a nitrifying yield of 0.92 ± 0.04 mg NO3−-N/mg NH4+-N consumed. The consumption efficiency for 2-CP was 100% and the halogenated compound was mineralized to CO2. Denaturing gradient gel electrophoresis (DGGE) patterns showed the shift in microbial community structure, indicating that microbial diversity was due to the acclimation process. This is the first evidence where nitrifying culture acclimated to 4-mp completely removed ammonium and 2-CP.

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The Predictive Value of Early Molecular Response in Chronic Phase CML Patients Treated with Dasatinib First Line Therapy

Blood ◽

10.1182/blood.v118.21.785.785 ◽

2011 ◽

Vol 118 (21) ◽

pp. 785-785 ◽

Cited By ~ 2

Author(s):

David Marin ◽

Corinne Hedgley ◽

Richard E Clark ◽

Jane F Apperley ◽

Letizia Foroni ◽

...

Keyword(s):

Peripheral Blood ◽

Predictive Value ◽

Conflicts Of Interest ◽

Chronic Phase ◽

Transcript Level ◽

Molecular Response ◽

Costal Margin ◽

Molecular Responses ◽

Transcript Levels ◽

International Scale

Abstract Abstract 785 We assessed the correlation between molecular response at 3 and 6 months of dasatinib 100mg daily treatment and subsequent cytogenetic and molecular responses in 150 newly-diagnosed chronic phase CML patients treated with front line dasatinib in the UK SPIRIT 2 study (imatinib vs dasatinib). The median age was 54 years (range 18.4–82.1); 90 patients were male. The Sokal risk distribution was: 39 low, 65 intermediate and 46 high. At diagnosis 26 patients had splenomegaly >10cm below the costal margin; median WBC and platelet count were 65.7 (2.2-428) and 404 (101-2,433). The median hemoglobin level was 11.0 g/dl (4.17-15.8). The median percentage of blasts and basophils in peripheral blood was 0.4% (0-13.5) and 3.6% (0-19.2) respectively. The dose of dasatinib was adjusted according to tolerance. BCR-ABL1 transcripts in the peripheral blood were analyzed at 12 week intervals using RQ-PCR. Results were expressed as percentage ratios relative to an ABL1 internal control and expressed on the international scale. Complete molecular response (CMR) was defined as two consecutive samples with no detectable transcripts (RQ-PCR negative) and ABL1 control >40,000 (the median ABL1 control in the CMR samples was 96,000). In addition, we also explored a less stringent definition of CMR, namely CMR4.5 which was recently defined by the EUTOS group as BCR-ABL1 ratio of 0.0032 on the international scale, consistent with a 4.5 log reduction in the transcript level, without necessarily being RQ-PCR negative. With a median follow up of 15 months (range 6–29) the 2 year cumulative incidences (CI) of CCyR, MMR, CMR4.5 and CMR were 84.5, 72.1, 24.1 and 5.6% respectively. The median BCR-ABL/ABL ratios at 3, 6, 12 and 24 months were 0.830%, 0.093%, 0.040% and 0.034% respectively. We investigated the predictive value of the BCR-ABL1 transcript levels at 3 (>10% vs ≤10% and >1% vs ≤1%) and 6 months (>1% vs ≤1%) of dasatinib therapy on the 2 years CI of cytogenetic and molecular responses. The 135 patients who at 3 months had a BCR-ABL1/ABL1 ratio ≤10% and the 81 patients who had a ratio ≤1% had a significantly better 2 year CI of CCyR (89.1% vs 50.2%, p=0.02 and 100% vs 84.7%, p=0.01), MMR (83.7% vs 14.2%, p=0.004 and 85.2% vs 54.3 p<0.001), CMR4.5 (25.0% vs 0%, p<0.18 and 37.6 v 3.3% p=0.001) but not CMR (6.7 vs 0%, p=0.51 and 7.1 vs 0% p=0.46). Similarly, the 109 patients who at 6 months had a transcript ratio ≤1% had a better 2 year CI of MMR (86.3 vs 13.9%, p<0.001), CMR4.5 (31.2 vs 0%, p=0.03) and CMR (14.3 vs 0%, p=0.04) than the remaining patients. We used a receiver operating characteristic (ROC) curve to identify the optimal cut-off in the transcript level at 3 and 6 months that would predict the probability of each outcome with maximal sensitivity and specificity. Table 1 shows the results of applying the optimal cutoffs for each outcome in the 3-month analysis. Then we investigated whether the various outcomes could be better predicted using the cut-offs defined at 3 or at 6 months (including both the 1 and 10% cut-offs and the newly identified cut-offs) by using a multivariate model. For each outcome the cut-off defined at 3 months shown in Table 1 was superior. No pre-therapy patient characteristics were an independent predictor for cytogenetic or molecular response.Table 1.CI of the various responses according to cut-offs identified in the ROC analysis.3 month BCR-ABL1/ABL1 ratio (%)n2 year CI (%)pCCyR10493.3p<0.001≤2.724675.9>2.72MMR7987.6p<0.001≤0.967152.7≥0.96CMR4.55649.7p<0.001≤0.378947.1>0.387CMR4220.1p=0.01≤0.241080>0.24 The key finding from this analysis is that patients who achieve a transcript level ≤10% after 3 months of dasatinib (135 of 150) have an 89.1% probability of eventually achieving CCyR, compared to 50.2% for patients with higher transcript levels (p=0.02). This preliminary observation may allow the identification of around 10% of dasatinib-treated patients for whom other forms of treatment might be considered although our conclusions require verification in further studies. The predictive power of RQ-PCR assessment can be greatly improved by identifying the optimal cut-offs for the specific outcomes, which is particularly important when predicting for the achievement of CMR. It remains uncertain whether these differences in response will translate into differences in survival and the SPIRIT 2 study continues to address this question. Disclosures: No relevant conflicts of interest to declare.

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Kinetics of Molecular Response with Different Tyrosine Kinase Inhibitors (TKI) Used As Frontline Therapy in Chronic Myeloid Leukemia-Chronic Phase (CML CP),

Blood ◽

10.1182/blood.v118.21.3784.3784 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3784-3784 ◽

Cited By ~ 1

Author(s):

Kiran Naqvi ◽

Hagop M Kantarjian ◽

Rajyalakshmi Luthra ◽

Elias Jabbour ◽

Susan O'Brien ◽

...

Keyword(s):

Research Funding ◽

Transcript Level ◽

Initial Therapy ◽

Molecular Response ◽

Term Outcome ◽

Long Term Outcome ◽

Molecular Responses ◽

Transcript Levels ◽

Frontline Therapy

Abstract Abstract 3784 Background: TKI are standard therapy for patients with CML CP. Imatinib was first established as frontline therapy and more recently dasatinib and nilotinib have shown improved rates and speed of response. Early molecular response has been associated with improved long-term outcome (Blood 2009; 113: 6315), thus the kinetics and rates of molecular response are important predictors of long-term outcome. Aim: To determine the kinetics and rates of molecular response with different TKIs used as initial therapy for patients with CML CP. Methods: We evaluated all pts treated with frontline TKIs (imatinib standard dose or high dose, dasatinib and nilotinib) in consecutive or parallel trials. Cytogenetic and molecular responses were assessed at least every 3 months for the first 12 months, then every 6 months, and were defined using the recommendations of European LeukemiaNet. Molecular responses were defined using international scale. Survival was calculated by the Kaplan-Meier method. Results: Of the 485 pts treated, 73 received imatinib 400mg; 208 imatinib 800mg; 99 dasatinib, and 105 nilotinib. Median age was 48 years (15–86) and median time from diagnosis to TKI therapy was 1 mo (1–13). The median follow-up for each group were 109 months (mo) with imatinib 400, 69 mo with imatinib 800, 30 with dasatinib and 25 mo with nilotinib. Nineteen pts with clonal evolution, but otherwise in CP, were included. Sokal risk score was high in 7%, intermediate in 24% and low in 69%. Cumulative rates of complete cytogenetic response (CCyR) were: imatinib 400mg 87%; imatinib 800mg 91%; dasatinib 96%; and nilotinib 94%. The rate of MMR with imatinib 400mg was 73%, with imatinib 800mg 87%, dasatinib 86%, and nilotinib 88%. Rates of CMR (BCR-ABL/ABL ≤0.0032% IS) were 51%, 71%, 61% and 62%. Median time to achieve MMR and CMR were: imatinib 400mg, 12 mo (3–60) and 18 mo (3–60); imatinib 800mg, 6 mo (3–60) and 9 mo (3–60); dasatinib, 6 mo (3–36) and 12 mo (3–54), and nilotinib 6 mo (3–48) and 6 mo (3–42). The median transcript levels at 3, 6, 12, 18, 24 and 36 mo by treatment arm are shown in table 1. The rates of MMR and CMR at 36 mo for imatinib 400mg were 58% and 34%. Corresponding rates for imatinib 800mg were 87% and 59%; for dasatinib 87% and 54%; and for nilotinib 90% and 63%. We then assessed the probability of achieving MMR and CMR at 12 mo according to the BCR-ABL/ABL levels at earlier timepoints. Two of 9 (22%) evaluable pts with transcript level >10 at 3 mo achieved a MMR at 12 mo but none achieved a CMR. In contrast, 31/52 (60%) evaluable pts with transcript level >1–10 at 3 mo, achieved a MMR at 12 mo and 4 (8%) achieved a CMR. Similarly, pts with level >0.1–1 at 3 mo, 72/129 (56%) evaluable pts achieved a MMR and 29 pts (22%) a CMR at 12 months. For each individual TKI, a similar trend was noted where a higher transcript level (>10; >1–10; >0.1–1) at 3 mo was associated with a decline in achieving a MMR and CMR at 12 mo (MMR- imatinib 400mg: 0%; 50%; 67%, imatinib 800mg: 0%; 62%; 80%, dasatinib: 33%; 67%; 71%, nilotinib: 100%; 50%, 88%, CMR-imatinib 400mg: 0%, imatinib 800mg: 0%; 8%; 10%, dasatinib:0%; 17%; 29%, nilotinib: 0%; 0%; 32%). The probability of transformation to AP/BP by transcript levels at 3 mo (>10; >1–10; >0.1–1, ≤0.1) was 0%, 3%, 2% and 1% for the overall population, with similar trends for the different therapies. Conclusion: New TKI provide a faster improvement in molecular response among pts with CML CP receiving TKI as initial therapy. Early responses are equally predictive of long-term outcome across all treatment options. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; ChemGenex: ChemGenex is now Cephalon, Inc., Consultancy, Research Funding; Deciphera: Research Funding.

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Role of DBP in the Circadian Oscillatory Mechanism

Molecular and Cellular Biology ◽

10.1128/mcb.20.13.4773-4781.2000 ◽

2000 ◽

Vol 20 (13) ◽

pp. 4773-4781 ◽

Cited By ~ 141

Author(s):

Shun Yamaguchi ◽

Shigeru Mitsui ◽

Lily Yan ◽

Kazuhiro Yagita ◽

Shigeru Miyake ◽

...

Keyword(s):

Transcription Factor ◽

Leucine Zipper ◽

The Other ◽

Suprachiasmatic Nuclei ◽

Transcription Factor Family ◽

Transcript Levels ◽

Oscillatory Mechanism ◽

Central Clock ◽

E Boxes

ABSTRACT Transcript levels of DBP, a member of the PAR leucine zipper transcription factor family, exhibit a robust rhythm in suprachiasmatic nuclei, the mammalian circadian center. Here we report that DBP is able to activate the promoter of a putative clock oscillating gene,mPer1, by directly binding to the mPer1promoter. The mPer1 promoter is cooperatively activated by DBP and CLOCK-BMAL1. On the other hand, dbp transcription is activated by CLOCK-BMAL1 through E-boxes and inhibited by the mPER and mCRY proteins, as is the case for mPer1. Thus, a clock-controlled dbp gene may play an important role in central clock oscillation.

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