10 research outputs found
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Get PDFThe neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. Through expanded architectural comparisons between these complexes and HIF-1α-ARNT, HIF-2α-ARNT and CLOCK-BMAL1, we show the wider mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs.sponsorship: [
"National Institutes of Health NIGMS 1R01GM117013 Fraydoon Rastinejad",
"Army Research Office W81XWH-16-1-0322 Fraydoon Rastinejad"
] (National Institutes of Health|NIGMS 1R01GM117013, Army Research Office|W81XWH-16-1-0322)status: Publishe
A comparative evaluation of the efficacy of probiotic and chlorhexidine mouthrinses on clinical inflammatory parameters of gingivitis: A randomized controlled clinical study
No full textBackground: The aim of our clinical trial was to assess and compare the antiplaque and anti-inflammatory potential of a probiotic mouthwash with 0.2% chlorhexidine and saline. Materials and Methods: A randomized parallel group study was designed for a period of 4 weeks on 45 systemically healthy subjects between 20 and 30 years having chronic gingivitis. The study population was divided into three groups. Group A - 15 subjects were advised experimental (probiotic) mouthwash. Group B - 15 subjects were advised positive control (chlorhexidine) mouthwash and Group C - 15 subjects into a negative control group (normal saline). Oral prophylaxis was done for all groups at baseline. After the proper oral hygiene instructions, all the three groups were instructed to rinse their mouth with 10 ml of their respective mouthrinse, undiluted for 1 min twice daily, 30 min after brushing. Clinical parameters such as plaque index (PI), gingival index (GI), and oral hygiene index simplified (OHI-S) were assessed at baseline, 2 weeks and 4 weeks, respectively. Results: At day 28, the PI, GI, and OHI-S were significantly reduced by all treatment modalities ranking probiotic and chlorhexidine is greater than saline. Conclusion: The probiotic mouthrinses tested was effectively used as an adjunct to mechanical plaque control in the prevention of plaque and gingivitis. Thus, the probiotic mouthrinse has a great therapeutic potential
Tailored fibre placement of commingled carbon-thermoplastic fibres for notch-insensitive composites
No full textTailored fibre placement (TFP) is an embroidery-based technology that allows the fibre tows to be placed exactly where they are most needed for structural performance and stitched into position on a compatible textile or polymer substrate. In this study commingled carbon-nylon fibre tows were utilised to produce thermoplastic cross-ply net-shaped preforms using TFP. Four TFP composite plaques were manufactured; baseline (blank), machined-hole, tailored-hole-1 and tailored-hole-2. Steering the tows was used to create the hole in tailored-hole-1 and tailored-hole-2. In comparison to the design of tailored-hole-1, a different fibre trajectory, with a circular reinforcement around the hole, was suggested for the tailored-hole-2. Fibre volume fraction, optical microscopy, X-ray-CT scans, tensile and open-hole tests were carried out. With the exception of the baseline sample, the modified design of tailored-hole-2 composite exhibited the highest axial strength and modulus compared to the machined-hole and tailored-hole-1 composites. Only the tailored-hole-2 specimens exhibited less than 10 % reduction of the notched strength compared to the un-notched strength. This study highlights the importance of the stress/load-paths and associated fibre-orientations. While TFP can be an extremely valuable design tool for composite preforms and resulting structural components, a deep understanding of stress distributions is inevitable to achieve optimal TFP-design
H-Index Predicts Academic Rank Among Orthopaedic Surgery Faculty
No full textBackground:. Research productivity, education, and clinical performance have become increasingly central to faculty promotion decisions in orthopaedic surgery. The Hirsch index (h-index) has emerged as an objective tool for quantifying academic impact, but its relationship with academic rank in orthopaedic surgery remains incompletely understood.
Methods:. We analyzed faculty data from the top 50 academic orthopaedic surgery programs ranked by Doximity. We identified faculty members from institutional websites and collected academic metrics from Scopus, including h-index, publication counts, first-author publications, last-author publications, career length, and m-index (h-index divided by the career length). We used a multivariate analysis and recursive partitioning to identify predictors of senior academic rank (associate or full professor).
Results:. Of 2,744 faculty reviewed, 1,520 academic orthopaedic surgeons met the inclusion criteria. The median h-index was 15 (interquartile range [IQR]: 7-27), and the median career length was 19 years (IQR: 13-28). In multivariate analysis, h-index and career duration emerged as the strongest predictors of senior academic rank. Multivariate recursive partitioning identified the h-index, number of publications, first-author publications, and career length as influential predictors. Faculty at institutions ranked 1 to 25 demonstrated significantly higher academic productivity across all metrics than those ranked 26 to 50 (p < 0.001). The trajectory of research productivity shows a consistent increase with career duration, with the m-index plateauing mid-career.
Conclusions:. Our findings indicate that the h-index and career length are significant predictors of senior academic rank. Academic productivity was higher at programs ranked 1 to 25 by Doximity compared with those ranked 26 to 50. While productivity metrics generally increase with career duration, the m-index plateaus in mid-career.
Level of Evidence:. Level III, Prognostic Study. See Instructions for Authors for a complete description of levels of evidence
Effect of Amnioguard and Biomesh GTR Membranes with Novabone Putty in the Treatment of Periodontal Osseous Defects—A Communication
No full text(1) Background: Guided tissue regeneration was an effective surgical procedure in the management of intrabony defects and has undergone a number of changes in terms of materials and techniques. The aim of this study is to compare AmnioGuard and BioMesh in combination with NovaBone putty in intrabony defects. (2) Methodology: Ten patients who needed regenerative periodontal therapy were randomly allocated into two groups based on the inclusion criteria. These patients were subjected to phase I therapy followed by which Group A patients were treated with AmnioGuard + NovaBone putty whereas Group B with BioMesh + NovaBone putty. The clinical indices were obtained at baseline, 3 months and 6 months post-operatively while radiographic parameters were obtained at 6 months post-op. (3) Results & Conclusion: At six months after surgery, Group B (33% bone gain) showed a statistically significant change from Group A (16% bone gain) in both the clinical and radiographic measures (p < 0.05)
Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1
Get PDF\ua9 2024 The Author(s). AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier
Subtype-specific regulatory network rewiring in acute myeloid leukemia
Get PDF\ua9 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype–specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance
The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation
Get PDF\ua9 2018 The Author(s) Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML. Using in vitro and in vivo screens to identify essential RUNX1/ETO transcriptional targets in AML, Martinez-Soria identify CCND2 as required for leukemia maintenance and self-renewal. Targeting this dependency using the CDK4/6 inhibitor palbociclib prolongs the survival of AML PDX models
Venetoclax combinations delay the time to deterioration of HRQoL in unfit patients with acute myeloid leukemia
No full textPhase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups were analyzed using Kaplan-Meier and unadjusted log-rank analyses. VEN + AZA vs PBO + AZA patients had longer TTD in GHS/QoL (P = 0.066) and fatigue (P = 0.189), and significantly longer TTD in PF (P = 0.028) and HS-VAS (P < 0.001). VEN + LDAC vs PBO + LDAC patients had significantly longer TTD in GHS/QoL (P = 0.011), PF (P = 0.020), and fatigue (P = 0.004), and a trend in HS-VAS (P = 0.057). Approximately 43%, 35%, 32%, and 18% of patients treated with VEN + AZA, AZA + PBO, VEN + LDAC, or LDAC + PBO, respectively, saw improvements >MCT in GHS/QoL. Overall, VEN may positively impact HRQoL in patients with AML ineligible for intensive chemotherapy, leading to longer preservation of functioning and overall health status. © 2022, The Author(s)
The molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influence
No full textIncludes bibliographical references.The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance that may include by genetic heterogeneity, genetic epistasis, gene-environment interactions, incomplete penetrance and variable expressivity. In this thesis three strategies were employed to ameliorate these confounding factors. The first strategy was to focus on a theoretically genetically-homogeneous population with BPD. A unique South African sample including 190 individuals of the relativity reproductively-isolated Afrikaner population yielded promising evidence of linkage to chromosome 1 q31-32 and weaker peaks at lOq23 and 13q32, regions previously implicated in the disorder. A family-based analysis suggested that the 3' variable number tandem repeat (VNTR) variant of the dopamine transporter gene (DAT) is associated with bipolar-spectrum illness in the 132-strong sample of British ancestry. The second strategy was to carry out genetic linkage and association analyses using quantitative traits (elldophenotypes) that were closely associated with BPD. As part of this process a variety of personality traits were evaluated in the cohort, and anxiety related, novelty-seeking, hyperthymic, and cyclothymic personality traits were found to aggregate in participants with BPD and to a lesser extent repeated unipolar illness (MDE-R). These traits were therefore used as quantitative markers or endophenotypes of BPD. The quantitative linkage analysis indicated that a variant in the region of 13q32 may influence the development of novelty-seeking-related traits in the largest Afrikaner pedigree, while the personality trait, ""Stability"", was weakly linked to 4p16 in the total sample. The catechol-o-methytransferase (COM1) Va1l58Mct and the Brain Derived Neurotrophic Factor (BDNF) Va1l66Met polymorphisms were associated with mood-labile-cyclothymic and hyperthymic·-novelty-seeking traits, respectively. the DA T VNTR and the Notch4 exonic repeat variants were associated with a broad range of ""pathological"" personality traits in the sa11lples of British and Afrikaner origin, respectively. The sample was also evaluated with a battery of neuropsychological tasks and the BPD 1 and MDE-R groups displayed both verbal and visual memory recall deficits while the BPD 1 sample also suffered from recognition memory deficits. The neurocognitive trait, ""Memory"" was therefore used as a second endophenotype generating potential linkage signals on IOq23 and 22q 11. The exonic 48bp VNTR polymorphism in the dopamine 4 receptor (DRD4) gene was associated with '""Memory"" performance. As a third strategy, a potentially important aetiological factor, childhood trauma, was measured, and used to test for gene-environment interactions between the various candidate genes and bipolar-illness or BPD-related endophenotypes in the cohort. BPD and M DE-R individuals displayed significantly higher levels of emotional and physical abuse, and the former variable was also associated with the development of anxiety-related and unstable personality traits. A functional variant of the COM1 gene was found to interact with abuse to predispose to anxiety-related, unstable cyclothymic and novelty-seeking related personality traits. The combination of childhood abuse and possession of low-activity MAO-A gene variants was also associated the development of more anxious and unstable personality traits. All interaction between sexual abuse and the B])NF gene modulated performance on verbal and visual memory tasks. A similar interaction between the ApoE gene and sexual abuse was observed. Although a number of theoretical obstacles remain to be resolved, the analyses of isolated populations coupled with the use of endophenotypes and the testing or gene environment interactions, holds out great promise for the eventual elucidation of the genetic basis of hi polar affective disorder
