Flavopiridol Inhibits TGF-ß-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2.

Transforming growth factor-ß (TGF-ß) is a pleiotropic growth factor implicated in the development of atherosclerosis for its role in mediating glycosaminoglycan (GAG) chain hyperelongation on the proteoglycan biglycan, a phenomenon that increases the binding of atherogenic lipoproteins in the vessel wall. Phosphorylation of the transcription factor Smad has emerged as a critical step in the signaling pathways that control the synthesis of biglycan, both the core protein and the GAG chains. We have used flavopiridol, a well-known cyclin-dependent kinase inhibitor, to study the role of linker region phosphorylation in the TGF-ß-stimulated synthesis of biglycan. We used radiosulfate incorporation and SDS-PAGE to assess proteoglycan synthesis, real-time polymerase chain reaction to assess gene expression, and chromatin immunoprecipitation to assess the binding of Smads to the promoter region of GAG Synthesizing genes. Flavopiridol blocked TGF-ß-stimulated synthesis of mRNA for the GAG synthesizing enzymes, and chondroitin 4-sulfotransferase (C4ST-1), chondroitin sulfate synthase-1 (ChSy-1) and TGF-ß-mediated proteoglycans synthesis as well as GAG hyperelongation. Flavopiridol blocked TGF-ß-stimulated Smad2 phosphorylation at both the serine triplet and the isolated threonine residue in the linker region. The binding of Smad to the promoter region of the C4ST-1 and ChSy-1 genes was stimulated by TGF-ß, and this response was blocked by flavopiridol, demonstrating that linker region phosphorylated Smad can pass to the nucleus and positively regulate transcription. These results demonstrate the validity of the kinases, which phosphorylate the Smad linker region as potential therapeutic target(s) for the development of an agent to prevent atherosclerosis.

Identification of α-tocopherol as a bioactive component of Dicranopteris linearis with disrupting property against preformed biofilm of Staphylococcus aureus.

AIMS: The potential of Dicranopteris linearis leaves' extract and its bioactive components were investigated for the first time for its disrupting ability against Staphylococcus aureus biofilms. METHODS AND RESULTS: The leaves of D. linearis were subjected to sonication-assisted extraction using hexane (HEX), dichloromethane, ethyl acetate and methanol (MeOH). It was found that only the MeOH fraction exhibited antimicrobial activity using broth microdilution assay; while all four fractions do not exhibit biofilm inhibition activity against S. aureusATCC 6538P, S. aureusATCC 43300, S. aureusATCC 33591 and S. aureusATCC 29213 using crystal violet assay. Among the four fractions tested, only the HEX fraction showed biofilm disrupting ability, with 60-90% disruption activity at 5 mg ml-1 against all four S. aureus strains tested. Bioassay-guided purification of the active fraction has led to the isolation of α-tocopherol. α-Tocopherol does not affect the cells within the biofilms but instead affects the biofilm matrix in order to disrupt S. aureus biofilms. CONCLUSIONS: α-Tocopherol was identified to be the bioactive component of D. linearis with disruption activity against S. aureus biofilm matrix. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of α-tocopherol as a biofilm disruptive agent might potentially be useful to treat biofilm-associated infections in the future.

Investigation on the antimicrobial activities of gingers (Etlingera coccinea (Blume) S.Sakai & Nagam and Etlingera sessilanthera R.M.Sm.) endemic to Borneo.

AIMS: To investigate the antimicrobial properties of Etlingera coccinea and Etlingera sessilanthera and to isolate and identify the antimicrobial compounds. METHODS AND RESULTS: Extracts were obtained via sequential solvent extraction method using hexane, dichloromethane, ethyl acetate, methanol and water. Antimicrobial activity testing was done using broth microdilution assay against 17 strains of bacteria. The leaf hexane extract of E. coccinea and rhizome hexane extract of E. sessilanthera showed best antimicrobial activities, with minimum inhibitory concentration (MIC) values ranging from 0·016 to 1 mg ml-1 against Gram-positive bacteria. From these active extracts, two antimicrobials were isolated and identified as trans-2-dodecenal and 8(17),12-labdadiene-15,16-dial with MIC values ranging from 4 to 8 µg ml-1 against Bacillus cereus, Bacillus subtilis and Staphylococcus aureus. CONCLUSION: Etlingera coccinea and E. sessilanthera demonstrated good antimicrobial activities against clinically relevant bacteria strains. The antimicrobial compounds isolated showed low MIC values, hence suggesting their potential use as antimicrobial agents. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first to identify the potent antimicrobials from these gingers. The antimicrobials isolated could potentially be developed further for use in treatment of bacterial infections. Also, this study warrants further research into other Etlingera species in search for more antimicrobial compounds.

Generation mean analysis of grain quality traits in selected rice populations derived from different amylose characteristics.

BACKGROUND: Genetic analysis using generation mean analysis is a tool for designing the most appropriate breeding approaches to developing varieties of rice. It estimates the gene actions that control quantitative traits, as well as the additive, dominance and epistatic effects. This study was conducted using three rice populations that were derived from parental lines with different amylose content. The aim was to partition the gene actions using generation mean analysis for the selected populations. RESULTS: A scaling test was carried out to evaluate the fulfilment of the additive-dominance model. Non-allelic interaction was observed for milled grain length, length-to-width ratio and milled rice recovery of all populations evaluated. An additive-dominance model was not adequate for amylose, gel consistency, grain length, grain width, milled grain width and head rice recovery, thus epistasis was involved in the populations evaluated. The importance of additive gene action was observed for grain length, milled grain length and milled rice recovery for populations of high- and low-amylose parents. However, populations with intermediate- and high-amylose parents and intermediate- and low-amylose parents shared almost similar dominance gene actions for most of the physical grain quality traits. CONCLUSION: These results suggested that delayed selection is the best approach for traits governed by dominance and epistasis effects. Meanwhile, the traits that were governed by additive effects should undergo thorough selection at an early stage.

Peptidyl-prolyl isomerases: functionality and potential therapeutic targets in cardiovascular disease.

Peptidyl-prolyl cis/trans isomerases (PPIases) are a conserved group of enzymes that catalyse the conversion between cis and trans conformations of proline imidic peptide bonds. These enzymes play critical roles in regulatory mechanisms of cellular function and pathophysiology of disease. There are three different classes of PPIases and increasing interest in the development of specific PPIase inhibitors. Cyclosporine A, FK506, rapamycin and juglone are known PPIase inhibitors. Herein, we review recent advances in elucidating the role and regulation of the PPIase family in vascular disease. We focus on peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1), an important member of the PPIase family that plays a role in cell cycle progression, gene expression, cell signalling and cell proliferation. In addition, Pin1 may be involved in atherosclerosis. The unique role of Pin1 as a molecular switch that impacts on multiple downstream pathways necessitates the evaluation of a highly specific Pin1 inhibitor to aid in potential therapeutic drug discovery.

Respiratory infection risk in athletes: association with antigen-stimulated IL-10 production and salivary IgA secretion.

The purpose of this study was to examine factors influencing susceptibility to upper respiratory tract infections (URTI) in 18-35-year-old men and women engaged in endurance-based physical activity during the winter months. Eighty individuals (46 males, 34 females) provided resting blood and saliva samples for determination of markers of systemic immunity. Weekly training and illness logs were kept for the following 4 months. Thirty subjects did not experience an URTI episode and 24 subjects experienced 3 or more weeks of URTI symptoms. These illness-prone subjects had higher training loads and had ∼2.5-fold higher interleukin (IL)-4 and IL-10 production by antigen-stimulated whole blood culture than the illness-free subjects. Illness-prone subjects also had significantly lower saliva S-IgA secretion rate and higher plasma IgM (but not IgA or IgG) concentration than the illness-free subjects. There were no differences in circulating numbers of leukocyte subtypes or lymphocyte subsets between the illness-prone and illness-free subjects. The production of IL-10 was positively correlated and the S-IgA secretion rate was negatively correlated with the number of weeks with infection symptoms. It is concluded that high IL-10 production in response to antigen challenge and low S-IgA secretion are risk factors for development of URTI in physically active individuals.

A rare association of Down syndrome with Dandy -Walker variant, pulmonary hypertension and childhood interstitial lung disease: A case report of a prognostic dilemma.

Associations among Down syndrome (DS), Dandy-Walker variant (DWv), pulmonary hypertension (PH) and childhood interstitial lung disease (chILD) are extremely rare. Several cases of trisomy disorders with Dandy-Walker malformation (DWM) and neurodevelopmental outcomes have been reported. The extent to which moderate to severe pulmonary hypertension with complications of patent ductus arteriosus (PDA), PH and chILD leads to substantial morbidity and mortality in infants with DS and DWM should be studied. We report the case of an ex-premature 15-month-old girl with confirmed DS with DWv, who developed PH and chILD. This is the first case study reporting the complexity of multiple associations involving DS and DWv. This case led to a prognostic dilemma and required compassionate parental counselling because of the child's uncertain future.

Prediction of clinical outcomes in women with placenta accreta spectrum using machine learning models: an international multicenter study.

INTRODUCTION: Placenta accreta spectrum is a major obstetric disorder that is associated with significant morbidity and mortality. The objective of this study is to establish a prediction model of clinical outcomes in these women. MATERIALS AND METHODS: PAS-ID is an international multicenter study that comprises 11 centers from 9 countries. Women who were diagnosed with PAS and were managed in the recruiting centers between 1 January 2010 and 31 December 2019 were included. Data were reanalyzed using machine learning (ML) models, and 2 models were created to predict outcomes using antepartum and perioperative features. ML model was conducted using python® programing language. The primary outcome was massive PAS-associated perioperative blood loss (intraoperative blood loss ≥2500 ml, triggering massive transfusion protocol, or complicated by disseminated intravascular coagulopathy). Other outcomes include prolonged hospitalization >7 days and admission to the intensive care unit (ICU). RESULTS: 727 women with PAS were included. The area under curve (AUC) for ML antepartum prediction model was 0.84, 0.81, and 0.82 for massive blood loss, prolonged hospitalization, and admission to ICU, respectively. Significant contributors to this model were parity, placental site, method of diagnosis, and antepartum hemoglobin. Combining baseline and perioperative variables, the ML model performed at 0.86, 0.90, and 0.86 for study outcomes, respectively. Ethnicity, pelvic invasion, and uterine incision were the most predictive factors in this model. DISCUSSION: ML models can be used to calculate the individualized risk of morbidity in women with PAS. Model-based risk assessment facilitates a priori delineation of management.

Chronic allergic fungal sinusitis invading the skull base in an immunocompetent male: illustrative case.

BACKGROUND: Allergic fungal sinusitis (AFS) is an immunoglobulin E-mediated reaction to fungal organisms in the sinonasal region and can be categorized as acute or chronic. Acute infection is typical in immunocompromised patients, while chronic infection is classically seen in immunocompetent patients. Spread of infection to the skull base is a rare and potentially lethal complication of prolonged infection. Surgical management is frequently augmented with steroid therapy to prevent recurrence. OBSERVATIONS: The authors present a case of a 20-year-old African American male with prolonged headaches and blurred vision who was diagnosed with chronic invasive fungal sinusitis resulting in invasion of fungal burden into the anterior skull base and the posterior aspect of the clivus, in addition to complete obliteration of the maxillary sinus. The patient was managed surgically without complication and with gradual improvement in vision. LESSONS: Early management and detection of AFS should be a focus to prevent erosion of the fungal burden into the skull base. Neurosurgery and ear, nose, and throat surgery have a multidisciplinary role in the management of advanced AFS cases.

Successful treatment of IgG4-related hypertrophic pachymeningitis with induction rituximab and dexamethasone followed by maintenance rituximab.

IgG4-related disease (IgG4RD) with intracranial involvement is rare. We report a 56-year-old male who had an excellent response to rituximab and dexamethasone after going undiagnosed for 5 years. After 3 years of rituximab maintenance, he has no evidence of disease on brain MRI.

Biosynthesis of Silver Nanoparticles from Citrobacter freundii as Antibiofilm Agents with their Cytotoxic Effects on Human Cells.

BACKGROUND: Nanomaterials have recently been identified for their potential benefits in the areas of medicine and pharmaceuticals. Among these nanomaterials, silver nanoparticles (Ag-NPs) have been widely utilized in the fields of diagnostics, antimicrobials, and catalysis. OBJECTIVE: To investigate the potential utility of Citrobacter freundii in the synthesis of silver Nanoparticles (Ag-NPs), and to determine the antimicrobial activities of the Ag-NPs produced. METHODS: Aqueous Ag+ ions were reduced when exposed to C. freundii extract and sunlight, leading to the formation of Ag-NPs. Qualitative microanalysis for the synthesized Ag-NPs was done using UVvis spectrometry, Energy Dispersive X-ray analysis (EDX), and scanning and transmission electron microscopy. The hydrodynamic size and stability of the particles were detected using Dynamic Light Scattering (DLS) analysis. The Ag-NPs' anti-planktonic and anti-biofilm activities against Staphylococcus aureus and Pseudomonas aeruginosa, which are two important skin and wound pathogens, were investigated. The cytotoxicity on human dermal fibroblast cell line was also determined. RESULTS: Ag-NPs were spherical with a size range between 15 to 30 nm. Furthermore, Ag-NPs displayed potent bactericidal activities against both S. aureus and P. aeruginosa and showed noticeable anti-biofilm activity against S. aureus biofilms. Ag-NPs induced minor cytotoxic effects on human cells as indicated by a reduction in cell viability, a disruption of plasma membrane integrity, and apoptosis induction. CONCLUSION: Ag-NPs generated in this study might be a future potential alternative to be used as antimicrobial agents in pharmaceutical applications for wound and skin related infections.

Prediction of success of uterus-preserving management in women with placenta accreta spectrum (CON-PAS score): A multicenter international study.

OBJECTIVE: To create a model for prediction of success of uterine-preserving procedures in women with placenta accreta spectrum (PAS). METHODS: PAS-ID is a multicenter study that included 11 centers from 9 countries. Women with PAS, who were managed between January 1, 2010 and December 31, 2019, were retrospectively included. Data were split into model development and validation cohorts, and a prediction model was created using logistic regression. Main outcome was success of uterine preservation. RESULTS: Out of 797 women with PAS, 587 were eligible. Uterus-preserving procedures were successful in 469 patients (79.9%). Number of previous cesarean sections (CS) was inversely associated with management success (adjusted odds ratio [aOR] 0.02, 95% confidence interval [CI] 0.001-3.63 with five previous CS). Other variables were complete placental invasion (aOR 0.14, 95% CI 0.05-0.43), type of CS incision (aOR 0.04, 95% CI 0.01-0.25 for classical incision), compression sutures (aOR 2.48, 95% CI 1.00-6.16), accreta type (aOR 3.76, 95% CI 1.13-12.53), incising away from placenta (aOR 5.09, 95% CI 1.52-16.97), and uterine resection (aOR 102.57, 95% CI 3.97-2652.74). CONCLUSION: The present study provides a prediction model for success of uterine preservation, which may assist preoperative and intraoperative decisions, and promote incorporation of uterine preservation procedures in comprehensive PAS protocols.

Effects of Spirogyra jaoensis as a dietary supplement on growth, pectoralis muscle performance, and small intestine morphology of broiler chickens.

AIM: This study aimed to examine the effect of dietary Spirogyra jaoensis in starter feed on growth performance, pectoralis muscle (PM) growth, and small intestine morphology of broiler chickens. MATERIALS AND METHODS: One hundred twenty one-day-old Cobb-500 broilers (body weight 46±2.6 g) were divided into four equal groups with 3 replicates in each group and given basal feed supplemented with dried S. jaoensis at doses of 0%, 0.5%, 1%, or 2%. The treatment was carried out until the chickens were 18 days old to examine growth of broiler chicks at starter period (8-21 days old). RESULTS: Supplementation with S. jaoensis at doses of 0.5% and 1% resulted in increased weight and improved feed conversion ratio compared to the control group. At the end of treatment, chickens fed with 0.5% and 1% S. jaoensis weighed 428.3±47.8 g and 426.9±31.8 g, respectively, and were significantly heavier than the control group (373.1±44.1 g). Furthermore, parameters related to PM growth and small intestine morphology of chickens supplemented with 0.5% S. jaoensis in basal feed were improved compared to the control group. CONCLUSION: The results of this research indicate that S. jaoensis at a dose of 0.5% improves growth performance, PM growth, and small intestine morphology in broiler chickens.

Invasive and antiplatelet treatment of patients with non-ST-segment elevation myocardial infarction: Understanding and addressing the global risk-treatment paradox.

Clinical guidelines for the treatment of patients with non-ST-segment elevation myocardial infarction (NSTEMI) recommend an invasive strategy with cardiac catheterization, revascularization when clinically appropriate, and initiation of dual antiplatelet therapy regardless of whether the patient receives revascularization. However, although patients with NSTEMI have a higher long-term mortality risk than patients with ST-segment elevation myocardial infarction (STEMI), they are often treated less aggressively; with those who have the highest ischemic risk often receiving the least aggressive treatment (the "treatment-risk paradox"). Here, using evidence gathered from across the world, we examine some reasons behind the suboptimal treatment of patients with NSTEMI, and recommend approaches to address this issue in order to improve the standard of healthcare for this group of patients. The challenges for the treatment of patients with NSTEMI can be categorized into four "P" factors that contribute to poor clinical outcomes: patient characteristics being heterogeneous; physicians underestimating the high ischemic risk compared with bleeding risk; procedure availability; and policy within the healthcare system. To address these challenges, potential approaches include: developing guidelines and protocols that incorporate rigorous definitions of NSTEMI; risk assessment and integrated quality assessment measures; providing education to physicians on the management of long-term cardiovascular risk in patients with NSTEMI; and making stents and antiplatelet therapies more accessible to patients.

The safety and efficacy of switching stavudine to tenofovir df in combination with lamivudine and efavirenz in hiv-1-infected patients: three-year follow-up after switching therapy.

BACKGROUND: Study 903 is a phase 3 trial with a completed 144-week, double-blind phase comparing tenofovir DF (TDF) with stavudine (d4T), in combination with lamivudine (3TC) and efavirenz (EFV), and an ongoing 336-week open-label extension phase. METHOD: Patients in 3 countries completing the d4T treatment phase were allowed to switch d4T to TDF and receive once-daily TDF+3TC+EFV in the extension phase. RESULTS: At the time of switch, 100% and 99% of patients (n = 85; 60% male, 64% White; mean age 37 years; mean CD4 = 650 cells/mm3) had HIV RNA <400 and <50 copies/mL. At 144 weeks after the switch, 89% (missing = failure) had HIV RNA <400 copies/mL and 87% had HIV RNA <50 copies/mL. Mean CD4 cell count increased 155 cells/mm3. No patient had virologic failure. Significant decreases from switch to week 144 in mean fasting total cholesterol (-22 mg/dL, p < .0001) and triglycerides (-78 mg/dL, p < .0001) were observed. Mean limb fat increased significantly from 4.5 kg to 5.8 kg, 144 weeks after switch (p < .0001). CONCLUSION: In virologically suppressed patients, switching d4T to TDF as part of a once-daily regimen with 3TC and EFV resulted in maintenance of virologic suppression and continued CD4 cell increases through 144 weeks, with significant improvements in metabolic parameters.

The safety and efficacy of tenofovir DF in combination with lamivudine and efavirenz through 6 years in antiretroviral-naïve HIV-1-infected patients.

BACKGROUND: Study 903 is a phase 3 trial with a completed 144-week, double-blind phase comparing tenofovir DF (TDF) to stavudine (d4T) in combination with lamivudine (3TC) and efavirenz (EFV) and an ongoing additional 336-week open-label extension phase. METHOD: Patients in Brazil, Argentina, and the Dominican Republic who completed the 144-week double-blind phase on TDF were eligible to roll over to the extension phase (weeks 144-480). Results from an interim week 288 analysis are presented. RESULTS: Eighty-six patients (62% male, 70% white) initially randomized to the TDF arm continued treatment with TDF. At the end of the 144-week, double-blind phase, 85 of the 86 had HIV-1 RNA <400 copies/mL, of whom 84% maintained virologic suppression through week 288. CD4 counts continued to improve with a mean increase of 135 cells/mm(3) from entry into the open-label extension to week 288. No patient discontinued due to renal adverse events. Small changes in bone mineral density at the lumbar spine and hip were seen in the first 48 weeks but were nonprogressive through 288 weeks. Mean limb fat increased from 8.0 kg at week 96 to 8.8 kg at week 288. CONCLUSION: Through 288 weeks, once-daily TDF+3TC+EFV demonstrated sustained antiretroviral activity with continued immunologic recovery. TDF treatment was not associated with renal adverse events or limb fat loss in antiretroviral-naïve patients.

Pharmacometabonomics Technique to Identify Warfarin Response Using Nuclear Magnetic Resonance Spectroscopy.

BACKGROUND: Warfarin, an anticoagulant medication, is prescribed regularly despite of its bleeding tendency for the prevention and/or treatment of various thromboembolic conditions, such as deep vein thrombosis, and complications associated with atrial fibrillation, and myocardial infarction, but because of its narrow therapeutic window, it has a lot of interactions with drugs and diet. METHODS: Warfarin relies on regular monitoring of International Normalized Ratio which is a standardized test to measure prothrombin time and appropriate dose adjustment. Pharmacometabonomics is a novel scientific field which deals with identification and quantification of the metabolites present in the metabolome using spectroscopic techniques such as Nuclear Magnetic Resonance (NMR). Pharmacometabonomics helps to indicate perturbation in the levels of metabolites in the cells and tissues due to drug or ingestion of any substance. NMR is one of the most widely-used spectroscopic techniques in metabolomics because of its reproducibility and speed. RESULTS: There are many factors that influence the metabolism of warfarin, making changes in drug dosage common, and clinical factors like drug-drug interactions, dietary interactions and age explain for the most part the variability in warfarin dosing. Some studies have showed that pharmacogenetic testing for warfarin dosing does not improve health outcomes, and around 26% of the variation in warfarin dose requirements remains unexplained yet. CONCLUSION: Many recent pharmacometabonomics studies have been conducted to identify novel biomarkers of drug therapies such as paracetamol, aspirin and simvastatin. Thus, a technique such as NMR based pharmacometabonomics to find novel biomarkers in plasma and urine might be useful to predict warfarin outcome.

The role of specific Smad linker region phosphorylation in TGF-ß mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle.

Hyperelongation of glycosaminoglycan chains on proteoglycans facilitates increased lipoprotein binding in the blood vessel wall and the development of atherosclerosis. Increased mRNA expression of glycosaminoglycan chain synthesizing enzymes in vivo is associated with the development of atherosclerosis. In human vascular smooth muscle, transforming growth factor-ß (TGF-ß) regulates glycosaminoglycan chain hyperelongation via ERK and p38 as well as Smad2 linker region (Smad2L) phosphorylation. In this study, we identified the involvement of TGF-ß receptor, intracellular serine/threonine kinases and specific residues on transcription factor Smad2L that regulate glycosaminoglycan synthesizing enzymes. Of six glycosaminoglycan synthesizing enzymes, xylosyltransferase-1, chondroitin sulfate synthase-1, and chondroitin sulfotransferase-1 were regulated by TGF-ß. In addition ERK, p38, PI3K and CDK were found to differentially regulate mRNA expression of each enzyme. Four individual residues in the TGF-ß receptor mediator Smad2L can be phosphorylated by these kinases and in turn regulate the synthesis and activity of glycosaminoglycan synthesizing enzymes. Smad2L Thr220 was phosphorylated by CDKs and Smad2L Ser250 by ERK. p38 selectively signalled via Smad2L Ser245. Phosphorylation of Smad2L serine residues induced glycosaminoglycan synthesizing enzymes associated with glycosaminoglycan chain elongation. Phosphorylation of Smad2L Thr220 was associated with XT-1 enzyme regulation, a critical enzyme in chain initiation. These findings provide a deeper understanding of the complex signalling pathways that contribute to glycosaminoglycan chain modification that could be targeted using pharmacological agents to inhibit the development of atherosclerosis.

The acetyllysine reader BRD3R promotes human nuclear reprogramming and regulates mitosis.

It is well known that both recipient cells and donor nuclei demonstrate a mitotic advantage as observed in the traditional reprogramming with somatic cell nuclear transfer (SCNT). However, it is not known whether a specific mitotic factor plays a critical role in reprogramming. Here we identify an isoform of human bromodomain-containing 3 (BRD3), BRD3R (BRD3 with Reprogramming activity), as a reprogramming factor. BRD3R positively regulates mitosis during reprogramming, upregulates a large set of mitotic genes at early stages of reprogramming, and associates with mitotic chromatin. Interestingly, a set of the mitotic genes upregulated by BRD3R constitutes a pluripotent molecular signature. The two BRD3 isoforms display differential binding to acetylated histones. Our results suggest a molecular interpretation for the mitotic advantage in reprogramming and show that mitosis may be a driving force of reprogramming.

Anatomy and Complications: Safe Sinus.

Safe sinus surgery is predicated on a clear understanding and knowledge of the anatomy. The paranasal sinuses are surrounded by vital vascular and neurologic structures. In every step during the surgical procedure, one should know the regional surrounding anatomy and the potential complications that can be encountered if the procedures traverse these areas. Preoperative assessment of the imaging is important to identify potential hazardous areas.