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- ArticleJanardan A, Prokhoda P, Razzak AN, Jethwa T, Paudel HR.Cureus. 2022 Sep;14(9):e29756.Aspergillus is a fungal genus found worldwide, which causes infection most commonly in the respiratory system and in other systems, including the central nervous system. Fungal species, such as Aspergillus fumigatus or flavus, are more common in immunocompromised patient populations, such as those taking immunosuppressants post-transplantation, those on long-term corticosteroids, or those with immunodeficiencies such as AIDS. In this paper, we describe a rare case of aspergillosis that occurred due to a history of taking corticosteroids to treat arthritis pain in a patient with type 2 diabetes. Given the rise in antifungal-resistant species and environmental changes, it is noteworthy for further research to be conducted on new treatment plans and the management of such fungal infections to prepare against opportunistic infections caused by Aspergillus in the future.
- ArticleYue W, Gao S, Lee SS, Kim ES, Choi DY.Sci Rep. 2016 07 13;6:29756.Highly efficient subtractive tri-color filters of cyan, magenta, and yellow with enhanced color purity and robustness have been proposed and realized, by exploiting a silicon-aluminum (Si-Al) hybrid-nanodisk (ND) metasurface atop a Si substrate. The aspect ratio of the Si-Al hybrid ND is much lower than that of the conventional Si nanowire, which is disadvantageous due to its fragility and low color purity. In response to incident light impinging upon the metasurface, the hybrid-NDs individually play the role in exciting a magnetic dipole (MD) resonance through the mediation of Mie-scattering between the hybrid ND and air. The light stored in the resonance is coupled to the substrate, giving rise to a suppressed reflection. By virtue of the top Al ND, the excited MD resonance is strongly confined by the Si ND. As a consequence, a near-zero resonant dip that exhibits high off-resonance reflection and narrow bandwidth is produced for embodying highly efficient tri-color filters with enhanced color purity. The spectral position can be tuned by a simple adjustment of the hybrid-ND diameter. A full-color palette was successfully created with a high color purity and large color gamut. The proposed devices may be applied for photorealistic high-resolution color printing and holographic displays.
- ArticleRudresh BB, Tater AK, Barot V, Patel N, Desai A, Mitra S, Deshpande A.Heliyon. 2024 Apr 30;10(8):e29756.The intricate network of glands and organs that makes up the endocrine system. Hormones are used to regulate and synchronize the nervous and physiological systems. The agents which perturbate an endocrine system are called endocrine disruptors and they can eventually affect cellular proliferation and differentiation in target tissues. A subclass of endocrine disruptors known as thyroid disruptors (TDs) or thyroid disrupting chemicals (TDCs) influence the hypothalamo-pituitary-thyroid axis or directly interfere with thyroid function by binding to thyroid hormone receptors. Thyroid hormone levels in circulation are now included in more test guidelines (OECD TG 441, 407, 408, 414, 421/422, 443/416). Although these might be adequate to recognize thyroid adversity, they are unable to explain the underlying mechanism of action. Thyroid peroxidase (TPO) and sodium iodide symporter (NIS), two proteins essential in the biosynthesis of thyroid hormones, are well-accepted molecular targets for inhibition. The screening of a large number of molecules using high throughput screening (HTS) requires a minimum quantity of sample, cost, and time consuming. Whereas 3-dimensional quantitative structure-activity relationship (3D-QSAR) analysis can screen the TDCs before synthesizing a compound. In the present study, the human TPO (hTPO) and NIS (hNIS) structures were modelled using homology modeling and the quality of the structures was validated satisfactorily using MD simulation for 100ns. Further, 190 human TPO inhibitors with IC50 were curated from Comptox and docked with the modelled structure of TPO using D238, H239 and D240 centric grid. The binding conformation of a molecule with low binding energy was used as a reference and the rest other molecules were aligned after generating the possible conformers. The activity-stratified partition was performed for aligned molecules and training set (139), test set (51) were defined. The machine learning models such as k Nearest Neighbor (kNN) and Random Forest (RF) models were built and validated using external experimental dataset containing 10 molecules. Among the 10 molecules, all 10 molecules were identified as TPO inhibitors and demonstrated 100 % accuracy qualitatively. To confirm the selective TPO inhibition all 10 molecules were docked with the modelled structure of hNIS and the results have demonstrated the selective TPO inhibition.
- ArticleViktorisson A, Sunnerhagen KS, Johansson D, Herlitz J, Axelsson Å.BMJ Open. 2019 07 03;9(7):e029756.OBJECTIVES: Few studies have investigated the psychological and health-related outcome after out-of-hospital cardiac arrest (OHCA) over time. This longitudinal study aims to evaluate psychological distress in terms of anxiety and depression, self-assessed health and predictors of these outcomes in survivors of OHCA, 3 and 12 months after resuscitation.
METHODS: Recruitment took place from 2008 to 2011 and survivors of OHCA were identified through the national Swedish Cardiopulmonary Resuscitation Registry. Inclusion criteria were age ≥18 years, survival ≥12 months and a Cerebral Performance Category score ≤2. Questionnaires containing the Hospital Anxiety and Depression Scale and European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) were administered at 3 and 12 months after the OHCA. Participants were also asked to report treatment-requiring comorbidities.
RESULTS: Of 298 survivors, 85 (29%) were eligible for this study and 74 (25%) responded. Clinically relevant anxiety was reported by 22 survivors at 3 months and by 17 at 12 months, while clinical depression was reported by 10 at 3 months and 4 at 12 months. The mean EQ-5D-3L index value increased from 0.82 (±0.26) to 0.88 (±0.15) over time. There were significantly less symptoms of psychological distress (p=0.01) and better self-assessed health (p=0.003) at 12 months. Treatment-requiring comorbidity predicted anxiety (OR 4.07, p=0.04), while being female and young age predicted poor health (OR 6.33, p=0.04; OR 0.91, p=0.002) at 3 months. At 12 months, being female was linked to anxiety (OR 9.23, p=0.01) and depression (OR 14.78, p=0.002), while young age predicted poor health (OR 0.93, p=0.003).
CONCLUSION: The level of psychological distress and self-assessed health improves among survivors of OHCA between 3 and 12 months after resuscitation. Higher levels of psychological distress can be expected among female survivors and those with comorbidity, while survivors of young age and who are female are at greater risk of poor health. - ArticleZhou JC, Tan BB, Huang Y, Wu YY, Bai ZJ, Liang ML, Zhao WH.Medicine (Baltimore). 2022 Jul 01;101(26):e29756.Hodgkin lymphoma (HL)-related hemophagocytic lymphohistiocytosis (HLH) has been reported in the literature; however, there is almost no literature on the factors related to HL triggering HLH. One hundred forty patients with HL were retrospectively analyzed. The incidence of HL-related HLH (we call HL-related HLH as HL-HLH). And all HL-HLH patients in our cohort had HLH as the first manifestation and its clinical characteristics and the role of intrathoracic infection (ITI) in triggering HLH are discussed. The 140 patients with HL mainly included mixed-cellularity classic HL (MCCHL) in 81 (57.9%), nodular sclerosis classic HL (NSCHL) in 36 (25.7%), and lymphacyte-rich classic HL in 14 (10.0%) patients. Of the 137 patients who underwent chest computed tomography scans on admission, 44 had ITI, and most of these ITI were mildly ill and had no respiratory symptoms. Among 140 HL patients, 8 patients from MCCHL were diagnosed as HL-HLH. Among 81 MCCHL patients, 26 patients with ITI had a significantly higher incidence of HL-HLH than those without ITI (26.9% vs 1.8%, P = .002). The median survival time of 8 cases of HL-HLH was only 2 months. When HL patients were first admitted to the hospital, 5.7% had HLH as the first manifestation, and 32.1% had ITI. These ITI can cooperate with HL to trigger HLH, despite their mild illness. The prognosis of HL-HLH was poor.
- ArticleMader L, Sláma T, Schindera C, Rössler J, von der Weid NX, Belle FN, Kuehni CE.Pediatr Blood Cancer. 2022 09;69(9):e29756.BACKGROUND: The cancer diagnosis and its intensive treatment may affect the long-term psycho-social adjustment of childhood cancer survivors. We aimed to describe social, emotional, and behavioral functioning and their determinants in young childhood cancer survivors.
PROCEDURE: The nationwide Swiss Childhood Cancer Survivor Study sends questionnaires to parents of survivors aged 5-15 years, who have survived at least 5 years after diagnosis. We assessed social, emotional, and behavioral functioning using the Strengths and Difficulties Questionnaire (SDQ). The SDQ includes four difficulties scales (emotional, conduct, hyperactivity, peer problems), a total difficulties indicator, and one strength scale (prosocial). We compared the proportion of survivors with borderline and abnormal scores to reference values and used multivariable logistic regression to identify determinants.
RESULTS: Our study included 756 families (response rate of 72%). Thirteen percent of survivors had abnormal scores for the total difficulties indicator compared to 10% in the general population. The proportion of survivors with abnormal scores was highest for the emotional scale (15% vs. 8% in the general population), followed by the peer problems scale (14% vs. 7%), hyperactivity (8% vs. 10%), and conduct scale (6% vs. 7%). Few survivors (4% vs. 7%) had abnormal scores on the prosocial scale. Children with chronic health conditions had a higher risk of borderline and abnormal scores on all difficulties scales (all p < 0.05).
CONCLUSION: Most childhood cancer survivors do well in social, emotional, and behavioral life domains, but children with chronic health conditions experience difficulties. Therefore, healthcare professionals should offer specific psycho-social support to these survivors. - ArticleReuter KC, Loitsch SM, Dignass AU, Steinhilber D, Stein J.PLoS One. 2012;7(1):e29756.INTRODUCTION: Despite the excellent anti-inflammatory and immunosuppressive action of glucocorticoids (GCs), their use for the treatment of inflammatory bowel disease (IBD) still carries significant risks in terms of frequently occurring severe side effects, such as the impairment of intestinal tissue repair. The recently-introduced selective glucocorticoid receptor (GR) agonists (SEGRAs) offer anti-inflammatory action comparable to that of common GCs, but with a reduced side effect profile.
METHODS: The in vitro effects of the non-steroidal SEGRAs Compound A (CpdA) and ZK216348, were investigated in intestinal epithelial cells and compared to those of Dexamethasone (Dex). GR translocation was shown by immunfluorescence and Western blot analysis. Trans-repressive effects were studied by means of NF-κB/p65 activity and IL-8 levels, trans-activation potency by reporter gene assay. Flow cytometry was used to assess apoptosis of cells exposed to SEGRAs. The effects on IEC-6 and HaCaT cell restitution were determined using an in vitro wound healing model, cell proliferation by BrdU assay. In addition, influences on the TGF-β- or EGF/ERK1/2/MAPK-pathway were evaluated by reporter gene assay, Western blot and qPCR analysis.
RESULTS: Dex, CpdA and ZK216348 were found to be functional GR agonists. In terms of trans-repression, CpdA and ZK216348 effectively inhibited NF-κB activity and IL-8 secretion, but showed less trans-activation potency. Furthermore, unlike SEGRAs, Dex caused a dose-dependent inhibition of cell restitution with no effect on cell proliferation. These differences in epithelial restitution were TGF-β-independent but Dex inhibited the EGF/ERK1/2/MAPK-pathway important for intestinal epithelial wound healing by induction of MKP-1 and Annexin-1 which was not affected by CpdA or ZK216348.
CONCLUSION: Collectively, our results indicate that, while their anti-inflammatory activity is comparable to Dex, SEGRAs show fewer side effects with respect to wound healing. The fact that SEGRAs did not have a similar effect on cell restitution might be due to a different modulation of EGF/ERK1/2 MAPK signalling. - ArticleZhou B, Ma J, Wang J, Yuan P, Xie G, Qian L.Opt Express. 2020 Sep 28;28(20):29756-29765.Resonant cascaded nonlinearity (RCN) induced by optical parametric amplification (OPA) in a chirped quasi-phase-matching chip can be applied to control the group velocity of ultrafast lasers. However, the group delay produced in a single-stage OPA is limited to the pulse duration, and its sign cannot be altered. In this study, we propose a tandem RCN configuration with multiple OPA stages that can produce large-magnitude and sign-controllable group delays. The group delay produced in the multi-stage configuration is shown to be a linear superposition of each single-stage group delay. By virtue of the byproduct idler in the OPA process, the signal-group delay can be altered from positive to negative (and vice versa) with the same chip structure and pump condition. In the numerical simulation with two OPA stages, both a positive and negative group delay of six-fold pulse duration were achieved for 100-fs pulses at 1550 nm. A much larger group delay can be achieved by increasing the number of OPA stages.
- ArticleKumar K, Dave RP, Dev S, Singh M.RSC Adv. 2022 Oct 17;12(46):29734-29756.We synthesized graphene oxide (GO) doped with transition metal ions and characterized it using XPS, FT-IR, TGA/DTG, XRD, SEM, AFM, ICP-OES, UV/vis, and Raman spectroscopy. An intrinsic viscosity [η] of 0.002-0.012 g% @ 0.002 aq-GO was determined for viscosity average molecular weight (M v) of GO at 288.15, 298.15, and 308.15 K. Mark-Houwink (M-H) constants k (cm3 g-1) and a (cm3 mol g-2) were calculated for 5-15 mg/100 mL polyvinylpyrrolidone (PVP), using 29, 40, 55 kg mol-1 as markers for calculating M v by fitting the [η] to the Mark-Houwink-Sakurada equation (MHSE). We obtained 48 134.19 g mol-1 M v at 298.15 K, and the apparent molar (V ϕ m , cm3 mol-1), limiting molar volumes (V 0 GO)GO⃑0, enthalpy (ΔH m, J mol-1), entropy (ΔS m, J mol-1 K-1), viscosity (η m, mPa s mol-1), surface tension (γ m, mN m-1 mol-1), friccohesity (σ m, scm-1 mol-1), fractional volume (ϕ m, cm3 mol-1), isentropic compressibility (K sϕ,m, 10-4 cm s2 g-1 mol), infer GO molar consistency throughout the chemical processes. Molar properties (MPs) infer a GO monodispersion producing negative electrons (e-) and positive holes (h+) under sunlight. The transition metal ions (Fe2+, Mn2+, Ni2+, Cr3+, TMI) doped onto GO (TMI-GO), can photodegrade methylene blue (MB) in 60 min compared with 120 min using GO alone. The 4011 C atoms, 688 hexagonal sheets, 222 π-conjugations, and 4011 FE were calculated from the 48 134.19 g mol-1. The functional edges are the negative and positive holes generating centres of the GO 2D sheets.
- ArticleBlangy-Letheule A, Vergnaud A, Dupas T, Habert D, Montnach J, Oulehri W, Hassoun D, Denis M, Lecomte J, Persello A, Roquilly A, Courty J, Seve M, Leroux AA, Rozec B, Bourgoin-Voillard S, De Waard M, Lauzier B.J Med Virol. 2024 Jun;96(6):e29756.In intensive care units, COVID-19 viral pneumonia patients (VPP) present symptoms similar to those of other patients with Nonviral infection (NV-ICU). To better manage VPP, it is therefore interesting to better understand the molecular pathophysiology of viral pneumonia and to search for biomarkers that may clarify the diagnosis. The secretome being a set of proteins secreted by cells in response to stimuli represents an opportunity to discover new biomarkers. The objective of this study is to identify the secretomic signatures of VPP with those of NV-ICU. Plasma samples and clinical data from NV-ICU (n = 104), VPP (n = 30) or healthy donors (HD, n = 20) were collected at Nantes Hospital (France) upon admission. Samples were enriched for the low-abundant proteins and analyzed using nontarget mass spectrometry. Specifically deregulated proteins (DEP) in VPP versus NV-ICU were selected. Combinations of 2 to 4 DEPs were established. The differences in secretome profiles of the VPP and NV-ICU groups were highlighted. Forty-one DEPs were specifically identified in VPP compared to NV-ICU. We describe five of the best combinations of 3 proteins (complement component C9, Ficolin-3, Galectin-3-binding protein, Fibrinogen alpha, gamma and beta chain, Proteoglycan 4, Coagulation factor IX and Cdc42 effector protein 4) that show a characteristic receptor function curve with an area under the curve of 95.0%. This study identifies five combinations of candidate biomarkers in VPP compared to NV-ICU that may help distinguish the underlying causal molecular alterations.
- ArticleLiu L, Yan H, Yang C, Zhu G.RSC Adv. 2018 Aug 20;8(52):29756-29766.An ultrasound assisted Fe(ii)-activated persulfate oxidation method was put forward to improve the dewaterability of drilling sludge in this research. The water content in the filter cake and specific resistance to filtration (SRF) were measured to evaluate the sludge dewaterability. Volatile suspended solids (VSS), transmittance of supernatant, microstructure, particle size distribution and zeta potential were tested to justify the proposed mechanism. The results showed that appropriate ultrasound assisted Fe(ii)-activated persulfate oxidation could not only further enhance the sludge dewaterability but also reduce the reaction time as well. The optimal conditions for this method were 1.6% sodium persulfate, 0.8% ferrous sulfate, 40 W ultrasonic power and 45 min reaction time. Reduction of VSS and an increase of transmittance were further achieved compared to oxidation alone. SEM results and the decrease of particle size after the treatment confirmed the disintegration of sludge flocs, which promoted the release of bound water. A synergistic effect mechanism of ultrasound and chemical oxidation was proposed, with ultrasonic cavitation disintegrating the flocs, exposing the interior organics and persulfate further oxidizing the released organics.
- ArticleWang L, Liu YL, Wang MS.Phys Chem Chem Phys. 2022 Dec 14;24(48):29747-29756.Formation of organic co-crystals is an effective strategy to synthesize near infrared emission and nonlinear optical (NLO) materials, which often show "1 + 1 > 2" performance. Moreover, the crystallization process can be effectively regulated through supramolecular interactions; thus the properties of co-crystal materials can also be flexibly regulated. Here, in order to further understand the nature and formation mechanism of co-crystals from the perspective of theoretical research, we studied the structures, intermolecular interactions, absorption spectra, charge transfer (CT) characteristics and nonlinear optical (NLO) properties of the newly synthesized organic co-crystals formed between naphthalenediimide based triangles (NDI, acceptor) and coronene (COR, donor). According to the analysis of decomposition of intermolecular interaction energy, dispersion energy played a major role, so the co-crystal properties can be regulated by regulating the intermolecular dispersion energy. More importantly, the formation of co-crystals NDI-COR and NDI-2COR reduced the Egap values with respect to those of their components. And there was significant intermolecular CT from COR to NDI and the degree of CT in NDI-COR was larger than that in NDI-2COR, so that the αtot and γtot values of NDI-COR and NDI-2COR were significantly greater than those of their components. Thus, the NLO properties of organic co-crystals can be further improved by enhancing the electron-donating ability of the donor and the electron-withdrawing ability of the acceptor to enhance the degree of intermolecular interaction energy and CT.
- ArticleMurdachaew G, Nathanson GM, Benny Gerber R, Halonen L.Phys Chem Chem Phys. 2016 Nov 21;18(43):29756-29770.Deprotonation of organic acids at aqueous surfaces has important implications in atmospheric chemistry and other disciplines, yet it is not well-characterized or understood. This article explores the interactions of formic acid (FA), including ionization, in collisions at the air-water interface. Ab initio molecular dynamics simulations with dispersion-corrected density functional theory were used. The 8-50 picosecond duration trajectories all resulted in the adsorption of FA within the interfacial region, with no scattering, absorption into the bulk or desorption into the vapor. Despite the known weak acidity of FA, spontaneous deprotonation of the acid was observed at the interface on a broad picosecond timescale, ranging from a few picoseconds typical for stronger acids to tens of picoseconds. Deprotonation occurred in 4% of the trajectories, and was followed by Grotthuss proton transfer through adjacent water molecules. Both sequential and ultrafast concerted proton transfer were observed. The formation of contact ion pairs and solvent-separated ion pairs, and finally the reformation of neutral FA, both trans and cis conformers, occurred in different stages of the dynamics. To better understand the deprotonation mechanisms at the interface compared with the process in bulk water, we used well-tempered metadynamics to obtain deprotonation free energy profiles. While in bulk water FA deprotonation has a free energy barrier of 14.8 kJ mol-1, in fair agreement with the earlier work, the barrier at the interface is only 7.5 kJ mol-1. Thus, at the air-water interface, FA may dissociate more rapidly than in the bulk. This finding can be rationalized with reference to the dissimilar aqueous solvation and hydrogen-bonding environments in the interface compared to those in bulk liquid water.
- ArticleYou C, Khattak SI, Ahmad M.Environ Sci Pollut Res Int. 2022 Apr;29(20):29756-29777.Innovation in renewable energy generation, transmission, or distribution-related technologies (IREGT) is an effective way to deal with environmental pollution. Even though previous studies have focused on renewable energy generation in the USA, the impact of IREGT on carbon dioxide emissions (CO2e) remains widely unexplored. Recognizing this gap, this study inspected the IREGT-CO2e nexus in the USA, with international collaboration in green technology development (ICGTD), trade openness (TO), renewable energy consumption (REC), and gross domestic product per capita (GDPPC) as control variables from 1990Q1 to 2018Q4. The study applied the canonical cointegration regression (CCR), fully modified ordinary least squares (FMOLS) method, and dynamic ordinary least squares (DOLS) approach to assess the long-run association among variables. First, the findings validated the cointegration relationship among IREGT, ICGTD, TO, REC, GDPPC, and CO2e. Second, the results indicated that the IREGT, REC, and ICGTD had benefited the USA in mitigating CO2e. Third, GDPPC and TO were positively connected to CO2e. Fourth, the Granger causality depicted that GDPPC, TO, and ICGTD Granger caused CO2e in the USA, while IREGT and CO2e had a bidirectional relationship. The study's findings encourage the government should devise policies to induce higher research institutions and private enterprises to engage in IREGT.
- ArticleShi R, Tian Y, Zhu P, Tang X, Tian X, Zhou C, Wang L.ACS Appl Mater Interfaces. 2020 Jul 01;12(26):29747-29756.Heterotypic microfibers have been recognized as promising building blocks for the multifunctionality demanded in various fields, such as environmental and biomedical engineering. We present a novel microfluidics-based technique to generate bio-inspired microfibers with hourglass-shaped knots (named hourglass-shaped microfibers) via the integration of a non-solvent-induced phase separation (NIPS) process. The microfibers with spindle knots (named spindle-microfibers) are generated as templates at a large scale. The morphologies of spindle-microfibers can be precisely regulated by controlling the flow rates of the constituent fluids. After post-treatment of the partially gelled spindle-microfibers in ethanol, the encapsulated oil cores leak from knots, and the fibers morph into an hourglass shape. By controlling the oil core spillage and the template's configurations, a variety of hourglass-shaped microfibers can be obtained with adjustable morphologies and densities ranging from those of cavity-microfibers to those of spindle-microfibers. The hourglass-shaped microfibers preponderate spindle-microfibers in terms of changeable weight, adjustable morphologies, high specific surface areas, and enhanced surface roughness. Their unique macroscale topographies and properties lead to enhanced dehumidification and water collection abilities. This NIPS-integrated microfluidic technique offers a promising and novel way to manufacture microfibers by design, tailoring their structures and properties to suit a desired application.
- ArticleWang C, Zhang H, Li C, He Y, Zhang L, Zhao X, Yang Q, Xian D, Mao Q, Peng B, Zhou Z, Cui W, Hu Z.ACS Appl Mater Interfaces. 2018 Sep 05;10(35):29750-29756.In spite of recent rapid development of flexible electronics, voltage-tunable spintronic structures and devices on flexible substrates have been rarely studied. Here, voltage control of magnetic anisotropy (VCMA) is demonstrated via ionic gel (IG) gating on flexible polyimide substrates with a circuit operating voltage of 1.8 V. A reversible, nonvolatile VCMA switching of 114 Oe is achieved in Pt/Fe/Pt multilayer, where the spatial magnetic anisotropy distribution is determined quantitatively by electron spin resonance technique. This IG gating process is repeatable as the substrates are under different bending conditions. The voltage modulation of magnetic anisotropy through IG gating with excellent flexibility proposes potential applications in low-power wearable spintronic devices.
- Bookedited by Cristina R. Antonescu
- ArticleLim SK, Ju J, Zazopoulos E, Jiang H, Seo JW, Chen Y, Feng Z, Rajski SR, Farnet CM, Shen B.J Biol Chem. 2009 Oct 23;284(43):29746-56.iso-Migrastatin and related glutarimide-containing polyketides are potent inhibitors of tumor cell migration and their implied potential as antimetastatic agents for human cancers has garnered significant attention. Genome scanning of Streptomyces platensis NRRL 18993 unveiled two candidate gene clusters (088D and mgs); each encodes acyltransferase-less type I polyketide synthases commensurate with iso-migrastatin biosynthesis. Both clusters were inactivated by lambda-RED-mediated PCR-targeting mutagenesis in S. platensis; iso-migrastatin production was completely abolished in the DeltamgsF mutant SB11012 strain, whereas inactivation of 088D-orf7 yielded the SB11006 strain that exhibited no discernible change in iso-migrastatin biosynthesis. These data indicate that iso-migrastatin production is governed by the mgs cluster. Systematic gene inactivation allowed determination of the precise boundaries of the mgs cluster and the essentiality of the genes within the mgs cluster in iso-migrastatin production. The mgs cluster consists of 11 open reading frames that encode three acyltransferase-less type I polyketide synthases (MgsEFG), one discrete acyltransferase (MgsH), a type II thioesterase (MgsB), three post-PKS tailoring enzymes (MgsIJK), two glutarimide biosynthesis enzymes (MgsCD), and one regulatory protein (MgsA). A model for iso-migrastatin biosynthesis is proposed based on functional assignments derived from bioinformatics and is further supported by the results of in vivo gene inactivation experiments.
- ArticleNiknejad N, Morley M, Dimitroulakos J.J Biol Chem. 2007 Oct 12;282(41):29748-56.Lovastatin, a potent inhibitor of mevalonate synthesis, can readily induce apoptosis in a subset of human tumor types including head and neck squamous cell carcinomas (HNSCC). We recently identified activation of transcription factor (ATF) 4 as a lovastatin induced gene in HNSCC cells. ATF4 plays a significant role in regulating cellular responses to a wide variety of stress inducers known as the integrated stress response (ISR). These cell stresses lead to the phosphorylation of eukaryotic initiation factor (eIF) 2alpha shutting down global protein translation. However, the translation of ATF4 is enhanced. In this study, lovastatin treatment induced eIF2alpha phosphorylation and inhibited global protein translation. ATF4 expression was induced followed by increased ATF3 and CHOP expression, targets of ATF4 activity, in SCC25 HNSCC cells. In CHOP(-/-) murine embryonic fibroblasts (MEFs), lovastatin-induced apoptosis was attenuated indicating a role for CHOP in this response. Furthermore, the eIF2alpha kinase GCN2 mediates lovastatin induction of ATF4 and lovastatin-induced apoptosis was also attenuated in GCN2(-/-) MEFs. The pro-drug version of lovastatin has potential proteasome inhibitory activity and recently a variety of well established proteasome inhibitors were shown to activate the ISR. In this study, neither the pro-drug nor the active forms of lovastatin had any significant effect on proteasome activity. Therefore, lovastatin, by targeting mevalonate synthesis, is a potent inducer of the ISR through a novel and as yet unrecognized mechanism.