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Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic metabolism of most other renal cancers. This TFE3 fusion-driven OXPHOS program, together with heightened glutathione levels found in renal cancers, renders tRCCs sensitive to reductive stress - a metabolic stress state induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1a and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability to OXPHOS-dependent tRCC cells. Our study defines a distinctive tRCC-essential metabolic program driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy to counteract fusion-induced metabolic rewiring.
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Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.
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Xp11 translocation renal cell carcinoma (tRCC) is a female-predominant kidney cancer driven by translocations between the TFE3 gene on chromosome Xp11.2 and partner genes located on either chrX or on autosomes. The rearrangement processes that underlie TFE3 fusions, and whether they are linked to the female sex bias of this cancer, are largely unexplored. Moreover, whether oncogenic TFE3 fusions arise from both the active and inactive X chromosomes in females remains unknown. Here we address these questions by haplotype-specific analyses of whole-genome sequences of 29 tRCC samples from 15 patients and by re-analysis of 145 published tRCC whole-exome sequences. We show that TFE3 fusions universally arise as reciprocal translocations with minimal DNA loss or insertion at paired break ends. Strikingly, we observe a near exact 2:1 female:male ratio in TFE3 fusions arising via X:autosomal translocation (but not via X inversion), which accounts for the female predominance of tRCC. This 2:1 ratio is at least partially attributable to oncogenic fusions involving the inactive X chromosome and is accompanied by partial re-activation of silenced chrX genes on the rearranged chromosome. Our results highlight how somatic alterations involving the X chromosome place unique constraints on tumor initiation and exemplify how genetic rearrangements of the sex chromosomes can underlie cancer sex differences.
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Inverse vulcanization, a sustainable platform, can transform sulfur, an industrial by-product, into polymers with broad promising applications such as heavy metal capture, electrochemistry and antimicrobials. However, the process usually requires high temperatures (≥159 °C), and the crosslinkers needed to stabilize the sulfur are therefore limited to high-boiling-point monomers only. Here, we report an alternative route for inverse vulcanization-mechanochemical synthesis, with advantages of mild conditions (room temperature), short reaction time (3 h), high atom economy, less H2S, and broader monomer range. Successful generation of polymers using crosslinkers ranging from aromatic, aliphatic to volatile, including renewable monomers, demonstrates this method is powerful and versatile. Compared with thermal synthesis, the mechanochemically synthesized products show enhanced mercury capture. The resulting polymers show thermal and light induced recycling. The speed, ease, versatility, safety, and green nature of this process offers a more potential future for inverse vulcanization, and enables further unexpected discoveries.
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Polímeros , Azufre , Electroquímica , Reciclaje , Temperatura de TransiciónRESUMEN
The generation of hydrogen from water using light is currently one of the most promising alternative energy sources for humankind but faces significant barriers for large-scale applications due to the low efficiency of existing photo-catalysts. In this work we propose a new route to fabricate nano-hybrid materials able to deliver enhanced photo-catalytic hydrogen evolution, combining within the same nanostructure, a plasmonic antenna nanoparticle and semiconductor quantum dots (QDs). For each stage of our fabrication process we probed the chemical composition of the materials with nanometric spatial resolution, allowing us to demonstrate that the final product is composed of a silver nanoparticle (AgNP) plasmonic core, surrounded by satellite Pt decorated CdS QDs (CdS@Pt), separated by a spacer layer of SiO2 with well-controlled thickness. This new type of photoactive nanomaterial is capable of generating hydrogen when irradiated with visible light, displaying efficiencies 300% higher than the constituting photo-active components. This work may open new avenues for the development of cleaner and more efficient energy sources based on photo-activated hydrogen generation.
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Hydration layers play a key role in many technical and biological systems, but our understanding of these structures remains very limited. Here, we investigate the molecular processes driving hydration of a chiral metal-organic surface, bitartrate on Cu(110), which consists of hydrogen-bonded bitartrate rows separated by exposed Cu. Initially water decorates the metal channels, hydrogen bonding to the exposed O ligands that bind bitartrate to Cu, but does not wet the bitartrate rows. At higher temperature, water inserts into the structure, breaks the existing intermolecular hydrogen bonds, and changes the adsorption site and footprint. Calculations show this process is driven by the creation of stable adsorption sites between the carboxylate ligands, to allow hydration of O-Cu ligands within the interior of the structure. This work suggests that hydration of polar metal-adsorbate ligands will be a dominant factor in many systems during surface hydration or self-assembly from solution.
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Titanium implants in orthopedic applications can fail due to infection and impaired integration into the host. Most research efforts that facilitate osseointegration of the implant have not considered infection, and vice versa. Moreover, most infection control measures involve the use of conventional antibiotics which contributes to the global epidemic of antimicrobial resistance. Nitric oxide (NO) is a promising alternative to antibiotics, and while researchers have investigated NO releasing coatings, there are few reports on the function/robustness or the mechanism of NO release. Our comprehensive mechanistic study has allowed us to design, characterize, and optimize NO releasing coatings to achieve maximum antimicrobial efficacy toward bacteria with minimum cytotoxicity to human primary osteoblasts in vitro. As the antibiotic era is coming to an end and the future of infection control continues to demand new alternatives, the coatings described herein represent a promising therapeutic strategy for use in orthopedic surgeries.
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Donantes de Óxido Nítrico/farmacología , Óxido Nítrico/metabolismo , Oseointegración/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Prótesis e Implantes , Titanio/química , Antibacterianos/farmacología , Compuestos Azo/farmacología , Adhesión Bacteriana/efectos de los fármacos , Biopelículas/efectos de los fármacos , Materiales Biocompatibles Revestidos/química , Humanos , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/fisiología , Silanos/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/fisiología , HumectabilidadRESUMEN
Making new van der Waals materials with electronic or magnetic functionality is a chemical design challenge for the development of two-dimensional nanoelectronic and energy conversion devices. We present the synthesis and properties of the van der Waals material Bi4O4SeCl2, which is a 1:1 superlattice of the structural units present in the van der Waals insulator BiOCl and the three-dimensionally connected semiconductor Bi2O2Se. The presence of three anions gives the new structure both the bridging selenide anion sites that connect pairs of Bi2O2 layers in Bi2O2Se and the terminal chloride sites that produce the van der Waals gap in BiOCl. This retains the electronic properties of Bi2O2Se while reducing the dimensionality of the bonding network connecting the Bi2O2Se units to allow exfoliation of Bi4O4SeCl2 to 1.4 nm height. The superlattice structure is stabilized by the configurational entropy of anion disorder across the terminal and bridging sites. The reduction in connective dimensionality with retention of electronic functionality stems from the expanded anion compositional diversity.
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As the current global threat of antimicrobial resistance (AMR) persists, developing alternatives to antibiotics that are less susceptible to resistance is becoming an urgent necessity. Recent advances in biomaterials have allowed for the development and fabrication of materials with discrete surface nanotopographies that can deter bacteria from adhering to their surface. Using binary polymer blends of polystyrene (PS), poly(methyl methacrylate) (PMMA) and polycaprolactone (PCL) and varying their relative concentrations, PS/PCL, PS/PMMA and PCL/PMMA polymer demixed thin films were developed with nanoisland, nanoribbon and nanopit topographies. In the PS/PCL system, PS segregates to the air-polymer interface, with the lower solubility PCL preferring the substrate-polymer interface. In the PS/PMMA and PCL/PMMA systems, PMMA prefers the air-polymer interface due to its greater solubility and lower surface energy. The anti-adhesion efficacy of the demixed films were tested against Pseudomonas aeruginosa (PA14). PS/PCL and PCL/PMMA demixed films showed a significant reduction in cell counts adhered on their surfaces compared to pure polymer control films, while no reduction was observed in the counts adhered on PS/PMMA demixed films. While the specific morphology did not affect the adhesion, a relationship between bacterial cell and topographical surface feature size was apparent. If the surface feature was smaller than the cell, then an anti-adhesion effect was observed; if the surface feature was larger than the cell, then the bacteria preferred to adhere.
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Heterogeneous ice nucleation at solid surfaces impacts many areas of science, from environmental processes, such as precipitation, to microbiological systems and food processing, but the microscopic mechanisms underpinning nucleation remain unclear. Discussion of ice growth has often focused around the role of the surface in templating the structure of water, forcing the first layer to adopt the registry of the underlying substrate rather than that of ice. To grow a thick ice film, water in the first few ice layers must accommodate this strain, but understanding how this occurs requires detailed molecular-scale information that is lacking. Here we combine scanning tunneling microscopy, low-energy electron diffraction, and work-function measurements with electronic structure calculations to investigate the initial stages of ice growth on a Pt alloy surface, having a lattice spacing 6% larger than ice. Although the first layer of water forms a strictly commensurate hexagonal network, this behavior does not extend to the second layer. Instead, water forms a 2D structure containing extended defect rows made from face-sharing pentamer and octamer rings. The defect rows allow the majority of second-layer water to remain commensurate with the solid surface while compensating lateral strain by increasing the water density close to that of an ice surface. The observation of octamer-pentamer rows in ice films formed on several surfaces suggests that the octamer-pentamer defect motif acts as a flexible strain relief mechanism in thin ice films, providing a mechanism that is not available during the growth of strained films in other materials, such as semiconductors.
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Smart antimicrobial surfaces are a powerful tool to prevent bacterial colonization at surfaces. In this work, we report a successful strategy for the functionalization of polydimethylsiloxane (PDMS) surfaces, widely used in medical devices, with salicylic acid (SA), a biocide approved for use in humans. Antimicrobial PDMS surfaces were fabricated via a rational design in which bifunctional silane linker molecules were covalently grafted onto the PDMS via one end, while soft intermolecular interactions with SA were generated at the other end to enable reversible load and release of the biocide. A molecular level understanding of the interface was obtained using attenuated total reflectance Fourier transform infrared, Raman, and X-ray photoelectron spectroscopies, alongside density functional theory calculations. These reveal that the linker molecules dock the SA molecules at the surface via a 1:1 complexation interaction. Furthermore, each 1:1 complex acts as a nucleation point onto which multiple stacks of the biocide are subsequently stabilized via a combination of H-bonding and π-π stacking interactions, thus significantly enhancing SA uptake at the interface. The antimicrobial activity of these surfaces against model Gram-negative and Gram-positive bacteria represented by Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis is demonstrated by a log 6 reduction of planktonic bacterial populations and an efficient anti-biofilm activity at the surface.
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The performance of solar-thermal conversion systems can be improved by incorporation of nanocarbon-stabilized microencapsulated phase change materials (MPCMs). The geometry of MPCMs in the microcapsules plays an important role for improving their heating efficiency and reliability. Yet few efforts have been made to critically examine the formation mechanism of different geometries and their effect on MPCMs-shell interaction. Herein, through changing the cooling rate of original emulsions, we acquire MPCMs within the nanocarbon microcapsules with a hollow structure of MPCMs (h-MPCMs) or solid PCM core particles (s-MPCMs). X-ray photoelectron spectroscopy and atomic force microscopy reveals that the capsule shell of the h-MPCMs is enriched with nanocarbons and has a greater MPCMs-shell interaction compared to s-MPCMs. This results in the h-MPCMs being more stable and having greater heat diffusivity within and above the phase transition range than the s-MPCMs do. The geometry-dependent heating efficiency and system stability may have important and general implications for the fundamental understanding of microencapsulation and wider breadth of heating generating systems.
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The ability of nitric oxide (NO)-releasing polymer coatings to prevent biofilm formation is described. NO-releasing coatings on (poly(ethylene terephthalate) (PET) and silicone elastomer (SE)) were fabricated using aminosilane precursors. Pristine PET and SE were oxygen plasma treated, followed by immobilisation of two aminosilane molecules: N-(3-(trimethoxysilyl)propyl)diethylenetriamine (DET3) and N-(3-trimethoxysilyl)propyl)aniline (PTMSPA). N-diazeniumdiolate nitric oxide donors were formed at the secondary amine sites on the aminosilane molecules producing NO-releasing polymeric coatings. The NO payload and release were controlled by the aminosilane precursor, as DET3 has two secondary amine sites and PTMSPA only one. The antibacterial efficacy of these coatings was tested using a clinical isolate of Pseudomonas aeruginosa (PA14). All NO-releasing coatings in this study were shown to significantly reduce P. aeruginosa adhesion over 24 h with the efficacy being a function of the aminosilane modification and the underlying substrate. These NO-releasing polymers demonstrate the potential and utility of this facile coating technique for preventing biofilms for indwelling medical devices.
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The linker-free covalent immobilization of polymers on surfaces has the potential to impart new properties and functions to surfaces for a wide range of applications. However, most current methods for the production of these surfaces involve multiple chemical steps and do not have a high degree of control over the chemical functionalities at the surface. A comprehensive study detailing the facile two-step covalent grafting of the antimicrobial peptide nisin onto polystyrene surfaces is reported. Functionalization is achieved using an atmospheric pressure plasma jet, and the reaction is monitored and compared with a standard wet chemical functionalization approach using a variety of analytical techniques. The reactive species produced by the atmospheric pressure plasma jet were analyzed by mass spectrometry and optical emission spectroscopy. The surface chemistry and topography of the functionalized surfaces were determined using contact angle measurements, Fourier infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy and atomic force microscopy respectively. Following surface analysis, the antimicrobial efficacy of the covalently grafted nisin against two major food borne pathogens (Staphylococcus aureus and Listeria monocytogenes) was assessed at two different pHs. The results demonstrated that a post-plasma treatment step after nisin deposition is required to covalently graft the peptide onto the surface. The covalent immobilization of nisin resulted in a significant reduction in bacterial counts within a short 30 minutes contact time. These surfaces were also significantly more antimicrobial compared to those prepared via a more traditional wet chemical approach indicating that the reported method could be a less expensive and less time consuming alternative.
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AIMS: Establishing biochemical markers of pre-hypertension and early hypertension could help earlier diagnostics and therapeutic intervention. We assess dynamics of junctional adhesion molecule-A (JAM-A) expression in rat models of hypertension and test whether JAM-A expression could be driven by angiotensin (ANG) II and whether JAM-A contributes to the progression of hypertension. We also compare JAM-A expression in normo- and hypertensive humans. METHODS AND RESULTS: In pre-hypertensive and spontaneously hypertensive rats (SHRs), JAM-A protein was overexpressed in the brainstem microvasculature, lung, liver, kidney, spleen, and heart. JAM-A upregulation at early and late stages was even greater in the stroke-prone SHR. However, JAM-A was not upregulated in leucocytes and platelets of SHRs. In Goldblatt 2K-1C hypertensive rats, JAM-A expression was augmented before any increase in blood pressure, and similarly JAM-A upregulation preceded hypertension caused by peripheral and central ANG II infusions. In SHRs, ANG II type 1 (AT(1)) receptor antagonism reduced JAM-A expression, but the vasodilator hydralazine did not. Body-wide downregulation of JAM-A with Vivo-morpholinos in juvenile SHRs delayed the progression of hypertension. In the human saphenous vein, JAM-A mRNA was elevated in hypertensive patients with untreated hypertension compared with normotensive patients but reduced in patients treated with renin-angiotensin system antagonists. CONCLUSION: Body-wide upregulation of JAM-A in genetic and induced models of hypertension in the rat precedes the stable elevation of arterial pressure. JAM-A upregulation may be triggered by AT(1) receptor-mediated signalling. An association of JAM-A with hypertension and sensitivity to blockers of ANG II signalling were also evident in humans. We suggest a prognostic and possibly a pathogenic role of JAM-A in arterial hypertension.
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Vasos Sanguíneos/metabolismo , Moléculas de Adhesión Celular/metabolismo , Hipertensión Renovascular/metabolismo , Hipertensión/metabolismo , Prehipertensión/metabolismo , Receptores de Superficie Celular/metabolismo , Angiotensina II , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Antihipertensivos/uso terapéutico , Presión Arterial , Biomarcadores/metabolismo , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/fisiopatología , Estudios de Casos y Controles , Moléculas de Adhesión Celular/genética , Línea Celular , Modelos Animales de Enfermedad , Humanos , Hidralazina/farmacología , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Hipertensión/fisiopatología , Hipertensión Renovascular/tratamiento farmacológico , Hipertensión Renovascular/etiología , Hipertensión Renovascular/fisiopatología , Losartán/farmacología , Masculino , Morfolinos/metabolismo , Prehipertensión/inducido químicamente , Prehipertensión/tratamiento farmacológico , Prehipertensión/genética , Prehipertensión/fisiopatología , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores de Superficie Celular/genética , Factores de Tiempo , Regulación hacia Arriba , Vasodilatadores/farmacologíaRESUMEN
Recent studies show that structures based on the traditional "icelike" water bilayer are not stable on flat transition metal surfaces and, instead, more complex wetting layers are formed. Here we show that an ordered bilayer can be formed on a SnPt(111) alloy template and determine the structure of the water layer by low energy electron diffraction. Close agreement is found between experiment and the structure calculated by density functional theory. Corrugation of the alloy surface allows only alternate water molecules to chemisorb, stabilizing the H-down water bilayer by reducing the metal-hydrogen repulsion compared to a flat surface.