Abstract
Metal promotion in heterogeneous catalysis requires nanoscale-precision architectures to attain maximized and durable benefits. Herein, we unravel the complex interplay between nanostructure ...and product selectivity of nickel-promoted In
2
O
3
in CO
2
hydrogenation to methanol through in-depth characterization, theoretical simulations, and kinetic analyses. Up to 10 wt.% nickel, InNi
3
patches are formed on the oxide surface, which cannot activate CO
2
but boost methanol production supplying neutral hydrogen species. Since protons and hydrides generated on In
2
O
3
drive methanol synthesis rather than the reverse water-gas shift but radicals foster both reactions, nickel-lean catalysts featuring nanometric alloy layers provide a favorable balance between charged and neutral hydrogen species. For nickel contents >10 wt.%, extended InNi
3
structures favor CO production and metallic nickel additionally present produces some methane. This study marks a step ahead towards green methanol synthesis and uncovers chemistry aspects of nickel that shall spark inspiration for other catalytic applications.
The possible effects of mutations on stability and function of a protein can only be understood in the context of protein 3D structure. The MutationExplorer webserver maps sequence changes onto ...protein structures and allows users to study variation by inputting sequence changes. As the user enters variants, the 3D model evolves, and estimated changes in energy are highlighted. In addition to a basic per-residue input format, MutationExplorer can also upload an entire replacement sequence. Previously the purview of desktop applications, such an upload can back-mutate PDB structures to wildtype sequence in a single step. Another supported variation source is human single nucelotide polymorphisms (SNPs), genomic coordinates input in VCF format. Structures are flexibly colorable, not only by energetic differences, but also by hydrophobicity, sequence conservation, or other biochemical profiling. Coloring by interface score reveals mutation impacts on binding surfaces. MutationExplorer strives for efficiency in user experience. For example, we have prepared 45 000 PDB depositions for instant retrieval and initial display. All modeling steps are performed by Rosetta. Visualizations leverage MDsrv/Mol*. MutationExplorer is available at: http://proteinformatics.org/mutation_explorer/.
Metal promotion in heterogeneous catalysis requires nanoscale-precision architectures to attain maximized and durable benefits. Herein, we unravel the complex interplay between nanostructure and ...product selectivity of nickel-promoted In
O
in CO
hydrogenation to methanol through in-depth characterization, theoretical simulations, and kinetic analyses. Up to 10 wt.% nickel, InNi
patches are formed on the oxide surface, which cannot activate CO
but boost methanol production supplying neutral hydrogen species. Since protons and hydrides generated on In
O
drive methanol synthesis rather than the reverse water-gas shift but radicals foster both reactions, nickel-lean catalysts featuring nanometric alloy layers provide a favorable balance between charged and neutral hydrogen species. For nickel contents >10 wt.%, extended InNi
structures favor CO production and metallic nickel additionally present produces some methane. This study marks a step ahead towards green methanol synthesis and uncovers chemistry aspects of nickel that shall spark inspiration for other catalytic applications.
Os últimos anos testemunharam um aumento na entrada de migrantes africanos no Brasil e na América do Sul em geral. Os senegaleses representam um dos maiores grupos deste novo movimento migratório. A ...literatura especializada sugere que o desenvolvimento de novos corredores de migração intercontinental sul-sul é, por um lado, resultado do desenvolvimento econômico e geopolítico na região, enquanto que, por outro lado, as dificuldades na migração para a Europa conduzem os senegaleses, ganeses e outros imigrantes africanos a buscarem alternativas e expandir seu horizonte migratório para outros continentes. Embora as migrações tenham sido sempre complexas e heterogêneas, a rapidez com que os fluxos migratórios atuais emergem, mudam de direção ou composição e desenvolvem novos padrões é notável. As dimensões espaciais e temporais da migração tornam-se cada vez mais não-lineares e a distinção entre ‘país de trânsito’ e ‘de destino’ fica menos evidente no contexto de mudanças rápidas e transformações globais o que coloca as dificuldades de categorizar esses fluxos. Os imigrantes recentes no Brasil têm que se adaptar às mudanças das condições durante a migração; eles precisam constantemente refletir sobre as circunstâncias que encontram, identificar novas oportunidades e obstáculos e reagir a eles. Esse artigo tem o intuito de compreender como os migrantes navegam através de estruturas em mudança durante a migração para e dentro do Brasil, bem como apresenta alguns dados empíricos sobre o desenvolvimento de novos corredores migratórios entre alguns países africanos e o Brasil. O presente trabalho concentra-se nos padrões de mobilidade, tanto antes quanto depois da chegada ao Brasil, e tenta conectar esses padrões com a agência dos migrantes. Ao analisar os padrões de movimento e a forma como e por que as decisões e aspirações da migração podem mudar ao longo do curso da migração, o trabalho aborda sobretudo as dimensões espaciais e temporais deste caso específico de migração sul-sul.
Ferroptosis is a regulated form of necrotic cell death that is caused by the accumulation of oxidized phospholipids, leading to membrane damage and cell lysis
. Although other types of necrotic death ...such as pyroptosis and necroptosis are mediated by active mechanisms of execution
, ferroptosis is thought to result from the accumulation of unrepaired cell damage
. Previous studies have suggested that ferroptosis has the ability to spread through cell populations in a wave-like manner, resulting in a distinct spatiotemporal pattern of cell death
. Here we investigate the mechanism of ferroptosis execution and discover that ferroptotic cell rupture is mediated by plasma membrane pores, similarly to cell lysis in pyroptosis and necroptosis
. We further find that intercellular propagation of death occurs following treatment with some ferroptosis-inducing agents, including erastin
and C' dot nanoparticles
, but not upon direct inhibition of the ferroptosis-inhibiting enzyme glutathione peroxidase 4 (GPX4)
. Propagation of a ferroptosis-inducing signal occurs upstream of cell rupture and involves the spreading of a cell swelling effect through cell populations in a lipid peroxide- and iron-dependent manner.
Distinct genetic forms of autism are hypothesized to share a common increase in excitation-inhibition (E-I) ratio in cerebral cortex, causing hyperexcitability and excess spiking. We provide a ...systematic test of this hypothesis across 4 mouse models (Fmr1−/y, Cntnap2−/−, 16p11.2del/+, Tsc2+/−), focusing on somatosensory cortex. All autism mutants showed reduced feedforward inhibition in layer 2/3 coupled with more modest, variable reduction in feedforward excitation, driving a common increase in E-I conductance ratio. Despite this, feedforward spiking, synaptic depolarization, and spontaneous spiking were largely normal. Modeling revealed that E and I conductance changes in each mutant were quantitatively matched to yield stable, not increased, synaptic depolarization for cells near spike threshold. Correspondingly, whisker-evoked spiking was not increased in vivo despite detectably reduced inhibition. Thus, elevated E-I ratio is a common circuit phenotype but appears to reflect homeostatic stabilization of synaptic drive rather than driving network hyperexcitability in autism.
•Four mouse models of autism share a common increase in E-I ratio in sensory cortex•E-I ratio changes acted to stabilize synaptic depolarization and spiking•Sensory-evoked firing rate in vivo was remarkably normal and sometimes decreased•These findings suggest E-I ratio changes are compensatory in autism
This study tests the E-I ratio hypothesis of autism in four mouse models. All show increased E-I ratio, but E-I changes are precisely coordinated to stabilize synaptic depolarization and spiking, not increase them. E-I changes therefore appear compensatory in autism.
Malignant liver tumours include a wide range of primary and secondary tumours. Although surgery remains the mainstay of curative treatment, modern therapies integrate a variety of neoadjuvant and ...adjuvant strategies and have achieved dramatic improvements in survival. Extensive tumour loads, which have traditionally been considered unresectable, are now amenable to curative treatment through systemic conversion chemotherapies followed by a variety of interventions such as augmentation of the healthy liver through portal vein occlusion, staged surgeries or ablation modalities. Liver transplantation is established in selected patients with hepatocellular carcinoma but is now emerging as a promising option in many other types of tumour such as perihilar cholangiocarcinomas, neuroendocrine or colorectal liver metastases. In this Review, we summarize the available therapies for the treatment of malignant liver tumours, with an emphasis on surgical and ablative approaches and how they align with other therapies such as modern anticancer drugs or radiotherapy. In addition, we describe three complex case studies of patients with malignant liver tumours. Finally, we discuss the outlook for future treatment, including personalized approaches based on molecular tumour subtyping, response to targeted drugs, novel biomarkers and precision surgery adapted to the specific tumour.
Angiocrine signaling by liver sinusoidal endothelial cells (LSECs) regulates hepatic functions such as growth, metabolic maturation, and regeneration. Recently, we identified GATA4 as the master ...regulator of LSEC specification during development. Herein, we studied the role of endothelial GATA4 in the adult liver and in hepatic pathogenesis.
We generated adult Clec4g-icretg/0xGata4fl/fl (Gata4LSEC-KO) mice with LSEC-specific depletion of Gata4. Livers were analyzed by histology, electron microscopy, immunohistochemistry/immunofluorescence, in situ hybridization, and LSECs were isolated for gene expression profiling, ChIP- and ATAC-sequencing. Partial hepatectomy was performed to assess regeneration. We used choline-deficient, l-amino acid-defined (CDAA) diet and chronic carbon tetrachloride exposure to model liver fibrosis. Human single cell RNA-seq data sets were analyzed for endothelial alterations in healthy and cirrhotic livers.
Genetic Gata4 deficiency in LSECs of adult mice caused perisinusoidal liver fibrosis, hepatopathy and impaired liver regeneration. Sinusoidal capillarization and LSEC-to-continuous endothelial transdifferentiation were accompanied by a profibrotic angiocrine switch involving de novo endothelial expression of hepatic stellate cell-activating cytokine PDGFB. Increased chromatin accessibility and amplification by activated MYC mediated angiocrine Pdgfb expression. As observed in Gata4LSEC-KO livers, CDAA diet-induced perisinusoidal liver fibrosis was associated with GATA4 repression, MYC activation and a profibrotic angiocrine switch in LSECs. Comparison of CDAA-fed Gata4LSEC-KO and control mice demonstrated that endothelial GATA4 indeed protects against dietary-induced perisinusoidal liver fibrosis. In human cirrhotic livers, GATA4-positive LSECs and endothelial GATA4 target genes were reduced, while non-LSEC endothelial cells and MYC target genes including PDGFB were enriched.
Endothelial GATA4 protects against perisinusoidal liver fibrosis by repressing MYC activation and profibrotic angiocrine signaling at the chromatin level. Therapies targeting the GATA4/MYC/PDGFB/PDGFRβ axis offer a promising strategy for prevention and treatment of liver fibrosis.
The liver vasculature is supposed to play a major role in the development of liver fibrosis and cirrhosis, which can lead to liver failure and liver cancer. Herein, we discovered that structural and transcriptional changes induced by genetic deletion of the transcription factor GATA4 in the hepatic endothelium were sufficient to cause liver fibrosis. Activation of the transcription factor MYC and de novo expression of the “angiocrine” growth factor PDGFB were identified as downstream drivers of fibrosis and as potential therapeutic targets for this potentially fatal disease.
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•Genetic endothelial Gata4 deletion leads to liver fibrosis and hepatopathy.•Gata4 deficiency causes profibrotic angiocrine signaling via endothelial PDGFB.•Increased chromatin accessibility and activated MYC mediate Pdgfb expression in LSECs.•Dietary liver fibrosis causes dysregulation of the endothelial GATA4/MYC/PDGFB axis.•In human cirrhosis, single-cell data implicate the GATA4/PDGFB axis.
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