Hyperglycemia-induced Renal P2X7 Receptor Activation Enhances Diabetes-related Injury

Diabetes is a leading cause of renal disease. Glomerular mesangial expansion and fibrosis are hallmarks of diabetic nephropathy and this is thought to be promoted by infiltration of circulating macrophages. Monocyte chemoattractant protein-1 (MCP-1) has been shown to attract macrophages in kidney diseases. P2X7 receptors (P2X7R) are highly expressed on macrophages and are essential components of pro-inflammatory signaling in multiple tissues. Here we show that in diabetic patients, renal P2X7R expression is associated with severe mesangial expansion, impaired glomerular filtration (≤40 ml/min/1.73 sq. m.), and increased interstitial fibrosis. P2X7R activation enhanced the release of MCP-1 in human mesangial cells cultured under high glucose conditions. In mice, P2X7R-deficiency prevented glomerular macrophage attraction and collagen IV deposition; however, the more severe interstitial inflammation and fibrosis often seen in human diabetic kidney diseases was not modelled. Finally, we demonstrate that a P2X7R inhibitor (AZ11657312) can reduce renal macrophage accrual following the establishment of hyperglycemia in a model of diabetic nephropathy. Collectively these data suggest that P2X7R activation may contribute to the high prevalence of kidney disease found in diabetics

The evolutionary paths towards complexity: a metabolic perspective

As sessile organisms, land plants have exploited their metabolic systems to produce a panoply of structurally and functionally diverse natural chemicals and polymers to adapt to challenging ecosystems. Many of these core and specialized metabolites confer chemical shields against a multitude of abiotic stresses, while others play important roles in plants' interactions with their biotic environments. Plant specialized metabolites can be viewed as complex traits in the sense that the biosynthesis of these molecules typically requires multistep metabolic pathways comprising numerous specific enzymes belonging to diverse protein fold families. Resolving the evolutionary trajectories underlying the emergence of these specialized metabolic pathways will impact a fundamental question in biology – how do complex traits evolve in a Darwinian fashion? Here, I discuss several general patterns observed in rapidly evolving specialized metabolic systems in plants, and surmise mechanistic features at enzyme, pathway and organismal levels that rationalize the remarkable malleability of these systems through stepwise evolution. Future studies, focused on fine sampling of metabolic enzymes and pathways in phylogenetically related plant species, or employing directed evolution strategies in synthetic systems, will significantly broaden our perspective on how biological complexity arises at the metabolic level.Howard Hughes Medical InstitutePioneer Foundation (Postdoctoral Fellowship

Attenuation of Notch and Hedgehog Signaling Is Required for Fate Specification in the Spinal Cord

During the development of the spinal cord, proliferative neural progenitors differentiate into postmitotic neurons with distinct fates. How cells switch from progenitor states to differentiated fates is poorly understood. To address this question, we studied the differentiation of progenitors in the zebrafish spinal cord, focusing on the differentiation of Kolmer-Agduhr″ (KA″) interneurons from lateral floor plate (LFP) progenitors. In vivo cell tracking demonstrates that KA″ cells are generated from LFP progenitors by both symmetric and asymmetric cell divisions. A photoconvertible reporter of signaling history (PHRESH) reveals distinct temporal profiles of Hh response: LFP progenitors continuously respond to Hh, while KA″ cells lose Hh response upon differentiation. Hh signaling is required in LFP progenitors for KA″ fate specification, but prolonged Hh signaling interferes with KA″ differentiation. Notch signaling acts permissively to maintain LFP progenitor cells: activation of Notch signaling prevents differentiation, whereas inhibition of Notch signaling results in differentiation of ectopic KA″ cells. These results indicate that neural progenitors depend on Notch signaling to maintain Hh responsiveness and rely on Hh signaling to induce fate identity, whereas proper differentiation depends on the attenuation of both Notch and Hh signaling

A Complex Cell Division Machinery Was Present in the Last Common Ancestor of Eukaryotes

Background: The midbody is a transient complex structure containing proteins involved in cytokinesis. Up to now, it has been described only in Metazoa. Other eukaryotes present a variety of structures implied in the last steps of cell division, such as the septum in fungi or the phragmoplast in plants. However, it is unclear whether these structures are homologous (derive from a common ancestral structure) or analogous (have distinct evolutionary origins). Recently, the proteome of the hamster midbody has been characterized and 160 proteins identified. Methodology/Principal Findings: Using phylogenomic approaches, we show here that nearly all of these 160 proteins (95%) are conserved across metazoan lineages. More surprisingly, we show that a large part of the mammalian midbody components (91 proteins) were already present in the last common ancestor of all eukaryotes (LECA) and were most likely involved in the construction of a complex multi-protein assemblage acting in cell division. Conclusions/Significance: Our results indicate that the midbodies of non-mammalian metazoa are likely very similar to the mammalian one and that the ancestor of Metazoa possessed a nearly modern midbody. Moreover, our analyses support the hypothesis that the midbody and the structures involved in cytokinesis in other eukaryotes derive from a large and complex structure present in LECA, likely involved in cytokinesis. This is an additional argument in favour of the idea of a comple

Natural variation of potato allene oxide synthase 2 causes differential levels of jasmonates and pathogen resistance in Arabidopsis

Natural variation of plant pathogen resistance is often quantitative. This type of resistance can be genetically dissected in quantitative resistance loci (QRL). To unravel the molecular basis of QRL in potato (Solanum tuberosum), we employed the model plant Arabidopsis thaliana for functional analysis of natural variants of potato allene oxide synthase 2 (StAOS2). StAOS2 is a candidate gene for QRL on potato chromosome XI against the oömycete Phytophthora infestans causing late blight, and the bacterium Erwinia carotovora ssp. atroseptica causing stem black leg and tuber soft rot, both devastating diseases in potato cultivation. StAOS2 encodes a cytochrome P450 enzyme that is essential for biosynthesis of the defense signaling molecule jasmonic acid. Allele non-specific dsRNAi-mediated silencing of StAOS2 in potato drastically reduced jasmonic acid production and compromised quantitative late blight resistance. Five natural StAOS2 alleles were expressed in the null Arabidopsis aos mutant under control of the Arabidopsis AOS promoter and tested for differential complementation phenotypes. The aos mutant phenotypes evaluated were lack of jasmonates, male sterility and susceptibility to Erwinia carotovora ssp. carotovora. StAOS2 alleles that were associated with increased disease resistance in potato complemented all aos mutant phenotypes better than StAOS2 alleles associated with increased susceptibility. First structure models of ‘quantitative resistant’ versus ‘quantitative susceptible’ StAOS2 alleles suggested potential mechanisms for their differential activity. Our results demonstrate how a candidate gene approach in combination with using the homologous Arabidopsis mutant as functional reporter can help to dissect the molecular basis of complex traits in non model crop plants

The arabidopsis DNA polymerase δ has a role in the deposition of transcriptionally active epigenetic marks, development and flowering

DNA replication is a key process in living organisms. DNA polymerase α (Polα) initiates strand synthesis, which is performed by Polε and Polδ in leading and lagging strands, respectively. Whereas loss of DNA polymerase activity is incompatible with life, viable mutants of Polα and Polε were isolated, allowing the identification of their functions beyond DNA replication. In contrast, no viable mutants in the Polδ polymerase-domain were reported in multicellular organisms. Here we identify such a mutant which is also thermosensitive. Mutant plants were unable to complete development at 28°C, looked normal at 18°C, but displayed increased expression of DNA replication-stress marker genes, homologous recombination and lysine 4 histone 3 trimethylation at the SEPALLATA3 (SEP3) locus at 24°C, which correlated with ectopic expression of SEP3. Surprisingly, high expression of SEP3 in vascular tissue promoted FLOWERING LOCUS T (FT) expression, forming a positive feedback loop with SEP3 and leading to early flowering and curly leaves phenotypes. These results strongly suggest that the DNA polymerase δ is required for the proper establishment of transcriptionally active epigenetic marks and that its failure might affect development by affecting the epigenetic control of master genes.Fil: Iglesias, Francisco Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Bruera, Natalia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Dergan Dylon, Leonardo Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Marino, Cristina Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Lorenzi, Hernán. J. Craig Venter Institute; Estados UnidosFil: Mateos, Julieta Lisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina. Max Planck Institute for Plant Breeding Research; AlemaniaFil: Turck, Franziska. Max Planck Institute for Plant Breeding Research; AlemaniaFil: Coupland, George. Max Planck Institute for Plant Breeding Research; AlemaniaFil: Cerdan, Pablo Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina. Universidad de Buenos Aires. Departamento de Ciencias Exactas; Argentin

A synergistic ozone-climate control to address emerging ozone pollution challenges

Tropospheric ozone threatens human health and crop yields, exacerbates global warming, and fundamentally changes atmospheric chemistry. Evidence has pointed toward widespread ozone increases in the troposphere, and particularly surface ozone is chemically complex and difficult to abate. Despite past successes in some regions, a solution to new challenges of ozone pollution in a warming climate remains unexplored. In this perspective, by compiling surface measurements at ∼4,300 sites worldwide between 2014 and 2019, we show the emerging global challenge of ozone pollution, featuring the unintentional rise in ozone due to the uncoordinated emissions reduction and increasing climate penalty. On the basis of shared emission sources, interactive chemical mechanisms, and synergistic health effects between ozone pollution and climate warming, we propose a synergistic ozone-climate control strategy incorporating joint control of ozone and fine particulate matter. This new solution presents an opportunity to alleviate tropospheric ozone pollution in the forthcoming low-carbon transition.This study was supported by the Research Grants Council of Hong Kong Special Administrative Region via General Research Funds (HKBU 15219621 and PolyU 15212421) and a Theme-based Research Scheme (T24-504/17-N). The authors acknowledge the support of the Australia–China Centre on Air Quality Science and Management. R.S. acknowledges support from ANID/FONDAP/1522A0001. D.S. thanks the program of Coordination for the Improvement of Higher Education Personnel (CAPES) (436466/2018-0). X.X. acknowledges funding from the Natural Science Foundation of China (41330422) and the Chinese Academy of Meteorological Sciences (2020KJ003). K.L. is supported by the Natural Science Foundation of China (42205114), Jiangsu Carbon Peak and Neutrality Science and Technology Innovation fund (BK20220031), and the Startup Foundation for Introducing Talent of NUIST. We sincerely appreciate all the organizations and programs introduced in the section “experimental procedures” for freely providing ozone data. We thank Dr. Owen Cooper (University of Colorado, Boulder, and NOAA) for insightful guidance and discussion. No organization or program will be responsible for the results generated from their data.Peer reviewe

Molecular psychiatry of zebrafish

Due to their well-characterized neural development and high genetic homology to mammals, zebrafish (Danio rerio) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling central nervous system (CNS) disorders. In particular, we outline recent genetic and technological developments allowing for in vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern molecular psychiatry research