@article{15257,
abstract = {Root gravitropic bending represents a fundamental aspect of terrestrial plant physiology. Gravity is perceived by sedimentation of starch-rich plastids (statoliths) to the bottom of the central root cap cells. Following gravity perception, intercellular auxin transport is redirected downwards leading to an asymmetric auxin accumulation at the lower root side causing inhibition of cell expansion, ultimately resulting in downwards bending. How gravity-induced statoliths repositioning is translated into asymmetric auxin distribution remains unclear despite PIN auxin efflux carriers and the Negative Gravitropic Response of roots (NGR) proteins polarize along statolith sedimentation, thus providing a plausible mechanism for auxin flow redirection. In this study, using a functional NGR1-GFP construct, we visualized the NGR1 localization on the statolith surface and plasma membrane (PM) domains in close proximity to the statoliths, correlating with their movements. We determined that NGR1 binding to these PM domains is indispensable for NGR1 functionality and relies on cysteine acylation and adjacent polybasic regions as well as on lipid and sterol PM composition. Detailed timing of the early events following graviperception suggested that both NGR1 repolarization and initial auxin asymmetry precede the visible PIN3 polarization. This discrepancy motivated us to unveil a rapid, NGR-dependent translocation of PIN-activating AGCVIII kinase D6PK towards lower PMs of gravity-perceiving cells, thus providing an attractive model for rapid redirection of auxin fluxes following gravistimulation.},
author = {Kulich, Ivan and Schmid, Julia and Teplova, Anastasiia and Qi, Linlin and Friml, Jiří},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Rapid translocation of NGR proteins driving polarization of PIN-activating D6 protein kinase during root gravitropism}},
doi = {10.7554/elife.91523},
volume = {12},
year = {2024},
}
@article{14683,
abstract = {Mosaic analysis with double markers (MADM) technology enables the generation of genetic mosaic tissue in mice and high-resolution phenotyping at the individual cell level. Here, we present a protocol for isolating MADM-labeled cells with high yield for downstream molecular analyses using fluorescence-activated cell sorting (FACS). We describe steps for generating MADM-labeled mice, perfusion, single-cell suspension, and debris removal. We then detail procedures for cell sorting by FACS and downstream analysis. This protocol is suitable for embryonic to adult mice.
For complete details on the use and execution of this protocol, please refer to Contreras et al. (2021).1},
author = {Amberg, Nicole and Cheung, Giselle T and Hippenmeyer, Simon},
issn = {2666-1667},
journal = {STAR Protocols},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Neuroscience},
number = {1},
publisher = {Elsevier},
title = {{Protocol for sorting cells from mouse brains labeled with mosaic analysis with double markers by flow cytometry}},
doi = {10.1016/j.xpro.2023.102771},
volume = {5},
year = {2024},
}
@article{15033,
abstract = {The GNOM (GN) Guanine nucleotide Exchange Factor for ARF small GTPases (ARF-GEF) is among the best studied trafficking regulators in plants, playing crucial and unique developmental roles in patterning and polarity. The current models place GN at the Golgi apparatus (GA), where it mediates secretion/recycling, and at the plasma membrane (PM) presumably contributing to clathrin-mediated endocytosis (CME). The mechanistic basis of the developmental function of GN, distinct from the other ARF-GEFs including its closest homologue GNOM-LIKE1 (GNL1), remains elusive. Insights from this study largely extend the current notions of GN function. We show that GN, but not GNL1, localizes to the cell periphery at long-lived structures distinct from clathrin-coated pits, while CME and secretion proceed normally in gn knockouts. The functional GN mutant variant GNfewerroots, absent from the GA, suggests that the cell periphery is the major site of GN action responsible for its developmental function. Following inhibition by Brefeldin A, GN, but not GNL1, relocates to the PM likely on exocytic vesicles, suggesting selective molecular associations en route to the cell periphery. A study of GN-GNL1 chimeric ARF-GEFs indicates that all GN domains contribute to the specific GN function in a partially redundant manner. Together, this study offers significant steps toward the elucidation of the mechanism underlying unique cellular and development functions of GNOM.},
author = {Adamowski, Maciek and Matijevic, Ivana and Friml, Jiří},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Developmental patterning function of GNOM ARF-GEF mediated from the cell periphery}},
doi = {10.7554/elife.68993},
volume = {13},
year = {2024},
}
@article{12117,
abstract = {To understand how potential gene manipulations affect in vitro microglia, we provide a set of short protocols to evaluate microglia identity and function. We detail steps for immunostaining to determine microglia identity. We describe three functional assays for microglia: phagocytosis, calcium response following ATP stimulation, and cytokine expression upon inflammatory stimuli. We apply these protocols to human induced-pluripotent-stem-cell (hiPSC)-derived microglia, but they can be also applied to other in vitro microglial models including primary mouse microglia.
For complete details on the use and execution of this protocol, please refer to Bartalska et al. (2022).1},
author = {Hübschmann, Verena and Korkut, Medina and Siegert, Sandra},
issn = {2666-1667},
journal = {STAR Protocols},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Neuroscience},
number = {4},
publisher = {Elsevier},
title = {{Assessing human iPSC-derived microglia identity and function by immunostaining, phagocytosis, calcium activity, and inflammation assay}},
doi = {10.1016/j.xpro.2022.101866},
volume = {3},
year = {2022},
}
@article{12157,
abstract = {Polygenic adaptation is thought to be ubiquitous, yet remains poorly understood. Here, we model this process analytically, in the plausible setting of a highly polygenic, quantitative trait that experiences a sudden shift in the fitness optimum. We show how the mean phenotype changes over time, depending on the effect sizes of loci that contribute to variance in the trait, and characterize the allele dynamics at these loci. Notably, we describe the two phases of the allele dynamics: The first is a rapid phase, in which directional selection introduces small frequency differences between alleles whose effects are aligned with or opposed to the shift, ultimately leading to small differences in their probability of fixation during a second, longer phase, governed by stabilizing selection. As we discuss, key results should hold in more general settings and have important implications for efforts to identify the genetic basis of adaptation in humans and other species.},
author = {Hayward, Laura and Sella, Guy},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Polygenic adaptation after a sudden change in environment}},
doi = {10.7554/elife.66697},
volume = {11},
year = {2022},
}
@article{12173,
abstract = {With increasing urbanization and industrialization, the prevalence of inflammatory bowel diseases (IBDs) has steadily been rising over the past two decades. IBD involves flares of gastrointestinal (GI) inflammation accompanied by microbiota perturbations. However, microbial mechanisms that trigger such flares remain elusive. Here, we analyzed the association of the emerging pathogen atypical enteropathogenic E. coli (aEPEC) with IBD disease activity. The presence of diarrheagenic E. coli was assessed in stool samples from 630 IBD patients and 234 age- and sex-matched controls without GI symptoms. Microbiota was analyzed with 16S ribosomal RNA gene amplicon sequencing, and 57 clinical aEPEC isolates were subjected to whole-genome sequencing and in vitro pathogenicity experiments including biofilm formation, epithelial barrier function and the ability to induce pro-inflammatory signaling. The presence of aEPEC correlated with laboratory, clinical and endoscopic disease activity in ulcerative colitis (UC), as well as microbiota dysbiosis. In vitro, aEPEC strains induce epithelial p21-activated kinases, disrupt the epithelial barrier and display potent biofilm formation. The effector proteins espV and espG2 distinguish aEPEC cultured from UC and Crohn’s disease patients, respectively. EspV-positive aEPEC harbor more virulence factors and have a higher pro-inflammatory potential, which is counteracted by 5-ASA. aEPEC may tip a fragile immune–microbiota homeostasis and thereby contribute to flares in UC. aEPEC isolates from UC patients display properties to disrupt the epithelial barrier and to induce pro-inflammatory signaling in vitro.},
author = {Baumgartner, Maximilian and Zirnbauer, Rebecca and Schlager, Sabine and Mertens, Daniel and Gasche, Nikolaus and Sladek, Barbara and Herbold, Craig and Bochkareva, Olga and Emelianenko, Vera and Vogelsang, Harald and Lang, Michaela and Klotz, Anton and Moik, Birgit and Makristathis, Athanasios and Berry, David and Dabsch, Stefanie and Khare, Vineeta and Gasche, Christoph},
issn = {1949-0984},
journal = {Gut Microbes},
keywords = {Infectious Diseases, Microbiology (medical), Gastroenterology, Microbiology},
number = {1},
publisher = {Taylor & Francis},
title = {{Atypical enteropathogenic E. coli are associated with disease activity in ulcerative colitis}},
doi = {10.1080/19490976.2022.2143218},
volume = {14},
year = {2022},
}
@article{12261,
abstract = {Dose–response relationships are a general concept for quantitatively describing biological systems across multiple scales, from the molecular to the whole-cell level. A clinically relevant example is the bacterial growth response to antibiotics, which is routinely characterized by dose–response curves. The shape of the dose–response curve varies drastically between antibiotics and plays a key role in treatment, drug interactions, and resistance evolution. However, the mechanisms shaping the dose–response curve remain largely unclear. Here, we show in Escherichia coli that the distinctively shallow dose–response curve of the antibiotic trimethoprim is caused by a negative growth-mediated feedback loop: Trimethoprim slows growth, which in turn weakens the effect of this antibiotic. At the molecular level, this feedback is caused by the upregulation of the drug target dihydrofolate reductase (FolA/DHFR). We show that this upregulation is not a specific response to trimethoprim but follows a universal trend line that depends primarily on the growth rate, irrespective of its cause. Rewiring the feedback loop alters the dose–response curve in a predictable manner, which we corroborate using a mathematical model of cellular resource allocation and growth. Our results indicate that growth-mediated feedback loops may shape drug responses more generally and could be exploited to design evolutionary traps that enable selection against drug resistance.},
author = {Angermayr, Andreas and Pang, Tin Yau and Chevereau, Guillaume and Mitosch, Karin and Lercher, Martin J and Bollenbach, Mark Tobias},
issn = {1744-4292},
journal = {Molecular Systems Biology},
keywords = {Applied Mathematics, Computational Theory and Mathematics, General Agricultural and Biological Sciences, General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, Information Systems},
number = {9},
publisher = {Embo Press},
title = {{Growth‐mediated negative feedback shapes quantitative antibiotic response}},
doi = {10.15252/msb.202110490},
volume = {18},
year = {2022},
}
@article{12288,
abstract = {To understand the function of neuronal circuits, it is crucial to disentangle the connectivity patterns within the network. However, most tools currently used to explore connectivity have low throughput, low selectivity, or limited accessibility. Here, we report the development of an improved packaging system for the production of the highly neurotropic RVdGenvA-CVS-N2c rabies viral vectors, yielding titers orders of magnitude higher with no background contamination, at a fraction of the production time, while preserving the efficiency of transsynaptic labeling. Along with the production pipeline, we developed suites of ‘starter’ AAV and bicistronic RVdG-CVS-N2c vectors, enabling retrograde labeling from a wide range of neuronal populations, tailored for diverse experimental requirements. We demonstrate the power and flexibility of the new system by uncovering hidden local and distal inhibitory connections in the mouse hippocampal formation and by imaging the functional properties of a cortical microcircuit across weeks. Our novel production pipeline provides a convenient approach to generate new rabies vectors, while our toolkit flexibly and efficiently expands the current capacity to label, manipulate and image the neuronal activity of interconnected neuronal circuits in vitro and in vivo.},
author = {Sumser, Anton L and Jösch, Maximilian A and Jonas, Peter M and Ben Simon, Yoav},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Fast, high-throughput production of improved rabies viral vectors for specific, efficient and versatile transsynaptic retrograde labeling}},
doi = {10.7554/elife.79848},
volume = {11},
year = {2022},
}
@article{10639,
abstract = {With more than 80 members worldwide, the Orthobunyavirus genus in the Peribunyaviridae family is a large genus of enveloped RNA viruses, many of which are emerging pathogens in humans and livestock. How orthobunyaviruses (OBVs) penetrate and infect mammalian host cells remains poorly characterized. Here, we investigated the entry mechanisms of the OBV Germiston (GERV). Viral particles were visualized by cryo-electron microscopy and appeared roughly spherical with an average diameter of 98 nm. Labeling of the virus with fluorescent dyes did not adversely affect its infectivity and allowed the monitoring of single particles in fixed and live cells. Using this approach, we found that endocytic internalization of bound viruses was asynchronous and occurred within 30-40 min. The virus entered Rab5a+ early endosomes and, subsequently, late endosomal vacuoles containing Rab7a but not LAMP-1. Infectious entry did not require proteolytic cleavage, and endosomal acidification was sufficient and necessary for viral fusion. Acid-activated penetration began 15-25 min after initiation of virus internalization and relied on maturation of early endosomes to late endosomes. The optimal pH for viral membrane fusion was slightly below 6.0, and penetration was hampered when the potassium influx was abolished. Overall, our study provides real-time visualization of GERV entry into host cells and demonstrates the importance of late endosomal maturation in facilitating OBV penetration.},
author = {Windhaber, Stefan and Xin, Qilin and Uckeley, Zina M. and Koch, Jana and Obr, Martin and Garnier, Céline and Luengo-Guyonnot, Catherine and Duboeuf, Maëva and Schur, Florian KM and Lozach, Pierre-Yves},
issn = {1098-5514},
journal = {Journal of Virology},
keywords = {virology, insect science, immunology, microbiology},
number = {5},
publisher = {American Society for Microbiology},
title = {{The Orthobunyavirus Germiston enters host cells from late endosomes}},
doi = {10.1128/jvi.02146-21},
volume = {96},
year = {2022},
}
@article{10812,
abstract = {Several promising strategies based on combining or cycling different antibiotics have been proposed to increase efficacy and counteract resistance evolution, but we still lack a deep understanding of the physiological responses and genetic mechanisms that underlie antibiotic interactions and the clinical applicability of these strategies. In antibiotic-exposed bacteria, the combined effects of physiological stress responses and emerging resistance mutations (occurring at different time scales) generate complex and often unpredictable dynamics. In this Review, we present our current understanding of bacterial cell physiology and genetics of responses to antibiotics. We emphasize recently discovered mechanisms of synergistic and antagonistic drug interactions, hysteresis in temporal interactions between antibiotics that arise from microbial physiology and interactions between antibiotics and resistance mutations that can cause collateral sensitivity or cross-resistance. We discuss possible connections between the different phenomena and indicate relevant research directions. A better and more unified understanding of drug and genetic interactions is likely to advance antibiotic therapy.},
author = {Römhild, Roderich and Bollenbach, Mark Tobias and Andersson, Dan I.},
issn = {1740-1534},
journal = {Nature Reviews Microbiology},
keywords = {General Immunology and Microbiology, Microbiology, Infectious Diseases},
pages = {478--490},
publisher = {Springer Nature},
title = {{The physiology and genetics of bacterial responses to antibiotic combinations}},
doi = {10.1038/s41579-022-00700-5},
volume = {20},
year = {2022},
}
@article{11448,
abstract = {Studies of protein fitness landscapes reveal biophysical constraints guiding protein evolution and empower prediction of functional proteins. However, generalisation of these findings is limited due to scarceness of systematic data on fitness landscapes of proteins with a defined evolutionary relationship. We characterized the fitness peaks of four orthologous fluorescent proteins with a broad range of sequence divergence. While two of the four studied fitness peaks were sharp, the other two were considerably flatter, being almost entirely free of epistatic interactions. Mutationally robust proteins, characterized by a flat fitness peak, were not optimal templates for machine-learning-driven protein design – instead, predictions were more accurate for fragile proteins with epistatic landscapes. Our work paves insights for practical application of fitness landscape heterogeneity in protein engineering.},
author = {Gonzalez Somermeyer, Louisa and Fleiss, Aubin and Mishin, Alexander S and Bozhanova, Nina G and Igolkina, Anna A and Meiler, Jens and Alaball Pujol, Maria-Elisenda and Putintseva, Ekaterina V and Sarkisyan, Karen S and Kondrashov, Fyodor},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Heterogeneity of the GFP fitness landscape and data-driven protein design}},
doi = {10.7554/elife.75842},
volume = {11},
year = {2022},
}
@article{15138,
abstract = {RNA viruses induce the formation of subcellular organelles that provide microenvironments conducive to their replication. Here we show that replication factories of rotaviruses represent protein‐RNA condensates that are formed via liquid–liquid phase separation of the viroplasm‐forming proteins NSP5 and rotavirus RNA chaperone NSP2. Upon mixing, these proteins readily form condensates at physiologically relevant low micromolar concentrations achieved in the cytoplasm of virus‐infected cells. Early infection stage condensates could be reversibly dissolved by 1,6‐hexanediol, as well as propylene glycol that released rotavirus transcripts from these condensates. During the early stages of infection, propylene glycol treatments reduced viral replication and phosphorylation of the condensate‐forming protein NSP5. During late infection, these condensates exhibited altered material properties and became resistant to propylene glycol, coinciding with hyperphosphorylation of NSP5. Some aspects of the assembly of cytoplasmic rotavirus replication factories mirror the formation of other ribonucleoprotein granules. Such viral RNA‐rich condensates that support replication of multi‐segmented genomes represent an attractive target for developing novel therapeutic approaches.},
author = {Geiger, Florian and Acker, Julia and Papa, Guido and Wang, Xinyu and Arter, William E and Saar, Kadi L and Erkamp, Nadia A and Qi, Runzhang and Bravo, Jack Peter Kelly and Strauss, Sebastian and Krainer, Georg and Burrone, Oscar R and Jungmann, Ralf and Knowles, Tuomas PJ and Engelke, Hanna and Borodavka, Alexander},
issn = {1460-2075},
journal = {The EMBO Journal},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, Molecular Biology, General Neuroscience},
number = {21},
publisher = {Embo Press},
title = {{Liquid–liquid phase separation underpins the formation of replication factories in rotaviruses}},
doi = {10.15252/embj.2021107711},
volume = {40},
year = {2021},
}
@article{15270,
abstract = {Various toxic compounds disrupt bacterial physiology. While bacteria harbor defense mechanisms to mitigate the toxicity, these mechanisms are often coupled to the physiological state of the cells and become ineffective when the physiology is severely disrupted.},
author = {Le, Dai and Krasnopeeva, Ekaterina and Sinjab, Faris and Pilizota, Teuta and Kim, Minsu},
issn = {2150-7511},
journal = {mBio},
keywords = {Virology, Microbiology},
number = {4},
publisher = {American Society for Microbiology},
title = {{Active efflux leads to heterogeneous dissipation of proton motive force by protonophores in bacteria}},
doi = {10.1128/mbio.00676-21},
volume = {12},
year = {2021},
}
@article{15273,
abstract = {Synapses of glutamatergic mossy fibers (MFs) onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBC’s large dendritic brush. Using mouse brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBCs. The source of this ambient glutamate was spontaneous, spike-independent exocytosis from the MF terminal, and its level was dependent on activity of glutamate transporters EAAT1–2. Increasing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission.},
author = {Balmer, Timothy S and Borges Merjane, Carolina and Trussell, Laurence O},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse}},
doi = {10.7554/elife.63819},
volume = {10},
year = {2021},
}
@article{15274,
abstract = {Copper (Cu) is a redox-active micronutrient that is both essential and toxic. Its cellular homeostasis is critical for supporting cuproprotein maturation while avoiding excessive oxidative stress. The Cu importer CcoA is the prototype of the widespread CalT subfamily of the MFS-type transporters. Hence, understanding its molecular mechanism of function is significant. Here, we show that CcoA undergoes a thiol:disulfide oxidoreduction cycle, which is important for its Cu import activity.},
author = {Khalfaoui-Hassani, Bahia and Trasnea, Petru Iulian and Steimle, Stefan and Koch, Hans-Georg and Daldal, Fevzi},
issn = {2150-7511},
journal = {mBio},
keywords = {Virology, Microbiology},
number = {4},
publisher = {American Society for Microbiology},
title = {{Cysteine mutants of the major facilitator superfamily-type transporter CcoA provide insight into copper import}},
doi = {10.1128/mbio.01567-21},
volume = {12},
year = {2021},
}
@article{15276,
abstract = {Biotrophic plant pathogens secrete effector proteins to manipulate the host physiology. Effectors suppress defenses and induce an environment favorable to disease development. Sequence-based prediction of effector function is impeded by their rapid evolution rate. In the maize pathogen Ustilago maydis, effector-coding genes frequently organize in clusters. Here we describe the functional characterization of the pleiades, a cluster of ten effector genes, by analyzing the micro- and macroscopic phenotype of the cluster deletion and expressing these proteins in planta. Deletion of the pleiades leads to strongly impaired virulence and accumulation of reactive oxygen species (ROS) in infected tissue. Eight of the Pleiades suppress the production of ROS upon perception of pathogen associated molecular patterns (PAMPs). Although functionally redundant, the Pleiades target different host components. The paralogs Taygeta1 and Merope1 suppress ROS production in either the cytoplasm or nucleus, respectively. Merope1 targets and promotes the auto-ubiquitination activity of RFI2, a conserved family of E3 ligases that regulates the production of PAMP-triggered ROS burst in plants.},
author = {Navarrete, Fernando and Grujic, Nenad and Stirnberg, Alexandra and Saado, Indira and Aleksza, David and Gallei, Michelle C and Adi, Hazem and Alcântara, André and Khan, Mamoona and Bindics, Janos and Trujillo, Marco and Djamei, Armin},
issn = {1553-7374},
journal = {PLOS Pathogens},
keywords = {Virology, Genetics, Molecular Biology, Immunology, Microbiology, Parasitology},
number = {6},
publisher = {Public Library of Science},
title = {{The Pleiades are a cluster of fungal effectors that inhibit host defenses}},
doi = {10.1371/journal.ppat.1009641},
volume = {17},
year = {2021},
}
@article{10271,
abstract = {Understanding interactions between antibiotics used in combination is an important theme in microbiology. Using the interactions between the antifolate drug trimethoprim and the ribosome-targeting antibiotic erythromycin in Escherichia coli as a model, we applied a transcriptomic approach for dissecting interactions between two antibiotics with different modes of action. When trimethoprim and erythromycin were combined, the transcriptional response of genes from the sulfate reduction pathway deviated from the dominant effect of trimethoprim on the transcriptome. We successfully altered the drug interaction from additivity to suppression by increasing the sulfate level in the growth environment and identified sulfate reduction as an important metabolic determinant that shapes the interaction between the two drugs. Our work highlights the potential of using prioritization of gene expression patterns as a tool for identifying key metabolic determinants that shape drug-drug interactions. We further demonstrated that the sigma factor-binding protein gene crl shapes the interactions between the two antibiotics, which provides a rare example of how naturally occurring variations between strains of the same bacterial species can sometimes generate very different drug interactions.},
author = {Qi, Qin and Angermayr, S. Andreas and Bollenbach, Mark Tobias},
issn = {1664-302X},
journal = {Frontiers in Microbiology},
keywords = {microbiology},
publisher = {Frontiers},
title = {{Uncovering Key Metabolic Determinants of the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia coli}},
doi = {10.3389/fmicb.2021.760017},
volume = {12},
year = {2021},
}
@article{10301,
abstract = {De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.},
author = {Conde-Dusman, María J and Dey, Partha N and Elía-Zudaire, Óscar and Garcia Rabaneda, Luis E and García-Lira, Carmen and Grand, Teddy and Briz, Victor and Velasco, Eric R and Andero Galí, Raül and Niñerola, Sergio and Barco, Angel and Paoletti, Pierre and Wesseling, John F and Gardoni, Fabrizio and Tavalin, Steven J and Perez-Otaño, Isabel},
issn = {2050-084X},
journal = {eLife},
keywords = {general immunology and microbiology, general biochemistry, genetics and molecular biology, general medicine, general neuroscience},
publisher = {eLife Sciences Publications},
title = {{Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly}},
doi = {10.7554/elife.71575},
volume = {10},
year = {2021},
}
@article{9387,
abstract = {We report the complete analysis of a deterministic model of deleterious mutations and negative selection against them at two haploid loci without recombination. As long as mutation is a weaker force than selection, mutant alleles remain rare at the only stable equilibrium, and otherwise, a variety of dynamics are possible. If the mutation-free genotype is absent, generally the only stable equilibrium is the one that corresponds to fixation of the mutant allele at the locus where it is less deleterious. This result suggests that fixation of a deleterious allele that follows a click of the Muller’s ratchet is governed by natural selection, instead of random drift.},
author = {Khudiakova, Kseniia and Neretina, Tatiana Yu. and Kondrashov, Alexey S.},
issn = {0022-5193},
journal = {Journal of Theoretical Biology},
keywords = {General Biochemistry, Genetics and Molecular Biology, Modelling and Simulation, Statistics and Probability, General Immunology and Microbiology, Applied Mathematics, General Agricultural and Biological Sciences, General Medicine},
publisher = {Elsevier },
title = {{Two linked loci under mutation-selection balance and Muller’s ratchet}},
doi = {10.1016/j.jtbi.2021.110729},
volume = {524},
year = {2021},
}
@article{15153,
abstract = {Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24 hr periodicity. Here we pinpoint a key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind the BMAL1 transactivation domain similarly to sequester it from coactivators and repress CLOCK:BMAL1 activity. However, we find that CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We discovered a dynamic serine-rich loop adjacent to the secondary pocket in the photolyase homology region (PHR) domain that regulates differential binding of cryptochromes to the PAS domain core of CLOCK:BMAL1. Notably, binding of the co-repressor PER2 remodels the serine loop of CRY2, making it more CRY1-like and enhancing its affinity for CLOCK:BMAL1.},
author = {Fribourgh, Jennifer L and Srivastava, Ashutosh and Sandate, Colby R and Michael, Alicia Kathleen and Hsu, Peter L and Rakers, Christin and Nguyen, Leslee T and Torgrimson, Megan R and Parico, Gian Carlo G and Tripathi, Sarvind and Zheng, Ning and Lander, Gabriel C and Hirota, Tsuyoshi and Tama, Florence and Partch, Carrie L},
issn = {2050-084X},
journal = {eLife},
keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
publisher = {eLife Sciences Publications},
title = {{Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing}},
doi = {10.7554/elife.55275},
volume = {9},
year = {2020},
}