The experiment combined the spatial Stroop paradigm to examine the effect of background location on the perception of arrow or gaze direction in the vertical dimension by manipulating the congruence ...between the target direction and background location, and to validate a possible cognitive mechanism for gaze direction specificity – inhibiting background location. The results showed that when subjects were required to identify the target direction in a Stroop task (Experiment 1), the gaze cue failed to induce the Stroop effect. However, when subjects were required to judge the congruence between the target direction and the background location (Experiment 2), the gaze cue and the arrow cue both induced the Stroop effect. This suggests that “ inhibiting background location” is responsible for the elimination of the spatial Stroop effect by gaze direction, which may one of the mechanisms for gaze direction specificity.
Abstract DNA topoisomerases (topos) are major targets for antimicrobial and chemotherapeutic drugs due to their fundamental roles in regulating DNA topology. Type II topos are essential for ...chromosome segregation and relaxing positive DNA supercoils, and are exemplified by topo II in eukaryotes, topo IV and DNA gyrase in bacteria, and topo VI in archaea. Topo VI occurs ubiquitously in plants and sporadically in bacteria, algae, and other protists and is highly homologous to Spo11, which initiates eukaryotic homologous recombination. This homology makes the two complexes difficult to distinguish by sequence and leads to discrepancies such as the identity of the putative topo VI in malarial Plasmodium species. A lack of understanding of the role and distribution of topo VI outside of archaea hampers its pursuit as a potential drug target, and the present study addresses this with an up-to-date and extensive phylogenetic analysis. We show that the A and B subunits of topo VI and Spo11 can be distinguished using phylogenetics and structural modelling, and that topo VI is not present in Plasmodium nor other members of the phylum Apicomplexa. These findings provide insights into the evolutionary relationships between topo VI and Spo11, and their adoption alongside other type II topos.
The genomes of the fungus Magnaporthe oryzae that causes blast diseases on diverse grass species, including major crops, have indispensable core-chromosomes and may contain supernumerary chromosomes, ...also known as mini-chromosomes. These mini-chromosomes are speculated to provide effector gene mobility, and may transfer between strains. To understand the biology of mini-chromosomes, it is valuable to be able to detect whether a M. oryzae strain possesses a mini-chromosome. Here, we applied recurrent neural network models for classifying DNA sequences as arising from core- or mini-chromosomes. The models were trained with sequences from available core- and mini-chromosome assemblies, and then used to predict the presence of mini-chromosomes in a global collection of M. oryzae isolates using short-read DNA sequences. The model predicted that mini-chromosomes were prevalent in M. oryzae isolates. Interestingly, at least one mini-chromosome was present in all recent wheat isolates, but no mini-chromosomes were found in early isolates collected before 1991, indicating a preferential selection for strains carrying mini-chromosomes in recent years. The model was also used to identify assembled contigs derived from mini-chromosomes. In summary, our study has developed a reliable method for categorizing DNA sequences and showcases an application of recurrent neural networks in predictive genomics.The genomes of the fungus Magnaporthe oryzae that causes blast diseases on diverse grass species, including major crops, have indispensable core-chromosomes and may contain supernumerary chromosomes, also known as mini-chromosomes. These mini-chromosomes are speculated to provide effector gene mobility, and may transfer between strains. To understand the biology of mini-chromosomes, it is valuable to be able to detect whether a M. oryzae strain possesses a mini-chromosome. Here, we applied recurrent neural network models for classifying DNA sequences as arising from core- or mini-chromosomes. The models were trained with sequences from available core- and mini-chromosome assemblies, and then used to predict the presence of mini-chromosomes in a global collection of M. oryzae isolates using short-read DNA sequences. The model predicted that mini-chromosomes were prevalent in M. oryzae isolates. Interestingly, at least one mini-chromosome was present in all recent wheat isolates, but no mini-chromosomes were found in early isolates collected before 1991, indicating a preferential selection for strains carrying mini-chromosomes in recent years. The model was also used to identify assembled contigs derived from mini-chromosomes. In summary, our study has developed a reliable method for categorizing DNA sequences and showcases an application of recurrent neural networks in predictive genomics.
Prokaryotes encode an arsenal of highly diverse immune systems to protect themselves against invading nucleic acids such as viruses, plasmids and transposons. This includes invader-interfering ...systems that neutralize invaders to protect their host, and abortive-infection systems, which trigger dormancy or cell death in their host to offer population-level immunity. Most prokaryotic immune systems are found across different environments and prokaryotic phyla, but their distribution appears biased and the factors that influence their distribution are largely unknown. Here, we compared and combined the prokaryotic immune system identification tools DefenseFinder and PADLOC to obtain an expanded view of the immune system arsenal. Our results show that the number of immune systems encoded is positively correlated with genome size and that the distribution of specific immune systems is linked to phylogeny. Furthermore, we reveal that certain invader-interfering systems are more frequently encoded by hosts with a relatively high optimum growth temperature, while abortive-infection systems are generally more frequently encoded by hosts with a relatively low optimum growth temperature. Combined, our study reveals several factors that correlate with differences in the distribution of prokaryotic immune systems and extends our understanding of how prokaryotes protect themselves from invaders in different environments.Prokaryotes encode an arsenal of highly diverse immune systems to protect themselves against invading nucleic acids such as viruses, plasmids and transposons. This includes invader-interfering systems that neutralize invaders to protect their host, and abortive-infection systems, which trigger dormancy or cell death in their host to offer population-level immunity. Most prokaryotic immune systems are found across different environments and prokaryotic phyla, but their distribution appears biased and the factors that influence their distribution are largely unknown. Here, we compared and combined the prokaryotic immune system identification tools DefenseFinder and PADLOC to obtain an expanded view of the immune system arsenal. Our results show that the number of immune systems encoded is positively correlated with genome size and that the distribution of specific immune systems is linked to phylogeny. Furthermore, we reveal that certain invader-interfering systems are more frequently encoded by hosts with a relatively high optimum growth temperature, while abortive-infection systems are generally more frequently encoded by hosts with a relatively low optimum growth temperature. Combined, our study reveals several factors that correlate with differences in the distribution of prokaryotic immune systems and extends our understanding of how prokaryotes protect themselves from invaders in different environments.
Abstract Increased risk for the development of hepatocellular carcinoma (HCC) is driven by a number of etiological factors including hepatitis viral infection and dietary exposures to foods ...contaminated with aflatoxin-producing molds. Intracellular metabolic activation of aflatoxin B1 (AFB1) to a reactive epoxide generates highly mutagenic AFB1-Fapy-dG adducts. Previously, we demonstrated that repair of AFB1-Fapy-dG adducts can be initiated by the DNA glycosylase NEIL1 and that male Neil1−/− mice were significantly more susceptible to AFB1-induced HCC relative to wild-type mice. To investigate the mechanisms underlying this enhanced carcinogenesis, WT and Neil1−/− mice were challenged with a single, 4 mg/kg dose of AFB1 and frequencies and spectra of mutations were analyzed in liver DNAs 2.5 months post-injection using duplex sequencing. The analyses of DNAs from AFB1-challenged mice revealed highly elevated mutation frequencies in the nuclear genomes of both males and females, but not the mitochondrial genomes. In both WT and Neil1−/− mice, mutation spectra were highly similar to the AFB1-specific COSMIC signature SBS24. Relative to wild-type, the NEIL1 deficiency increased AFB1-induced mutagenesis with concomitant elevated HCCs in male Neil1−/− mice. Our data establish a critical role of NEIL1 in limiting AFB1-induced mutagenesis and ultimately carcinogenesis.
Antibiotic resistance poses a significant global health threat, necessitating innovative strategies to combat multidrug-resistant bacterial infections.
, a pathogen responsible for various ...infections, harbors highly conserved DNA quadruplexes in genes linked to its pathogenesis. In this study, we introduce a novel approach to counter antibiotic resistance by stabilizing G-quadruplex structures within the open reading frames of key resistance-associated genes (
,
and
). We synthesized
, a bis-anthracene derivative, using Cu(I)-catalyzed azide-alkyne cycloaddition, which exhibited remarkable binding and stabilization of the G-quadruplex in the
gene responsible for drug efflux.
effectively permeated multidrug-resistant
strains, leading to a substantial 12.5-fold reduction in ciprofloxacin resistance. Furthermore,
downregulated
gene expression, enhancing drug retention within bacterial cells. Remarkably, the
G-quadruplex cloned into the pET28a(+) plasmid transformed into
BL21 cells can template Cu-free bio-orthogonal synthesis of
from its corresponding alkyne and azide fragments. This study presents a pioneering strategy to combat antibiotic resistance by genetically reducing drug efflux pump expression through G-quadruplex stabilization, offering promising avenues for addressing antibiotic resistance.
Abstract Antibiotic resistance rapidly develops against almost all available therapeutics. Therefore, searching for new antibiotics to overcome the problem of antibiotic resistance alone is ...insufficient. Given that antibiotic resistance can be driven by mutagenesis, an avenue for preventing it is the inhibition of mutagenic processes. We previously showed that the DNA translocase Mfd is mutagenic and accelerates antibiotic resistance development. Here, we present our discovery of a small molecule that inhibits Mfd-dependent mutagenesis, ARM-1 (anti-resistance molecule 1). We found ARM-1 using a high-throughput, small molecule, in vivo screen. Using biochemical assays, we characterized the mechanism by which ARM-1 inhibits Mfd. Critically, we found that ARM-1 reduces mutagenesis and significantly delays antibiotic resistance development across highly divergent bacterial pathogens. These results demonstrate that the mutagenic proteins accelerating evolution can be directly inhibited. Furthermore, our findings suggest that Mfd inhibition, alongside antibiotics, is a potentially effective approach for prevention of antibiotic resistance development during treatment of infections.
Hsp70 (70 kDa heat shock protein) performs molecular chaperone functions by assisting the folding of newly synthesized and misfolded proteins, thereby counteracting various cell stresses and ...preventing multiple diseases, including neurodegenerative disorders and cancers. It is well established that, immediately after heat shock, Hsp70 gene expression is mediated by a canonical mechanism of cap-dependent translation. However, the molecular mechanism of Hsp70 expression during heat shock remains elusive. Intriguingly, the 5' end of Hsp70 messenger RNA (mRNA) appears to form a compact structure with the potential to regulate protein expression in a cap-independent manner. Here, we determined the minimal length of the mHsp70 5'-terminal mRNA sequence that is required for RNA folding into a highly compact structure. This span of this RNA element was mapped and the secondary structure characterized by chemical probing, resulting in a secondary structural model that includes multiple stable stems, including one containing the canonical start codon. All of these components, including a short stretch of the 5' open reading frame (ORF), were shown to be vital for RNA folding. This work provides a structural basis for future investigations on the role of translational regulatory structures in the 5' untranslated region and ORF sequences of Hsp70 during heat shock.
The
Chlorobiales
are anoxygenic phototrophs that produce solid, extracellular elemental sulfur globules as an intermediate step in the oxidation of sulfide to sulfate. These organisms must export ...sulfur while preventing cell encrustation during S
0
globule formation; during globule degradation they must find and mobilize the sulfur for intracellular oxidation to sulfate. To understand how the
Chlorobiales
address these challenges, we characterized the spatial relationships and physical dynamics of
Chlorobaculum tepidum
cells and S
0
globules by light and electron microscopy.
Cba. tepidum
commonly formed globules at a distance from cells. Soluble polysulfides detected during globule production may allow for remote nucleation of globules. Polysulfides were also detected during globule degradation, probably produced as an intermediate of sulfur oxidation by attached cells. Polysulfides could feed unattached cells, which made up over 80% of the population and had comparable growth rates to attached cells. Given that S
0
is formed remotely from cells, there is a question as to how cells are able to move toward S
0
in order to attach. Time-lapse microscopy shows that
Cba. tepidum
is in fact capable of twitching motility, a finding supported by the presence of genes encoding type IV pili. Our results show how
Cba. tepidum
is able to avoid mineral encrustation and benefit from globule degradation even when not attached. In the environment,
Cba. tepidum
may also benefit from soluble sulfur species produced by other sulfur-oxidizing or sulfur-reducing bacteria as these organisms interact with its biogenic S
0
globules.
Why did Europe experience industrialisation and modern economic growth before China, India or Japan? This is one of the most fundamental questions in Economic History and one that has provoked ...intense debate. The main concern of this book is to determine when the gap in living standards between the East and the West emerged. The established view, dating back to Adam Smith, is that the gap emerged long before the Industrial Revolution, perhaps thousands of years ago. While this view has been called into question - and many of the explanations for it greatly undermined - the issue demands much more empirical research than has yet been undertaken. How did the standard of living in Europe and Asia compare in the seventeenth and eighteenth centuries? The present book proposes an answer by considering evidence of three sorts. The first is economic, focusing on income, food production, wages, and prices. The second is demographic, comparing heights, life expectancy and other demographic indicators. The third combines the economic and demographic by investigating the demographic vulnerability to short-term economic stress. The contributions show the highly complex and diverse pattern of the standard of living in the pre-industrial period. The general picture emerging is not one of a great divergence between East and West, but instead one of considerable similarities. These similarities not only pertain to economic aspects of standard of living but also to demography and the sensitivity to economic fluctuations. In addition to these similarities, there were also pronounced regional differences within the East and within the West - regional differences that in many cases were larger than the average differences between Europe and Asia. This clearly highlights the importance of analysing several dimensions of the standard of living, as well as the danger of neglecting regional, social, and household specific differences when assessing the level of well-being in the past. Available in OSO: http://www.oxfordscholarship.com/oso/public/content/economicsfinance/0199280681/toc.html Contributors to this volume - Kenneth Pomeranz, University of California, Irvine Li Bozhong, Tsinghua University Osamu Saito, Hitotsubashi University Prasannan Parthasarathi, Boston College Robert C. Allen, Oxford University P. Hoffman, D. Jacks, P. Levin and P. Lindert, California Institute of Technology and University of California, Davis Jan Luiten van Zanden, IISG Jaime Reis, University of Lisbon Richard Steckel, Ohio State University Boris Mironov, St. Petersburg State University E. Hammel and A. Gullickson, University of California, Berkley and Columbia University Hans Christian Johansen, University of Southern Denmark M. Breschi, A. Fornasin, and G. Gonano, University of Udine T. Bengtsson and M. Dribe, Lund University M. Oris, G. Alter and M. Neven, University of Geneva, Indiana University and University of Liege C. Campbell and J. Lee, UCLA and University of Michigan N.Tsuya and S. Kurosu, Keio University and Keitaku University
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