bluuebunny/crossref_metadata_2025 huggingface dataset:
Seeing through noise in power laws
Authors: Lin Qianying , Newberry Mitchell
Published: August 2023

Despite widespread claims of power laws across the natural and social sciences, evidence in data is often equivocal. Modern data and statistical methods reject even classic power laws such as Pareto’s law of wealth and the Gutenberg–Richter law for earthquake magnitudes. We show that the maximum-likelihood estimators and Kolmogorov–Smirnov (K-S) statistics in widespread use are unexpectedly sensitive to ubiquitous errors in data such as measurement noise, quantization noise, heaping and censorship of small values. This sensitivity causes spurious rejection of power laws and biases parameter estimates even in arbitrarily large samples, which explains inconsistencies between theory and data. We show that logarithmic binning by powers ofλ> 1 attenuates these errors in a manner analogous to noise averaging in normal statistics and thatλthereby tunes a trade-off between accuracy and precision in estimation. Binning also removes potentially misleading within-scale information while preserving information about the shape of a distribution over powers ofλ, and we show that some amount of binning can improve sensitivity and specificity of K-S tests without any cost, while more extreme binning tunes a trade-off between sensitivity and specificity. We therefore advocate logarithmic binning as a simple essential step in power-law inference.
The ‘seductive scientist’: the emergence of a new persona centred on virility and joy in twentieth-century scientific memoirs
Authors: Drakman Annelie
Published: August 2023

This text investigates the twentieth-century scientific memoir genre from the perspective of two of its perhaps most influential contributors, the American Nobel laureates Richard Feynman and James Watson, by using theoretical tools from masculinity studies and the studies of scientific personae. The term ‘the seductive scientist’ is proposed to describe the main innovation to scientific personae that Watson introduces and Feynman perfects: a scientist who is brutally honest, openly seeks joy and fun, and is interested in sexual conquests. To include these topics is deliberately provocative in relation to earlier scientific personae, most importantly ‘the reverential scientist’, aiming for gravitas and depicting the scientific life as revolving around awe. As is shown, however, the seductive scientist, for all its bravado, is actually a persona which only promotes mild, non-disruptive rebellion. Rather than actually challenging the system, it incorporates several aspects of counter-cultural critique against science, showing it to not be pompous, conformist and boring, but rather fun, exciting and full of life. This reconfiguration of self-presentations by scientists, then, strongly influences the scientific memoir as a genre, affecting the ability of scientists to speak in the name of science.
Epidemiology and characterization of Providencia stuartii isolated from hospitalized patients in southern Brazil: A possible emerging pathogen
Authors: Guidone Gustavo Henrique Migliorini , Cardozo Jennifer Germiniani , Silva Luana Carvalho , Sanches Matheus Silva , Galhardi Ligia Carla Faccin , Kobayashi Renata Katsuko Takayama , Vespero Eliana Carolina , Rocha Sergio Paulo Dejato
Published: August 2023

The study aimed to characterize the virulence factors and antimicrobial resistance of Providencia stuartii, an opportunistic pathogen that causes infections in humans. Were examined the 45 isolates of P. stuartii genotypically and phenotypically by studying their adherence to HeLa cells, biofilm formation, cytotoxicity, and antimicrobial resistance, and analyzing their genomes for putative virulence and resistance genes. The study found that most isolates possessed multiple virulence genes, including fimA, mrkA, fptA, iutA, ireA and hlyA and were cytotoxic to Vero cells. All isolates were resistant to amoxicillin plus clavulanic acid, levofloxacin, and sulfamethoxazole plus trimethoprim, and most were resistant to ceftriaxone and cefepime. All isolates harbored extended spectrum beta-lactamases coding genes such as blaCTX-M-2 and 23/45 (51.11%) also harbored blaCTX-M-9 genes. The gene KPC-2 (carbapenemase) were found in 8/45 (17.77%) of isolates. The study also found clonality among the isolates, indicating the possible spread of the pathogen among patients at the hospital. The results have significant clinical and epidemiological implications and emphasize the importance of continued understanding of the virulence and antimicrobial resistance of this pathogen for the prevention and treatment of future infections.
Three Klebsiella pneumoniae lineages causing bloodstream infections variably dominated within a Greek hospital over a 15 year period
Authors: Afolayan Ayorinde O. , Rigatou Anastasia , Grundmann Hajo , Pantazatou Angeliki , Daikos George , Reuter Sandra
Published: August 2023

Carbapenem-resistant

Klebsiella pneumoniae

(CRKP) has emerged as a major clinical and public health threat. The rapid dissemination of this pathogen is driven by several successful clones worldwide. We aimed to investigate the CRKP clonal lineages, their antibiotic resistance determinants and their potential transmissions in a tertiary care hospital located in Athens, Greece. Between 2003 and 2018, 392 CRKP isolates from bloodstream infections were recovered from hospitalized patients. Whole genome sequencing (WGS) was performed on the Illumina platform to characterize 209 of these isolates. In total, 74 % (n=155) of 209 isolates belonged to three major clonal lineages: ST258 (n=108), ST147 (n=29) and ST11 (n=18). Acquired carbapenemase genes were the mechanisms of resistance in 205 isolates (bla
KPC, n=123; bla
VIM, n=56; bla
NDM, n=20; bla
OXA-48, n=6). Strong associations (P=0.0004) were observed between carbapenemase genes and clonal lineages. We first isolated bla
VIM-1-carrying ST147 strains during the early sampling period in 2003, followed by the emergence of bla
KPC-2-carrying ST258 in 2006 and bla
NDM-1-carrying ST11 in 2013. Analysis of genetic distances between the isolates revealed six potential transmission events. When contextualizing the current collection with published data, ST147 reflected the global diversity, ST258 clustered with isolates representing the first introduction into Europe and ST11 formed a distinct geographically restricted lineage indicative of local spread. This study demonstrates the changing profile of bloodstream CRKP in a tertiary care hospital over a 15 year period and underlines the need for continued genomic surveys to develop strategies to contain further dissemination. This article contains data hosted by Microreact.
In Vivo Antiviral Efficacy of LCTG-002, a Pooled, Purified Human Milk Secretory IgA product, Against SARS-CoV-2 in a Murine Model of COVID-19
Authors: Mane Viraj , Mehta Rikin , Alvarez Nadine , Sharma Vijeta , Park Steven , Fox Alisa , DeCarlo Claire , Yang Xiaoqi , Perlin David S. , Powell Rebecca L.R.
Published: August 2023

Immunoglobulin A (IgA) is the most abundant antibody (Ab) in human mucosal compartments including the respiratory tract, with the secretory form of IgA (sIgA) being dominant and uniquely stable in these environments. sIgA is naturally found in human milk, which could be considered a global resource for this biologic, justifying the development of human milk sIgA as a dedicated airway therapeutic for respiratory infections such as SARS-CoV-2. In the present study, methods were therefore developed to efficiently extract human milk sIgA from donors who were either immunologically naïve to SARS-CoV-2 (pooled as a control IgA) or had recovered from a PCR-confirmed SARS-CoV-2 infection that elicited high-titer anti-SARS-CoV-2 Spike sIgA Abs in their milk (pooled together to make LCTG-002). Mass spectrometry determined that proteins with a relative abundance of 1.0% or greater were all associated with sIgA. None of the proteins exhibited statistically significant differences between batches. Western blot demonstrated all batches consisted predominantly of sIgA. Compared to control IgA, LCTG-002 demonstrated significantly higher binding to Spike, and was also capable of blocking the Spike - ACE2 interaction in vitro with 6.3x greater potency compared to control IgA (58% inhibition at ∼240ug/mL). LCTG-002 was then tested in vivo for its capacity to reduce viral burden in the lungs of K18+hACE2 transgenic mice inoculated with SARS-CoV-2. LCTG-002 was demonstrated to significantly reduce SARS-CoV-2 titers in the lungs compared to control IgA when administered at either 250ug/day or 1 mg/day, as measured by TCID50, plaque forming units (PFU), and qRT-PCR, with a maximum reduction of 4.9 logs. This innovative study demonstrates that LCTG-002 is highly pure, efficacious, and well tolerated in vivo, supporting further development of milk-derived, polyclonal sIgA therapeutics against SARS-CoV-2 and other mucosal infections.
Brain mechanisms underlying the emotion processing bias in treatment-resistant depression
Authors: Fan Xiaoxu , Mocchi Madaline , Pascuzzi Bailey , Xiao Jiayang , Metzger Brian A. , Mathura Raissa K. , Hacker Carl , Adkinson Joshua A. , Bartoli Eleonora , Elhassa Salma , Watrous Andrew J. , Zhang Yue , Goodman Wayne , Pouratian Nader , Bijanki Kelly R.
Published: August 2023

Depression is associated with a cognitive bias towards negative information and away from positive information. This biased emotion processing may underlie core depression symptoms, including persistent feelings of sadness or low mood and a reduced capacity to experience pleasure. The neural mechanisms responsible for this biased emotion processing remain unknown. Here, we had a unique opportunity to record stereotactic electroencephalography (sEEG) signals in the amygdala and prefrontal cortex (PFC) from 5 treatment-resistant depression (TRD) patients and 12 epilepsy patients (as control) while they participated in an affective bias task in which happy and sad faces were rated. First, compared with the control group, patients with TRD showed increased amygdala responses to sad faces in the early stage (around 300 ms) and decreased amygdala responses to happy faces in the late stage (around 600 ms) following the onset of faces. Further, during the late stage of happy face processing, alpha-band activity in PFC as well as alpha-phase locking between the amygdala and PFC were significantly greater in TRD patients compared to the controls. Second, after deep brain stimulation (DBS) delivered to bilateral subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS), atypical amygdala and PFC processing of happy faces in TRD patients remitted toward the normative pattern. The increased amygdala activation during the early stage of sad face processing suggests an overactive bottom-up processing system in TRD. Meanwhile, the reduced amygdala response during the late stage of happy face processing could be attributed to inhibition by PFC through alpha-band oscillation, which can be released by DBS in SCC and VC/VS.
Differential seeding by exogenous R2 and R3 fibrils influences autophagic degradation of intracellular tau aggregates in Tau K18 P301S cells
Authors: Annadurai Narendran , Kubíčková Agáta , Frydrych Ivo , Hajdúch Marián , Das Viswanath
Published: August 2023

Aggregation of misfolded tau protein is a common feature of tauopathies. Cells employ diverse mechanisms to eliminate misfolded tau with different conformations, contributing to the varied clinical and pathological manifestations of tauopathies. This study focuses on the clearance of seeded tau aggregates following the induction of biosensor cells with R2 and R3 fibrils that exhibit distinct aggregation kinetics and seeding potencies. Our hypothesis is that the dissimilarity in time-dependent intracellular seeding induced by R2 and R3 fibrils underlies the variation in autophagy failure. These discrepancies may account for the heterogeneity of pathology and disease progression between 3R and 4R tauopathies, given the absence of R2 in 3R tau isoforms. In R2-induced cells, alterations in p62 and LC3II/I levels, indicative of proteotoxic stress and autophagy failure, occur sooner than in R3-induced cells. Conversely, LAMP1 levels remained unaffected, suggesting a failure in the fusion of aggregate-containing autophagosomes with lysosomes. This autophagic failure may increase seed-dependent intracellular aggregation in induced cells. Consequently, we assessed the impact of autophagy inducers on the clearance of intracellular tau aggregates in induced cells. Epigallocatechin gallate (EGCG) demonstrated the highest efficacy in inducing autophagy and reducing p62 levels, decreasing seeding and clearing aggregates. Overall, this study elucidates the differential effects of prion-like R2 and R3 strains on autophagy and highlights how compounds like EGCG can selectively reduce tau aggregation to treat specific tauopathies. We provide insights into the distinct mechanisms of autophagy failure and autophagy clearance of intracellular aggregates in cells induced with R2 and R3 fibrils.
Conservation value of low-elevation forests for birds in agroforestry-dominated landscapes in a biodiversity hotspot
Authors: Biswas Nayantara , Biniwale Siddharth , Sadekar Vishal , Taneja Yukti , Suryawanshi Kulbhushansingh , Osuri Anand M , Naniwadekar Rohit
Published: August 2023

Protected areas (PAs) and multi-use landscapes beyond PAs play important and complementary roles in conserving global biodiversity. Across the tropical forest biome, remnant forests and agroforestry plantations in mixed-use landscapes often have high taxonomic diversity, but their ability to sustain functionally and phylogenetically diverse assemblages and retain conservation-priority species is unclear. Additionally, our understanding of impacts of land-use change across species, function and communities is poor.

In India’s Western Ghats (WG) biodiversity hotspot, like in many other tropical regions, PAs cover just 12% of the land and are concentrated in higher elevations. Here, in an approximately 15,000 km2landscape in the northern WG, we compared bird communities across six land-use categories: state-owned high-elevation PAs and low-elevation Reserved Forests beyond PAs, and privately-owned periodically clear-felled low-elevation forests and three types of low-elevation agroforestry plantations (cashew, mango, and rubber).

We sampled 184 line transects totalling 137.5 km across habitats, compared taxonomic, functional, and phylogenetic diversity metrics and used joint species distribution models to test for species-trait-habitat associations.

Forests in general and lowland forests in particular had higher taxonomic, functional and phylogenetic diversity, and higher occurrence probabilities of evergreen forest-affiliated, conservation-priority, and frugivores than agroforestry plantations. The ranking of land-use types varied across indicators, with rubber ranking higher than cashew and mango for functional and phylogenetic diversity but lower in species occurrence probabilities.

Synthesis and Applications: Our findings underscore the irreplaceability of less-disturbed forests for birds in mixed-use landscapes, especially when considering multiple dimensions of biodiversity, habitat specialists, and conservation-priority species. We advocate the simultaneous examination at multiple levels (community, species and traits) to determine the impacts of land-use change as divergent information of conservation importance is gleaned from each level. Reserved and private forests of low elevations of the Northern Western Ghats are critical for avian conservation, given that they harbour significant diversity, and the absence of representative PAs in the region. Given the vulnerability of these low-elevation forests to conversion for non-forestry activities and overexploitation for fuelwood, there is a need to develop viable models of partnership with landowners in these multi-use landscapes for ecological restoration of degraded forests.
Convolutional neural network models of neuronal responses in macaque V1 reveal limited non-linear processing
Authors: Miao Hui-Yuan , Tong Frank
Published: August 2023

Computational models of the primary visual cortex (V1) have suggested that V1 neurons behave like Gabor filters followed by simple non-linearities. However, recent work employing convolutional neural network (CNN) models has suggested that V1 relies on far more non-linear computations than previously thought. Specifically, unit responses in an intermediate layer of VGG-19 were found to best predict macaque V1 responses to thousands of natural and synthetic images. Here, we evaluated the hypothesis that the poor performance of lower-layer units in VGG-19 might be attributable to their small receptive field size rather than to their lack of complexityper se. We compared VGG-19 with AlexNet, which has much larger receptive fields in its lower layers. Whereas the best-performing layer of VGG-19 occurred after seven non-linear steps, the first convolutional layer of AlexNet best predicted V1 responses. Although VGG-19’s predictive accuracy was somewhat better than standard AlexNet, we found that a modified version of AlexNet could match VGG-19’s performance after only a few non-linear computations. Control analyses revealed that decreasing the size of the input images caused the best-performing layer of VGG-19 to shift to a lower layer, consistent with the hypothesis that the relationship between image size and receptive field size can strongly affect model performance. We conducted additional analyses using a Gabor pyramid model to test for non-linear contributions of normalization and contrast saturation. Overall, our findings suggest that the feedforward responses of V1 neurons can be well explained by assuming only a few non-linear processing stages.
Complete correction of murine phenylketonuria by selection-enhanced hepatocyte transplantation
Authors: Vonada Anne , Wakefield Leslie , Martinez Michael , Harding Cary O. , Grompe Markus , Tiyaboonchai Amita
Published: August 2023

Hepatocyte transplantation for genetic liver diseases has several potential advantages over gene therapy. However, low efficiency of cell engraftment has limited its clinical implementation. This problem could be overcome by selectively expanding transplanted donor cells until they replace enough of the liver mass to achieve therapeutic benefit. We previously described a gene therapy method to selectively expand hepatocytes deficient in cytochrome p450 reductase (Cypor) using acetaminophen (APAP). Because Cypor is required for the transformation of APAP to a hepatotoxic metabolite, Cypor deficient cells are protected from toxicity and are able to expand following APAP-induced liver injury. Here, we apply this selection system to correct a mouse model of phenylketonuria (PKU) by cell transplantation. Hepatocytes from a wildtype donor animal were edited in vitro to create Cypor deficiency and then transplanted into PKU animals. Following selection with APAP, blood phenylalanine concentrations were fully normalized and remained stable following APAP withdrawal. Cypor-deficient hepatocytes expanded from <1% to ∼14% in corrected animals, and they showed no abnormalities in blood chemistries, liver histology, or drug metabolism. We conclude that APAP-mediated selection of transplanted hepatocytes is a potential therapeutic for PKU with long-term efficacy and a favorable safety profile.
Highfold: accurately predicting cyclic peptide monomers and complexes with AlphaFold
Authors: Zhang Chenhao , Zhang Chengyun , Shang Tianfeng , Wu Xinyi , Duan Hongliang
Published: August 2023

In recent years, cyclic peptides have gained growing traction as a therapeutic modality owing to their diverse biological activities. Understanding the structures of these cyclic peptides and their complexes can provide valuable insights. However, experimental observation needs much time and money, and there still are many limitations to CADD methods. As for DL-based models, the scarcity of training data poses a formidable challenge in predicting cyclic peptides and their complexes. In this work, we present “High-fold,” an AlphaFold-based algorithm that addresses this issue. By incorporating pertinent information about head-to-tailed circular and disulfide bridge structures, Highfold reaches the best performance in comparison to other various approaches. This model enables accurate prediction of cyclic peptides and their complexes, making a step to-wards resolving its structure-activity research.
Somatosensory cortical representations of assimilation effect by vibrotactile stimulation
Authors: Kim Ji-Hyun , Jung Dooyoung , Kim Junsuk , Kim Sung-Phil
Published: August 2023

This study investigated neural activity related to the assimilation effect in the perception of vibrotactile stimuli. The assimilation effect refers to a tactile perceptual bias in which the perception of the vibrotactile frequency on one finger is biased towards a distracting vibrotactile stimulus targeting other types of mechanoreceptors on the different finger. The assimilation effect occurs not only between fingers on the same hand (in-hand) but also between fingers on different hands (across-hand). These behavioral aspects of the assimilation effect lead to an assumption that neural processes related to the assimilation effect would involve the integration of different tactile information mediated by the somatosensory cortex. We addressed this hypothesis by investigating brain responses using functional magnetic resonance imaging (fMRI) to vibrotactile stimuli that induced assimilation effect under in-hand and across-hand conditions. We first observed that the vibrotactile stimuli presented in this study activated primary (S1) and secondary (S2) somatosensory cortices. Yet, neural responses in these regions did not show correlations with individual assimilation effects, indicating that neural processing of vibrotactile signals in S1 and S2 would not be directly linked to the assimilation effect. Instead, we found that connectivity between S1 and medial prefrontal cortex (mPFC) was correlated with individual in-hand assimilation effects and that connectivity between S2 and posterior parietal cortex (PPC) was correlated with individual across-hand assimilation effects. These results suggest that the assimilation effect may be related to tactile information integration via functional connections between the somatosensory cortex and higher-order brain regions.
Synaptic plasticity is required for oscillations in a V1 cortical column model with multiple interneuron types
Authors: Moreni Giulia , Pennartz Cyriel M. A. , Mejias Jorge F.
Published: August 2023

Neural rhythms are ubiquitous in cortical recordings, but it is unclear whether they emerge due to the basic structure of cortical microcircuits, or depend on function. Using detailed electrophysiological and anatomical data of mouse V1, we explored this question by building a spiking network model of a cortical column incorporating pyramidal cells, PV, SST and VIP inhibitory interneurons, and dynamics for AMPA, GABA and NMDA receptors. The resulting model matched in vivo cell-type-specific firing rates for spontaneous and stimulus-evoked conditions in mice, although rhythmic activity was absent. Upon introduction of long-term synaptic plasticity, broad-band (15-60 Hz) oscillations emerged, with feedforward/feedback input streams enhancing/suppressing the oscillatory drive, respectively. These plasticity-triggered rhythms relied on all cell types, and specific experience-dependent connectivity patterns were required to generate oscillations. Our results suggest that neural rhythms are not intrinsic properties of cortical circuits, but rather arise from structural changes elicited by learning-related mechanisms.
Developmentally distinct architectures in top-down circuits
Authors: Klune Cassandra B. , Goodpaster Caitlin M. , Gongwer Michael W. , Gabriel Christopher J. , Chen Rita , Jones Nico S. , Schwarz Lindsay A. , DeNardo Laura A.
Published: August 2023

The medial prefrontal cortex (mPFC) plays a key role in learning, mood and decision making, including in how individuals respond to threats1–6. mPFC undergoes a uniquely protracted development, with changes in synapse density, cortical thickness, long-range connectivity, and neuronal encoding properties continuing into early adulthood7–21. Models suggest that before adulthood, the slow-developing mPFC cannot adequately regulate activity in faster-developing subcortical centers22,23. They propose that during development, the enhanced influence of subcortical systems underlies distinctive behavioural strategies of juveniles and adolescents and that increasing mPFC control over subcortical structures eventually allows adult behaviours to emerge. Yet it has remained unclear how a progressive strengthening of top-down control can lead to nonlinear changes in behaviour as individuals mature24,25. To address this discrepancy, here we monitored and manipulated activity in the developing brain as animals responded to threats, establishing direct causal links between frontolimbic circuit activity and the behavioural strategies of juvenile, adolescent and adult mice. Rather than a linear strengthening of mPFC synaptic connectivity progressively regulating behaviour, we uncovered multiple developmental switches in the behavioural roles of mPFC circuits targeting the basolateral amygdala (BLA) and nucleus accumbens (NAc). We show these changes are accompanied by axonal pruning coinciding with functional strengthening of synaptic connectivity in the mPFC-BLA and mPFC-NAc pathways, which mature at different rates. Our results reveal how developing mPFC circuits pass through distinct architectures that may make them optimally adapted to the demands of age-specific challenges.
Recent visual experience reshapes V4 neuronal activity and improves perceptual performance
Authors: Stan Patricia L , Smith Matthew A
Published: August 2023

Recent visual experience heavily influences our visual perception, but how this is mediated by the reshaping of neuronal activity to alter and improve perceptual discrimination remains unknown. We recorded from populations of neurons in visual cortical area V4 while monkeys performed a natural image change detection task under different experience conditions. We found that maximizing the recent experience with a particular image led to an improvement in the ability to detect a change in that image. This improvement was associated with decreased neural responses to the image, consistent with neuronal changes previously seen in studies of adaptation and expectation. We found that the magnitude of behavioral improvement was correlated with the magnitude of response suppression. Furthermore, this suppression of activity led to an increase in signal separation, providing evidence that a reduction in activity can improve stimulus encoding. Within populations of neurons, greater recent experience was associated with decreased trial-to-trial shared variability, indicating that a reduction in variability is a key means by which experience influences perception. Taken together, the results of our study contribute to an understanding of how recent visual experience can shape our perception and behavior through modulating activity patterns in mid-level visual cortex.
Gene loss and cis-regulatory novelty shaped core histone gene evolution in the apiculate yeastHanseniaspora uvarum
Authors: Haase Max A. B. , Steenwyk Jacob L. , Boeke Jef D.
Published: August 2023

Across eukaryotic species, core histone genes display a remarkable diversity of cis-regulatory mechanisms despite their protein sequence conservation. However, the dynamics and significance of this regulatory turnover are not well understood. Here we describe the evolutionary history of core histone gene regulation across 400 million years in Saccharomycotina yeasts, revealing diverse lineage-specific solutions to core histone expression. We further characterize the emergence of a novel regulatory mode in theHanseniasporagenus, which coincided with the loss of one copy of its paralogous core histones genes from its fast-evolving lineage. By analyzing the growth dynamics using live cell imaging of genetically modifiedHanseniaspora uvarum, we observed a regulatory decoupling of core histone synthesis from DNA synthesis and propose that this may be adaptive for its rapid cell cycle progression. Overall, our findings imply that the frequent turnover of core histone cis-regulatory mechanisms likely provides distinct adaptive solutions for specific life histories.
Chloramphenicol and gentamicin reduce resistance evolution to phage ΦX174 by suppressing a subset ofE. coliC LPS mutants
Authors: Parab Lavisha , Dherbey Jordan Romeyer , Rivera Norma , Schwarz Michael , Gallie Jenna , Bertels Frederic
Published: August 2023

Bacteriophages infect Gram-negative bacteria by attaching to molecules present on the bacterial outer membrane, often lipopolysaccharides (LPS). Modification of LPS can lead to resistance to phage infection. In addition, LPS modifications can impact antibiotic susceptibility, allowing for phage-antibiotic synergism. The evolutionary mechanism(s) behind such synergistic interactions remain largely unclear. Here, we show that the presence of antibiotics can affect the evolution of resistance to phage infection, using phage ΦX174 andEscherichia coliC. We use a collection of 34E. coliC LPS strains, each of which is resistant to ΦX174, and has either a “rough” or “deep rough” LPS phenotype. Growth of the bacterial strains with the deep rough phenotype is inhibited at low concentrations of chloramphenicol (and, to a much lesser degree, gentamicin). TreatingE. coliC wildtype with ΦX174 and chloramphenicol eliminates the emergence of mutants with the deep rough phenotype, and thereby slows the evolution of resistance to phage infection. At slightly lower chloramphenicol concentrations, phage resistance rates are similar to those observed at high concentrations; yet, we show that the diversity of possible mutants is much larger than at higher chloramphenicol concentrations. These data suggest that specific antibiotic concentrations can lead to synergistic phage-antibiotic interactions that disappear at higher antibiotic concentrations. Overall, we show that the change in survival of various ΦX174-resistantE. coliC mutants in the presence of antibiotics can explain the observed phage-antibiotic synergism.

Classification: Biological Sciences, Evolution
Multi-dimensional profiling of hepatoblastomas and patient-derived tumor organoids uncovers tumor subpopulations with divergent WNT activation profiles and identifies pan-hepatoblastoma drug sensitivities
Authors: Kluiver Thomas A. , Lu Yuyan , Schubert Stephanie A. , Kraaier Lianne J. , Ringnalda Femke , Lijnzaad Philip , DeMartino Jeff , Megchelenbrink Wout L. , Amo-Addae Vicky , Eising Selma , de Faria Flavia W. , Münter Daniel J. , van de Wetering Marc , Kerl Kornelius , Duiker Evelien , van den Heuvel Marius , de Meijer Vincent E. , de Kleine Ruben H. , de Krijger Ronald R. , Molenaar Jan J. , Margaritis Thanasis , Stunnenberg Henk , Zsiros József , Clevers Hans , Peng Weng Chuan
Published: August 2023

Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activatingCTNNB1mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we performed comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq, spatial transcriptomics, single-cell ATAC-seq and high throughput drug profiling. We identified two distinct tumor epithelial signatures: hepatic ‘fetal-like’ and WNT-high ‘embryonal-like’ signatures, displaying divergent WNT signaling patterns. The liver-specific WNT targets were enriched in the fetal-like group, while the embryonal-like group was enriched in canonical WNT target genes. Gene regulatory network analysis revealed enrichment of regulons related to hepatic function such as bile acid, lipid and xenobiotic metabolism in the fetal-like subgroup but not in the embryonal-like subgroup. In addition, the dichotomous expression pattern of the transcription factors HNF4A and LEF1 allowed for a clear distinction between the fetal- and embryonal-like tumors. We also performed high-throughput drug screening using patient-derived tumor organoids and identified sensitivity to multiple inhibitor classes, most notably HDAC inhibitors. Intriguingly, embryonal-like tumor organoids, but not fetal-like tumor organoids, were sensitive to FGFR inhibitor treatments, suggesting a dependency on FGFR signaling. In summary, our data uncover the molecular and drug sensitivity landscapes of hepatoblastoma and pave the way for the development of targeted therapies.
Characterizing Subcortical Structural Heterogeneity in Autism
Authors: MacDonald David N. , Bedford Saashi A. , Olafson Emily , Park Min Tae M. , Devenyi Gabriel A. , Tullo Stephanie , Patel Raihaan , Anagnostou Evdokia , Baron-Cohen Simon , Bullmore Edward T. , Chura Lindsay R. , Craig Michael C. , Ecker Christine , Floris Dorothea L. , Holt Rosemary J. , Lenroot Rhoshel , Lerch Jason P. , Lombardo Michael V. , Murphy Declan G. M. , Raznahan Armin , Ruigrok Amber N. V. , Smith Elizabeth , Shinohara Russell T. , Spencer Michael D. , Suckling John , Taylor Margot J. , Thurm Audrey ,   MRC AIMS Consortium, Lai Meng-Chuan , Chakravarty M. Mallar
Published: August 2023

Autism presents with significant phenotypic and neuroanatomical heterogeneity, and neuroimaging studies of the thalamus, globus pallidus and striatum in autism have produced inconsistent and contradictory results. These structures are critical mediators of functions known to be atypical in autism, including sensory gating and motor function. We examined both volumetric and fine-grained localized shape differences in autism using a large (n=3145, 1045-1318 after strict quality control), cross-sectional dataset of T1-weighted structural MRI scans from 32 sites, including both males and females (assigned-at-birth). We investigated three potentially important sources of neuroanatomical heterogeneity: sex, age, and intelligence quotient (IQ), using a meta-analytic technique after strict quality control to minimize non-biological sources of variation. We observed no volumetric differences in the thalamus, globus pallidus, or striatum in autism. Rather, we identified a variety of localized shape differences in all three structures. Including age, but not sex or IQ, in the statistical model improved the fit for both the pallidum and striatum, but not for the thalamus. Age-centered shape analysis indicated a variety of age-dependent regional differences. Overall, our findings help confirm that the neurodevelopment of the striatum, globus pallidus and thalamus are atypical in autism, in a subtle location-dependent manner that is not reflected in overall structure volumes, and that is highly non-uniform across the lifespan.
A robust balancing mechanism for spiking neural networks
Authors: Politi Antonio , Torcini Alessandro
Published: August 2023

Dynamical balance of excitation and inhibition is usually invoked to explain the irregular low firing activity observed in the cortex. We propose a robust nonlinear balancing mechanism for a random network of spiking neurons, in absence of strong external currents. The mechanism exploits the plasticity of excitatory-excitatory synapses induced by short-term depression. A simple self-consistent analysis accompanied by direct simulations shows the emergence and stability of a balanced asynchronous state in the thermodynamic limit. This regime is essentially fluctuation driven and characterized by highly irregular spiking dynamics of all neurons.
The formation ofChlamydia-containing spheres, a novel non-lytic egress pathway of the zoonotic pathogenChlamydia psittaci
Authors: Scholz Jana , Holland Gudrun , Laue Michael , Banhart Sebastian , Heuer Dagmar
Published: August 2023

Egress of intracellular bacteria from host cells and cellular tissues is a critical process during the infection cycle. This egress process is essential for bacteria to spread inside the host and can influence the outcome of an infection. For the obligate intracellular Gram-negative zoonotic bacteriumChlamydia psittacilittle is known about the mechanisms resulting in chlamydial egress from the infected epithelium. Here, we describe and characterize a novel non-lytic egress pathway ofC. psittaciby formation ofChlamydia-containing spheres (CCS). CCS are spherical, low phase contrast structures surrounded by a phosphatidylserine exposing membrane with specific barrier functions. They contain infectious progeny and morphologically impaired cellular organelles. The formation of CCS shares characteristics of apoptotic cell death including a proteolytic cleavage of the peptide DEVD albeit independent of active caspase-3, an increase in the intracellular calcium concentration of infected cells, followed by blebbing of the plasma membrane and rupture of the inclusion membrane. Finally, infected blebbing cells detach and leave the monolayer thereby forming CCS. These results support thatChlamydia psittaciegresses the epithelial cell by a novel non-lytic egress pathway, a process beneficial for the bacterium, which might influence the outcome of the infection in organisms.

Importance

Host cell egress is essential for intracellular pathogens to spread within an organism and for host-to-host-transmission. Here, we describe CCS formation as a novel egress pathway for the intracellular, zoonotic bacterial pathogenC. psittaci. This non-lytic egress pathway is fundamentally different from previously describedChlamydiaegress pathways. Interestingly, CCS formation shares several characteristics of apoptotic cell death. However, the sequence of proteolytic activity, followed by plasma membrane blebbing and the final detachment of a whole phosphatidylserine exposing former host cell is unique forC. psittaci. Thus, CCS formation represents a new egress pathway for intracellular pathogens that could possibly be linked toC. psittacibiology including host tropism, protection from host cell defense mechanisms or bacterial pathogenicity.
Post-glacial recolonization and multiple scales of secondary contact contribute to contemporary Atlantic salmon (Salmo salar) genomic variation in North America
Authors: Nugent Cameron M. , Kess Tony , Langille Barbara L. , Beck Samantha V. , Duffy Steven , Messmer Amber , Smith Nicole , Lehnert Sarah J. , Wringe Brendan F. , Kent Matthew , Bentzen Paul , Bradbury Ian R.
Published: August 2023

Aim

In northern environments, periods of isolation during Pleistocene glaciations and subsequent recolonization and secondary contact have had a significant influence on contemporary diversity of many species. The recent advent of high-resolution genomic analyses allows unprecedented power to resolve genomic signatures of such events in northern species. Here, we provide the highest resolution genomic characterization of Atlantic salmon in North America to infer glacial refugia and the geographic scales of postglacial secondary contact.

Location

North America.

Taxon

Atlantic salmon,Salmo salar.

Methods

Samples were collected for 5455 individuals from 148 populations encompassing the majority of Atlantic salmon’s native range in North America, from Labrador to Maine. Individuals were genotyped using a 220K SNP array aligned to the Atlantic salmon (Salmo salar) genome. Spatial genetic structure (PCA, k-means clustering, admixture) was evaluated in conjunction with genomic comparisons of identified lineages to infer the refugia during the last glacial maximum and regions of secondary contact following recolonization.

Results

Spatial genomic analyses identified three phylogeographic groups, consistent with the northward recolonization from two southern glacial refugia in North America (a western Maritime lineage and an eastern Newfoundland and Labrador lineage), with subsequent differentiation of the eastern lineage into two separate groups. Secondary contact among these North American groups was present within the northern Gulf of St. Lawrence and evidence of trans-Atlantic secondary contact was detected within the eastern Newfoundland and Labrador lineage. Comparison of groups from insular Newfoundland with those from mainland Labrador suggests genomic regions displaying high differentiation were characterized by elevated European admixture, suggesting a possible role of European secondary contact in population divergence.

Main Conclusions

These findings present the first evidence suggesting that genomic diversity in extant North American Atlantic salmon populations has resulted from allopatric isolation in two glacial refugia followed by both regional and trans-Atlantic recolonization and secondary contact and demonstrate the power of genomic tools to resolve historical drivers of diversity in wild populations.
Neural and behavioral organization of rapid eye movement sleep in zebrafish
Authors: Choudhary Vikash , Heller Charles R. , Aimon Sophie , de Sardenberg Schmid Lílian , Robson Drew N. , Li Jennifer M.
Published: August 2023

Sleep is ubiquitous across the animal kingdom. However, the definition for sleep varies significantly across species. In organisms such asC. elegans, Drosophila, and zebrafish, sleep is classically defined as periods of locomotor quiescence with an increased arousal threshold1–6. In mammals, sleep is further subdivided into rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, but the evolutionary origin of these two sleep states remains unclear7–12. Using longitudinal, high-resolution imaging of naturalistic sleep-wake behavior, we find that the classical definition of larval zebrafish sleep encompasses two clearly distinct quiescent states, one with rapid eye movements (qREM) and one without rapid eye movements (qNREM). Remarkably, qREM states are maintained in congenitally blind larval zebrafish, suggesting that qREM emerged during vertebrate evolution not as a response to internally generated visual imagery (i.e., the “scanning hypothesis”)13, but potentially as a strategy to maintain oculomotor stimulation during rest14. Lastly, using brain-wide imaging in freely swimming animals, we find that, in contrast to fixed point attractor models of sleep developed in invertebrates15, population-level activity during zebrafish qREM unfolds along smooth committed trajectories through state-space. This work suggests a significant rethinking of the behavioral and neural organization of sleep in early vertebrates and the emergence of REM during vertebrate evolution.
WITHDRAWN: Sindbis Virus in Wild Pigeons, Thailand
Authors: Yodjan Naluepanat , Wongwatthanacharat Suphawat , Khamsri Boonruang
Published: August 2023

Withdrawal Statement

The authors have withdrawn their manuscript owing to some missteps or inaccuracies discovered in the methodology that may significantly impact the findings. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, please contact the corresponding author.
The β6 Integrin Negatively Regulates TLR7-Mediated Epithelial Immunity via Autophagy During Influenza A Virus Infection
Authors: Smith Maria , Meliopoulos Victoria , Tan Shaoyuan , Bub Theresa , Brigleb Pamela H. , Sharp Bridgett , Crawford Jeremy Chase , Prater Mollie S. , Pruett-Miller Shondra M. , Schultz-Cherry Stacey
Published: August 2023

Integrins are essential surface receptors that sense extracellular changes to initiate various intracellular signaling cascades. The rapid activation of the epithelial-intrinsic β6 integrin during influenza A virus (IAV) infection has been linked to innate immune impairments. Yet, how β6 regulates epithelial immunity remains undefined. Here, we identify the role of β6 in mediating the Toll-like receptor 7 (TLR7) through the regulation of intracellular trafficking. We demonstrate that deletion of the β6 integrin in lung epithelial cells significantly enhances the TLR7-mediated activation of the type I interferon (IFN) response during homeostasis and respiratory infection. IAV-induced β6 facilitates TLR7 trafficking to lysosome-associated membrane protein (LAMP2a) components, leading to a reduction in endosomal compartments and associated TLR7 signaling. Our findings reveal an unappreciated role of β6-induced autophagy in influencing epithelial immune responses during influenza virus infection.
Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice
Authors: En Atsuki , Bogireddi Hanumakumar , Thomas Briana , Stutzman Alexis , Ikegami Sachie , LaForest Brigitte , Almakki Omar , Pytel Peter , Moskowitz Ivan P. , Ikegami Kohta
Published: August 2023

Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we tested a prevailing hypothesis that NE ruptures trigger pathological cGAS-STING cytosolic DNA-sensing pathway, using a mouse model of Lamin-cardiomyopathy. Reduction of Lamin A/C in cardiomyocytes of adult mice caused pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures were followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remained inactive. DeletingcGasorStingdid not rescue cardiomyopathy. The lack of cGAS-STING activation was likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling was activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin-cardiomyopathy.
Tau fibrils induce nanoscale membrane damage and nucleate cytosolic tau at lysosomes
Authors: Rose Kevin , Jepson Tyler , Shukla Sankalp , Maya-Romero Alex , Kampmann Martin , Xu Ke , Hurley James H.
Published: August 2023

The prion-like spread of protein aggregates is a leading hypothesis for the propagation of neurofibrillary lesions in the brain, including the spread of tau inclusions associated with Alzheimer’s disease. The mechanisms of cellular uptake of tau seeds and subsequent nucleated polymerization of cytosolic tau are major questions in the field, and the potential for coupling between the entry and nucleation mechanisms has been little explored. We found that in primary astrocytes, endocytosis of tau seeds leads to their accumulation in lysosomes. This in turn leads to lysosomal swelling, deacidification and recruitment of ESCRT proteins, but not Galectin-3, to the lysosomal membrane. These observations are consistent with nanoscale damage of the lysosomal membrane. Using live cell and STORM, imaging, nucleation of cytosolic tau occurs primarily at the lysosome membrane under these conditions. These data suggest that tau seeds escape from lysosomes via nanoscale damage rather than wholesale rupture, and that nucleation of cytosolic tau commences as soon as tau fibril ends emerge from the lysosomal membrane.