bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACTProtected 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

AbstractComputational 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

AbstractHepatocyte 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

ABSTRACTIn 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

AbstractThis 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

AbstractNeural 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

AbstractThe 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.
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

AbstractAcross 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

AbstractBacteriophages 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

SUMMARYHepatoblastoma, 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

AbstractAutism 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.
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

AbstractEgress 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.ImportanceHost 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.