bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxic injury triggers maladaptive repair in human kidney organoids
Authors: Nunez-Nescolarde Ana B. , Piran Mehran , Perlaza-Jiménez Laura , Barlow Chris K. , Steele Joel R. , Deveson Deanna , Lee Han-Chung , Moreau Julie L. M. , Schittenhelm Ralf B. , Nikolic-Paterson David J. , Combes Alexander N. 
Published: October 2023

ABSTRACTAcute kidney injury (AKI) is a common clinical disorder linked to high rates of illness and death. Ischemia is a leading cause of AKI, which can result in chronic kidney disease (CKD) through a maladaptive repair process characterised by failed epithelial regeneration, inflammation, and metabolic dysregulation. No targeted therapies exist to prevent the AKI to CKD transition and insight into ischemic AKI and maladaptive repair in humans remains limited. In this study, we report that human kidney organoids recapitulate select molecular and metabolic signatures of AKI and maladaptive repair in response to hypoxic injury. Transcriptional, proteomic, and metabolomic profiling revealed signatures of tubular injury, cell death, cell cycle arrest and altered metabolism in kidney organoids cultured in hypoxic conditions. After recovery in normoxic conditions, injured organoids displayed increased signatures associated with maladaptive repair like TNF, NF-κB, and JAK-STAT pathways, and S100A8/9. Single cell RNA sequencing localised biomarkers of AKI and maladaptive repair such as GDF15, MMP7, ICAM1, TGFB1, SPP1, C3 and CCN1 to injured proximal and distal tubules. Metabolic phenotypes linked to CKD were also evident including dysregulated glycolysis and gluconeogenesis, amino acid, bicarbonate and lipid metabolism, and elevated ceramide levels. Our multi-omic analysis provides compelling evidence for the use of kidney organoids as a model of human ischemic AKI and maladaptive repair, highlighting new and conserved biomarkers and mechanisms, and opportunities for drug screening.SummaryHuman kidney organoids recapitulate molecular and metabolic signatures of ischemic acute kidney injury and maladaptive repair, providing new insight into human disease mechanisms and opportunities for drug development.
Beyond the nucleus: Plastic chemicals activate G protein-coupled receptors
Authors: McPartland Molly , Stevens Sarah , Bartosova Zdenka , Gisnås Vardeberg Ingrid , Völker Johannes , Wagner Martin 
Published: October 2023

AbstractAbstract FigureG protein-coupled receptors (GPCRs) are central mediators of cell signaling and physiological function. Despite their biological significance, GPCRs have not been widely studied in the field of toxicology. Herein, we investigated these receptors are novel targets of plastic chemicals using a high-throughput drug screening assay with 126 human non-olfactory GPCRs. In a first-pass screen, we tested the activity of triphenol phosphate, bisphenol A, and diethyl phthalate as well as three real-world mixtures of chemicals extracted from plastic food packaging covering all major polymer types. We found 11 GPCR-chemical interactions, of which the chemical mixtures exhibited the most robust activity at Adenosine receptor 1 (ADORA1) and Melatonin receptor 1 (MTNR1A) in a confirmatory secondary screen. We further confirmed that polyvinyl chloride and polyurethane products contain ADORA1 or MTNRA1 agonists using pharmacological knockdown experiments. Finally, an analysis of the associated gene ontology terms suggests that ADORA1 and MTNR1A activation may be linked to downstream effects on circadian and metabolic processes. Our findings exemplify the diversity of endpoints plastic chemicals can target and demonstrate the relevance of non-genomic pathways which have thus far remained unexplored.
Opposing neural processing modes alternate rhythmically during sustained auditory attention
Authors: Kasten Florian H. , Busson Quentin , Zoefel Benedikt 
Published: October 2023

AbstractDuring continuous tasks, humans show spontaneous fluctuations in performance, putatively caused by varying attentional resources allocated to process external information. If neural resources are used to process other, presumably “internal” information, sensory input can be missed and explain an apparent dichotomy of “internal” versus “external” attention.In the current study, we extracted presumed neural signatures of these attentional modes in human electroencephalography (EEG): neural entrainment and α-oscillations (∼10-Hz), linked to the processing and suppression of sensory information, respectively. We tested whether they exhibit structured fluctuations over time, while listeners attended to an ecologically relevant stimulus like speech and completed a task that required full and continuous attention.Results showed an antagonistic relation between neural entrainment to speech and spontaneous α-oscillations in two distinct brain networks – one specialized in the processing of external information, the other reminiscent of the dorsal attention network. These opposing neural modes underwent slow, periodic fluctuations around ∼0.07 Hz and were related to the detection of auditory targets. Our study might have tapped into a general attentional mechanism that is conserved across species and has important implications for situations in which sustained attention to sensory information is critical.Graphical Abstract
Recurrent hybridization and gene flow shaped Norway and Siberian spruce evolutionary history over multiple glacial cycles
Authors: Zhou Qiujie , Karunarathne Piyal , Andersson-Li Lili , Chen Chen , Opgenoorth Lars , Heer Katrin , Vendramin Giovanni Giuseppe , Piotti Andrea , Nakvasina Elena , Lascoux Martin , Milesi Pascal 
Published: October 2023

AbstractOver the last decades, extensive genome-wide resequencing studies have highlighted the extent of hybridization and introgression between closely related species. Animal and plant species went through cycles of contractions and expansions as a result of glacial cycles. These repeated sequences of reproductive isolation and admixture at continental scales have led to the accumulation over time of an ancient, deep-seated and complex genetic structure. This structure was blurred by extensive gene flow, or reinforced by strong local adaptation. This already multi-layered structure has often been further enhanced by hybridization.We investigated this complexity in Norway spruce (Picea abies) and Siberian spruce (P. obovata), two closely related species dominating Eurasian boreal forests and forming a vast hybrid zone. Here, we genotyped 542 individuals of both species and their hybrids at 480K SNPs. Individuals came from 55 populations, extending from western Europe to Siberia with a focus on the main hybrid zone. Despite extensive gene flow and a clear Isolation-by-Distance pattern at the continental scale, distinct genetic clusters emerged, indicating barriers and corridors to migration. Coalescent-based demographic inferences revealed that Norway and Siberian spruce repeatedly hybridized during the Pleistocene with introgression pattern varying depending on the latitude. In northern ranges,P. obovataexpanded intoP. abieswhileP. abiesexpanded intoP. obovatain the southern parts. Two cryptic refugia located in the large hybrid zone played a critical role in shaping the current distribution of the two species. Our study highlights the importance of considering the whole species complex instead of separate entities to shed light on their complex demographic histories.
Sexual dimorphism of insular cortex function in persistent alcohol drinking despite aversion in mice
Authors: Fornari Claudia , Guerrero-Márquez Carmen , Namburi Praneeth , Couderc Yoni , Nicolas Céline , Beyeler Anna 
Published: October 2023

ABSTRACTBACKGROUNDOne major hallmark of alcohol use disorder (AUD) is the persistence of alcohol drinking despite negative consequences. Among the indicators of AUD vulnerability, binge drinking is a strong risk factor. Although the lifetime prevalence of binge and AUD has been historically higher in men than women, this gap dramatically narrowed in the last decade. Additionally, sex differences in AUD and binge drinking have been shown in clinical and preclinical studies, respectively. The insular cortex plays an important role in AUD, and the anterior (aIC) and posterior (pIC) divisions have dimorphic functions. However, the contributions of the aIC and pIC sections in alcohol binge drinking and alcohol persistent drinking despite aversion, as well as the sexual dimorphism of these contributions, remained to be uncovered.METHODSFirst, by combining the drinking in the dark model with chemogenetics, we studied the causal role of aIC and pIC excitatory neurons in binge and persistent ethanol drinking in C57BL6/J male (n=49) and female (n=49) mice. Second, using calcium fiber photometry, we investigated pIC neuronal activity in both sexes (male n=14, female n=11) during both binge and persistent ethanol drinking.RESULTSWe identified a higher binge and persistent ethanol consumption in females compared to males. Chemogenetic inhibition of aIC glutamatergic neurons reduced bitter solutions intake independently of the solvent (ethanol or water), in both sexes. In contrast, inhibition of pIC glutamatergic neurons exclusively reduced persistent ethanol drinking in female mice. Finally, using fiber photometry recordings, we uncovered that pIC glutamatergic neuron activity was selectivity increased during ethanol persistent drinking in female mice.CONCLUSIONSThese findings suggest a sex-dependent function of the pIC in persistent ethanol drinking, providing a starting point in our understanding of the insular cortex function in the neurobiology of AUD in both sexes.
Evolution of hind limb morphology of Titanosauriformes (Dinosauria, Sauropoda) analyzed via 3D Geometric Morphometrics reveals wide-gauge posture as an exaptation for gigantism
Authors: Paramo Blazquez Adrian , Mocho Pedro , Escaso Fernando , Ortega Francisco 
Published: October 2023

AbstractThe sauropod hind limb was the main support that allowed their gigantic body masses and a wide range of dynamic stability adaptations. It was closely related to the position of the centre of masses of their multi-ton barrel-shaped bodies, and experienced one of the most noticeable posture changes during macronarian evolution. Deeply branched macronarians achieved increasingly arched hind limbs in what is known as wide-gauge posture. However, it is not clear if this evolutionary trend is related to the evolutionary cascade toward gigantism even though some titanosaurians were the largest terrestrial vertebrates that ever existed. We tested evolutionary changes in hind limb morphology in the Macronaria phylogenetic tree by 3D geometric morphometrics. The macronarian hind limb does become progressively more arched toward deeply-branched groups, specifically Saltasauridae. However, there is morphological convergence between different macronarian subclades. Wide-gauge posture does not correlate with changes in body size deeper in the macronarian evolutionary tree, and acted as an exaptation to gigantism. Despite some titanosaurian subclades becoming some of the largest vertebrates, there is not a statistically-significant trend toward a particular body size but we identify a phyletic body size decrease in Macronaria.
Novel Cyclic Homogeneous Oscillation Detection Method for High Accuracy and Specific Characterization of Neural Dynamics
Authors: Cho Hohyun , Adamek Markus , Willie Jon T. , Brunner Peter 
Published: October 2023

AbstractDetecting temporal and spectral features of neural oscillations is essential to understanding dynamic brain function. Traditionally, the presence and frequency of neural oscillations are determined by identifying peaks over 1/f noise within the power spectrum. However, this approach solely operates within the frequency domain and thus cannot adequately distinguish between the fundamental frequency of a non-sinusoidal oscillation and its harmonics. Non-sinusoidal signals generate harmonics, significantly increasing the false-positive detection rate — a confounding factor in the analysis of neural oscillations. To overcome these limitations, we define the fundamental criteria that characterize a neural oscillation and introduce the Cyclic Homogeneous Oscillation (CHO) detection method that implements these criteria based on an auto-correlation approach that determines the oscillation’s periodicity and fundamental frequency. We evaluated CHO by verifying its performance on simulated sinusoidal and non-sinusoidal oscillatory bursts convolved with 1/f noise. Our results demonstrate that CHO outperforms conventional techniques in accurately detecting oscillations. Specifically, we determined the sensitivity and specificity of CHO as a function of signal-to-noise ratio (SNR). We further assessed CHO by testing it on electrocorticographic (ECoG, 8 subjects) and electroencephalographic (EEG, 7 subjects) signals recorded during the pre-stimulus period of an auditory reaction time task and on electrocorticographic signals (6 SEEG subjects and 6 ECoG subjects) collected during resting state. In the reaction time task, the CHO method detected auditory alpha and pre-motor beta oscillations in ECoG signals and occipital alpha and pre-motor beta oscillations in EEG signals. Moreover, CHO determined the fundamental frequency of hippocampal oscillations in the human hippocampus during the resting state (6 SEEG subjects). In summary, CHO demonstrates high precision and specificity in detecting neural oscillations in time and frequency domains. The method’s specificity enables the detailed study of non-sinusoidal characteristics of oscillations, such as the degree of asymmetry and waveform of an oscillation. Furthermore, CHO can be applied to identify how neural oscillations govern interactions throughout the brain and to determine oscillatory biomarkers that index abnormal brain function.
Rapid evolution of pesticide resistance via adaptation and interspecific introgression in a major North American crop pest
Authors: North Henry L. , Fu Zhen , Metz Richard , Stull Matt A. , Johnson Charles D. , Shirley Xanthe , Crumley Kate , Reisig Dominic , Kerns David L. , Gilligan Todd , Walsh Tom , Jiggins Chris D. , Sword Gregory A. 
Published: October 2023

AbstractInsect crop pests threaten global food security. This threat is amplified through the spread of non-native species and the evolution of pesticide resistance, which can be introduced to a population thoughde novomutation or gene flow. We investigate these processes in an economically important noctuid crop pest,Helicoverpa zea, which has rapidly evolved resistance to several pesticides. Its sister speciesHelicoverpa armigera, first detected as an invasive species in Brazil in 2013, introduced the pyrethroid resistance geneCYP337B3to South AmericanH. zeavia introgression. To understand whether this contributes to pesticide resistance in North America, we sequenced 237H. zeagenomes across 10 sample sites in the US. First, we reportH. armigeraintrogression into the North AmericanH. zeapopulation. Two individuals sampled in Texas in 2019 carryH. armigerahaplotypes in a 4Mbp region containingCYP337B3. Second, we show that the remarkable dispersal ability ofH. zearesults in a panmictic North American population. Third, we detect signatures of selection in non-admixedH. zea, identifying a selective sweep at a second pesticide resistance locus with a similar name:CYP333B3. We estimate that its derived allele conferred a ∼4.9% fitness advantage and show that this estimate explains independently observed rare nonsynonymousCYP333B3mutations approaching fixation over a ∼20-year period. We also detect putative signatures of selection at a kinesin gene associated with Bt resistance. Our results show that pesticide resistance inH. zeaevolved rapidly and recently via two independent mechanisms: interspecific introgression and rapid intraspecific adaptation.
spillR: Spillover Compensation in Mass Cytometry Data
Authors: Guazzini Marco , Reisach Alexander G. , Weichwald Sebastian , Seiler Christof 
Published: October 2023

AbstractChannel interference in mass cytometry can cause spillover and may result in miscounting of protein markers. Chevrieret al. (2018) introduce an experimental and computational procedure to estimate and compensate for spillover implemented in their R packageCATALYST. They assume spillover can be described by a spillover matrix that encodes the ratio between unstained and stained channels. They estimate the spillover matrix from experiments with beads. We propose to skip the matrix estimation step and work directly with the full bead distributions. We develop a nonparametric finite mixture model, and use the mixture components to estimate the probability of spillover. Spillover correction is often a pre-processing step followed by downstream analyses, choosing a flexible model reduces the chance of introducing biases that can propagate downstream. We implement our method in an R packagespillRusing expectation-maximization to fit the mixture model. We test our method on synthetic and real data fromCATALYST. We find that our method compensates low counts accurately, does not introduce negative counts, avoids overcompensating high counts, and preserves correlations between markers that may be biologically meaningful.
APOE, Immune Factors, Sex, and Diet Interact to Shape Brain Networks in Mouse Models of Aging
Authors: Winter Steven , Mahzarnia Ali , Anderson Robert J , Han Zay Yar , Tremblay Jessica , Stout Jacques , Moon Hae Sol , Marcellino Daniel , Dunson David B. , Badea Alexandra 
Published: October 2023

AbstractAlzheimer’s disease (AD) presents complex challenges due to its multifactorial nature, poorly understood etiology, and late detection. The mechanisms through which genetic, fixed and modifiable risk factors influence susceptibility to AD are under intense investigation, yet the impact of unique risk factors on brain networks is difficult to disentangle, and their interactions remain unclear. To model multiple risk factors including APOE genotype, age, sex, diet, and immunity we leveraged mice expressing the human APOE and NOS2 genes, conferring a reduced immune response compared to mouse Nos2. Employing graph analyses of brain connectomes derived from accelerated diffusion-weighted MRI, we assessed the global and local impact of risk factors in the absence of AD pathology. Aging and a high-fat diet impacted extensive networks comprising AD-vulnerable regions, including the temporal association cortex, amygdala, and the periaqueductal gray, involved in stress responses. Sex impacted networks including sexually dimorphic regions (thalamus, insula, hypothalamus) and key memory-processing areas (fimbria, septum). APOE genotypes modulated connectivity in memory, sensory, and motor regions, while diet and immunity both impacted the insula and hypothalamus. Notably, these risk factors converged on a circuit comprising 63 of 54,946 total connections (0.11% of the connectome), highlighting shared vulnerability amongst multiple AD risk factors in regions essential for sensory integration, emotional regulation, decision making, motor coordination, memory, homeostasis, and interoception. These network-based biomarkers hold translational value for distinguishing high-risk versus low-risk participants at preclinical AD stages, suggest circuits as potential therapeutic targets, and advance our understanding of network fingerprints associated with AD risk.Significance StatementCurrent interventions for Alzheimer’s disease (AD) do not provide a cure, and are delivered years after neuropathological onset. Addressing the impact of risk factors on brain networks holds promises for early detection, prevention, and revealing putative therapeutic targets at preclinical stages. We utilized six mouse models to investigate the impact of factors, including APOE genotype, age, sex, immunity, and diet, on brain networks. Large structural connectomes were derived from high resolution compressed sensing diffusion MRI. A highly parallelized graph classification identified subnetworks associated with unique risk factors, revealing their network fingerprints, and a common network composed of 63 connections with shared vulnerability to all risk factors. APOE genotype specific immune signatures support the design of interventions tailored to risk profiles.
The effects of resistance training on denervated myofibers, senescent cells, and associated protein markers in middle-aged adults
Authors: Ruple Bradley A. , Mattingly Madison L. , Godwin Joshua S. , McIntosh Mason C. , Kontos Nicholas J. , Agyin-Birikorang Anthony , Michel J. Max , Plotkin Daniel L. , Chen Shao-Yung , Ziegenfuss Tim. N. , Fruge Andrew D. , Gladden L. Bruce , Robinson Austin T. , Mobley C. Brooks , Mackey Abigail L. , Roberts Michael D. 
Published: October 2023

ABSTRACTDenervated myofibers and senescent cells are hallmarks of skeletal muscle aging. However, sparse research has examined how resistance training affects these outcomes. We investigated the effects of unilateral leg extensor resistance training on denervated myofibers, senescent cells, and associated protein markers in middle-aged participants (MA, 55±8 years old, 17 females, 9 males). We obtained vastus lateralis (VL) muscle cross-sectional area (mCSA), VL biopsies, and strength assessments before and after training. Fiber cross-sectional area (fCSA), satellite cells (Pax7+), denervated myofibers (NCAM+), senescent cells (p16+ or p21+), senescence-related proteins, and senescence-associated secretory phenotype (SASP) proteins were analyzed from biopsied muscle. Leg extensor peak torque increased after training (p<0.001), while VL mCSA trended upward (p=0.082). No significant changes were observed for fCSA, NCAM+ myofibers, or senescent (p16+ or p21+) cells, albeit satellite cells increased after training (p=0.037). While >90% satellite cells were not p16+ or p21+, most p16+ and p21+ cells were Pax7+ (>90% on average). Training altered 13/46 proteins related to muscle-nerve communication (all upregulated, p<0.05) and 10/19 proteins related to cellular senescence (9 upregulated, p<0.05). Only 1/17 SASP proteins increased with training (IGFBP-3, p=0.031). In conclusion, resistance training upregulates proteins associated with muscle-nerve communication in MA participants but does not alter NCAM+ myofibers. Moreover, while training increases senescence-related proteins in skeletal muscle, this coincided with an increase in satellite cells but not alterations in senescent cell content or SASP proteins. Hence, we interpret these collective findings as resistance training being an unlikely inducer of cellular senescence in humans.