bluuebunny/crossref_metadata_2025 huggingface dataset:
ProteoMixture: A Cell Type Deconvolution Tool for Bulk Tissue Proteomics Data
Authors: Teng Pang-ning , Schaaf Joshua P. , Abulez Tamara , Hood Brian L. , Wilson Katlin N. , Litzi Tracy J. , Mitchell David , Conrads Kelly A. , Hunt Allison L. , Olowu Victoria , Oliver Julie , Park Fred S. , Edwards Marshé , Chiang AiChun , Raj-Kumar Praveen-Kumar , Tarney Christopher M. , Darcy Kathleen M. , Phippen Neil T. , Maxwell G. Larry , Conrads Thomas P. , Bateman Nicholas W.
Published: July 2023

Numerous multi-omic investigations of cancer tissue have documented varying and poor pairwise transcript:protein quantitative correlations and most deconvolution tools aiming to predict cell type proportions (cell admixture) have been developed and credentialed using transcript-level data alone. To estimate cell admixture using protein abundance data, we analyzed proteome and transcriptome data generated from contrived admixtures of tumor, stroma, and immune cell models or those selectively harvested from the tissue microenvironment by laser microdissection from high grade serous ovarian cancer (HGSOC) tumors. Co-quantified transcripts and proteins performed similarly to estimate stroma and immune cell admixture in two commonly used deconvolution algorithms, ESTIMATE and ConsensusTME(r ≥ 0.63). Here we have developed and optimized protein-based signatures to estimate cell admixture proportions and benchmarked these using bulk tumor proteomics data from over 150 HGSOC patients. The optimized protein signatures supporting cell type proportion estimates from bulk tissue proteomics data are available at (https://lmdomics.org/ProteoMixture/.
Butyrate Protects against SARS-CoV-2-induced Tissue Damage in Golden Hamsters
Authors: Yu Huan , Yuan Lunzhi , Yan Zhigang , Zhou Ming , Ye Jianghui , Wu Kun , Chen Wenjia , Chen Rirong , Xia Ningshao , Guan Yi , Zhu Huachen
Published: July 2023

Butyrate, produced by gut microbe during dietary fiber fermentation, plays anti-inflammatory and antioxidant effects in chronic inflammation diseases, yet it remains to be explored whether butyrate has protective effects against viral infections. Here, we demonstrated that butyrate alleviated tissue injury in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected golden hamsters with supplementation of butyrate before and during the infection. Butyrate-treated hamsters showed augmentation of type I interferon (IFN) response and activation of endothelial cells without exaggerated inflammation. In addition, butyrate regulated redox homeostasis by enhancing the activity of superoxide dismutase (SOD) to inhibit excessive apoptotic cell death. Therefore, butyrate exhibited an effective prevention against SARS-CoV-2 by upregulating antiviral immune responses and promoting cell survival.

IMPORTANCE

Since SARS-CoV-2 has caused severe disease characterized by acute respiratory distress syndrome (ARDS) in humans, it is essential to develop therapeutics based on relieving such severe clinical symptoms. Current therapy strategies mainly focus on individuals who have COVID-19, however, there is still a strong need for prevention and treatment of SARS-CoV-2 infection. This study showed that butyrate, a bacterial metabolite, improved the response of SARS-CoV-2-infected hamsters by reducing immunopathology caused by impaired antiviral defenses and inhibiting excessive apoptosis through reduction in oxidative stress.
To unscramble an egg: admixed captive breeding populations can be rescued using local ancestry information
Authors: Lawson Daniel J. , Howard-McCombe Jo , Beaumont Mark , Senn Helen
Published: July 2023

This paper asks the question: can genomic information recover a species that is already on the pathway to extinction due to genetic swamping from a related and more numerous population? We show that whole genome sequencing can be used to identify and remove hybrid segments of DNA, when used as part of the breeding policy in a captive breeding program. The proposed policy uses a generalised measure of kinship or heterozygosity accounting for local ancestry, that is, whether a specific genetic location was inherited from from the target of conservation. We then show that optimising these measures would minimise undesired ancestry whilst also controlling undesired kinship or heterozygosity respectively, in a simulated breeding population. The process is applied to real data representing the hybridized Scottish wildcat breeding population, with the result that it should be possible to breed out the domestic cat ancestry. The ability to reverse introgression is a powerful new tool brought about from both sequencing and computational advances in ancestry estimation. Since it works best when applied early in the process, important decisions need to be made about which genetically distinct populations should benefit from it and which should be left to reform into a single population.
Prolonged exposure to lung-derived cytokines is associated with inflammatory activation of microglia in patients with COVID-19
Authors: Grant Rogan A. , Poor Taylor A. , Sichizya Lango , Diaz Estefani , Bailey Joseph I. , Soni Sahil , Senkow Karolina J. , Pérez-Leonor Xochítl G. , Abdala-Valencia Hiam , Lu Ziyan , Donnelly Helen K. , Tighe Robert M. , Lomasney Jon W. , Wunderink Richard G. , Singer Benjamin D. , Misharin Alexander V. , Budinger GR Scott ,   The NU SCRIPT Investigators
Published: July 2023

Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia1–4. Dysfunction in microglia, the primary immune cell in the brain, has been linked to cognitive impairment in murine models of dementia and in humans5. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF-ɑ and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-196, was associated with lower levels of CXCL10, CCL8, and CCL2—molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells7. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19.
Development of a PNGase Rc column for online deglycosylation of complex glycoproteins during HDX-MS
Authors: Lambert Thomas , Gramlich Marius , Stutzke Luisa , Smith Luke , Deng Dingyu , Kaiser Philipp D. , Rothbauer Ulrich , Benesch Justin L.P. , Wagner Cornelia , Koenig Maximiliane , Pompach Petr , Novak Petr , Zeck Anne , Rand Kasper
Published: July 2023

Protein glycosylation is one of the most common PTMs and many cell surface receptors, extracellular proteins and biopharmaceuticals are glycosylated. However, HDX-MS analysis of such important glycoproteins has so far been limited by difficulties in determining the HDX of the protein segments that contain glycans. We have developed a column containing immobilized PNGase Rc (fromRudaea cellulosilytica) that can readily be implemented into a conventional HDX-MS setup to allow improved analysis of glycoproteins. We show that HDX-MS with the PNGase Rc column enables efficient online removal of N-linked glycans and the determination of the HDX of glycosylated regions in several complex glycoproteins. Additionally, we use the PNGase Rc column to perform a comprehensive HDX-MS mapping of the binding epitope of a mAb to c-Met, a complex glycoprotein drug target. Importantly, the column retains high activity in the presence of common quench-buffer additives like TCEP and urea and performed consistent across 114 days of extensive use. Overall, our work shows that HDX-MS with the integrated PNGase Rc column can enable fast and efficient online deglycosylation at harsh quench conditions to provide comprehensive analysis of complex glycoproteins.
Cross-site reproducibility of human cortical organoids reveals consistent cell type composition and architecture
Authors: Glass Madison R , Waxman Elisa A. , Yamashita Satoshi , Lafferty Michael , Beltran Alvaro , Farah Tala , Patel Niyanta K , Matoba Nana , Ahmed Sara , Srivastava Mary , Drake Emma , Davis Liam T. , Yeturi Meghana , Sun Kexin , Love Michael I. , Hashimoto-Torii Kazue , French Deborah L. , Stein Jason L.
Published: July 2023

Background:

Reproducibility of human cortical organoid (hCO) phenotypes remains a concern for modeling neurodevelopmental disorders. While guided hCO protocols reproducibly generate cortical cell types in multiple cell lines at one site, variability across sites using a harmonized protocol has not yet been evaluated. We present an hCO cross-site reproducibility study examining multiple phenotypes.

Methods:

Three independent research groups generated hCOs from one induced pluripotent stem cell (iPSC) line using a harmonized miniaturized spinning bioreactor protocol. scRNA-seq, 3D fluorescent imaging, phase contrast imaging, qPCR, and flow cytometry were used to characterize the 3 month differentiations across sites.

Results:

In all sites, hCOs were mostly cortical progenitor and neuronal cell types in reproducible proportions with moderate to high fidelity to thein vivobrain that were consistently organized in cortical wall-like buds. Cross-site differences were detected in hCO size and morphology. Differential gene expression showed differences in metabolism and cellular stress across sites. Although iPSC culture conditions were consistent and iPSCs remained undifferentiated, primed stem cell marker expression prior to differentiation correlated with cell type proportions in hCOs.

Conclusions:

We identified hCO phenotypes that are reproducible across sites using a harmonized differentiation protocol. Previously described limitations of hCO models were also reproduced including off-target differentiations, necrotic cores, and cellular stress. Improving our understanding of how stem cell states influence early hCO cell types may increase reliability of hCO differentiations. Cross-site reproducibility of hCO cell type proportions and organization lays the foundation for future collaborative prospective meta-analytic studies modeling neurodevelopmental disorders in hCOs.
The Neuron-specific IIS/FOXO Transcriptome in Aged Animals Reveals Regulatory Mechanisms of Cognitive Aging
Authors: Weng Yifei , Zhou Shiyi , Morillo Katherine , Kaletsky Rachel , Lin Sarah , Murphy Coleen T.
Published: July 2023

Cognitive decline is a significant health concern in our aging society. Here, we used the model organismC. elegansto investigate the impact of the IIS/FOXO pathway on age-related cognitive decline. Thedaf-2Insulin/IGF-1 receptor mutant exhibits a significant extension of learning and memory span with age compared to wild-type worms, an effect that is dependent on the DAF-16 transcription factor. To identify possible mechanisms by which agingdaf-2mutants maintain learning and memory with age while wild-type worms lose neuronal function, we carried out neuron-specific transcriptomic analysis in aged animals. We observed downregulation of neuronal genes and upregulation of transcriptional regulation genes in aging wild-type neurons. By contrast, IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including upregulation of stress response genes and downregulation of specific insulin signaling genes. We tested the roles of significantly transcriptionally-changed genes in regulating cognitive functions, identifying novel regulators of learning and memory. In addition to other mechanistic insights, comparison of the aged vs youngdaf-2neuronal transcriptome revealed that a new set of potentially neuroprotective genes is upregulated; instead of simply mimicking a young state,daf-2may enhance neuronal resilience to accumulation of harm and take a more active approach to combat aging. These findings suggest a potential mechanism for regulating cognitive function with age and offer insights into novel therapeutic targets for age-related cognitive decline.
Application of monolayer graphene to cryo-electron microscopy grids for high-resolution structure determination
Authors: Grassetti Andrew V. , May Mira B. , Davis Joseph H.
Published: July 2023

In cryogenic electron microscopy (cryo-EM), purified macromolecules are typically applied to a grid bearing a holey carbon foil, blotted to remove excess liquid and rapidly frozen in a roughly 20-100 nm thick layer of vitreous ice that is suspended across roughly 1 μm-wide foil holes. The resulting sample is then imaged using cryogenic transmission electron microscopy and, after substantial image processing, near-atomic resolution structures can be determined. Despite cryo-EM’s widespread adoption, sample preparation remains a severe bottleneck in cryo-EM workflows, with users often encountering challenges related to samples behaving poorly in the suspended vitreous ice. Recently, methods have been developed to modify cryo-EM grids with a single continuous layer of graphene, which acts as a support surface that often increases particle density in the imaged area and can reduce interactions between particles and the air-water interface. Here, we provide detailed protocols for the application of graphene to cryo-EM grids, and for rapidly assessing the relative hydrophilicity of the resulting grids. Additionally, we describe an EM-based method to confirm the presence of graphene by visualizing its characteristic diffraction pattern. Finally, we demonstrate the utility of these graphene supports by rapidly reconstructing a 2.7 Å resolution density map of an exemplar Cas9 complex using a highly pure sample at a relatively low concentration.

The application of support layers, such as graphene, to cryo-electron microscopy grids can increase the density of particles imaged, limit particle interactions with the air-water interface, reduce the extent of beam-induced motion, and, in some instances, improve the distribution of particle orientations. This paper describes a robust protocol for coating cryo-EM grids with a monolayer of graphene for improved cryo-sample preparation.
Emergence and spread of the barley net blotch pathogen coincided with crop domestication and cultivation history
Authors: Taliadoros Demetris , Feurtey Alice , Wyatt Nathan , Gladieux Pierre , Friesen Timothy , Stukenbrock Eva
Published: July 2023

Fungal pathogens cause devastating disease in crops. Understanding the evolutionary origin of pathogens is essential to the prediction of future disease emergence and the potential of pathogens to disperse. The fungusPyrenophora teresf.terescauses net form net blotch (NFNB), an economically significant disease of barley. In this study, we have used 104P. teresf.teresgenomes from four continents to explore the population structure and demographic history of the fungal pathogen. We showed thatP. teresf.teresis structured into populations that tend to be geographically restricted to different regions. Using Multiple Sequentially Markovian Coalescent and machine learning approaches we demonstrated that the demographic history of the pathogen correlates with the history of barley, highlighting the importance of human migration and trade in spreading the pathogen. Exploring signatures of natural selection, we identified several population-specific selective sweeps that colocalized with genomic regions enriched in putative virulence genes, and loci previously identified as determinants of virulence specificities by quantitative trait locus analyses. This reflects rapid adaptation to local hosts and environmental conditions ofP. teresf.teresas it spread with barley. Our research highlights how human activities can contribute to the spread of pathogens that significantly impact the productivity of field crops.
Compositional editing of extracellular matrices by CRISPR/Cas9 engineering of human mesenchymal stem cell lines
Authors: Prithiviraj Sujeethkumar , Garcia Alejandro Garcia , Linderfalk Karin , Yiguang Bai , Ferveur Sonia , Falck Ludvig Nilsén , Subramaniam Agatheeswaran , Mohlin Sofie , Hidalgo David , Dupard Steven J , Zacharaki Dimitra , Raina Deepak Bushan , Bourgine Paul E
Published: July 2023

Tissue engineering strategies predominantly rely on the production of living substitutes, whereby implanted cells actively participate in the regenerative process. Beyond cost and delayed graft availability, the patient-specific performance of engineered tissues poses serious concerns on their clinical translation ability. A more exciting paradigm consists in exploiting cell-laid, engineered extracellular matrices (eECM), which can be used as off-the-shelf materials. Here, the regenerative capacity solely relies on the preservation of the eECM structure and embedded signals to instruct an endogenous repair. We recently described the possibility to exploit custom human stem cell lines for eECM manufacturing. In addition to the conferred standardization, the availability of such cell lines opened avenues for the design of tailored eECMs by applying dedicated genetic tools. In this study, we demonstrated the exploitation of CRISPR/Cas9 as a high precision system for editing the composition and function of eECMs. Human mesenchymal stromal/stem cell (hMSC) lines were modified to knockout VEGF and RUNX2 and assessed for their capacity to generate osteoinductive cartilage matrices. We report the successful editing of hMSCs, subsequently leading to targeted VEGF and RUNX2-knockout cartilage eECMs. Despite the absence of VEGF, eECMs retained full capacity to instruct ectopic endochondral ossification. Conversely, RUNX2-edited eECMs exhibited impaired hypertrophy, reduced ectopic ossification and superior cartilage repair in a rat osteochondral defect. In summary, our approach can be harnessed to identify the necessary eECM factors driving endogenous repair. Our work paves the road towards the compositional eECMs editing and their exploitation in broad regenerative contexts.
Neuroprotective role of lactate in a humanin vitromodel of the ischemic penumbra
Authors: Cerina Marta , Levers Marloes , Keller Jason M. , Frega Monica
Published: July 2023

In patients suffering from cerebral ischemic stroke, there is an urgent need for treatments to protect brain cells. Recently, treatment strategies that induce neuronal activity have been shown to be neuroprotective. However, the biological mechanisms underlying the benefit from neuronal activation are unknown. We hypothesized that neuronal activation might trigger the astrocyte-to-neuron lactate shuttle, whereby lactate is released from astrocytes to support the energy requirements of hypoxic neurons, and this leads to the observed neuroprotection. We tested this by establishing a human cell basedin vitromodel of the ischemic penumbra. We found that lactate transporters are involved in the neuroprotective effect mediated by neuronal activation, that lactate exogenously administered before hypoxia correlated with neuroprotection, and that stimulation of astrocyte with consequent endogenous production of lactate resulted in neuroprotection. We presented evidence that lactate contributes to neuroprotection during hypoxia providing a potential basis for therapeutic approaches in ischemic stroke.
A molecularly-defined non-redundant subpopulation of OPCs controls the generation of myelinating oligodendrocytes during postnatal development
Authors: Moghimyfiroozabad Shayan , Paul Maela A. , Bellenger Lea , Selimi Fekrije
Published: July 2023

Oligodendrocyte precursor cells (OPCs) are a class of glial cells that uniformly tiles the whole central nervous system. They play several key functions across the brain including the generation of oligodendrocytes and the control of myelination. Whether the functional diversity of OPCs is the result of genetically defined subpopulations or of their regulation by external factors has not been definitely established. We discovered that a subpopulation of OPCs found across the brain is defined by the expression ofC1ql1, a gene previously described for its synaptic function in neurons. This subpopulation starts to appear during the first postnatal week in the mouse brain. Ablation ofC1ql1-expressing OPCs in the mouse is not compensated by the remaining OPCs, and results in a massive lack of oligodendrocytes and myelination in many brain regions. Therefore,C1ql1is a molecular marker of a functionally non-redundant subpopulation of OPCs, which controls the generation of myelinating oligodendrocytes.
Neural correlates of spatiotemporal properties of lightness induction
Authors: Malik Amna , Boyaci Huseyin
Published: July 2023

The lightness of a surface depends not only on the amount of light reflected off it but also on the context it is embedded in. Despite a long history of research, neural correlates of context-dependent lightness perception remain a question of ongoing debate. The current study seeks to expand upon the existing literature by measuring fMRI responses to a dynamic version of a classical effect called simultaneous lightness induction (SLI), where a central disk appears lighter when embedded in a darker surround compared to when embedded in a lighter surround. During the fMRI experiment, we presented ten participants with a dynamic SLI stimulus by modulating the luminance of either the achromatic surround (surround-modulation condition) or the achromatic disk (disk-modulation condition) at four different frequencies ranging from 1 to 8 Hz. Behaviorally, when the surround luminance is modulated at low frequencies, participants perceive an illusory change in the lightness of the disk (lightness induction). In contrast, they perceive little or no induction at higher frequencies. Utilizing this temporal dependence and controlling for long-range responses to border contrast and luminance changes, we found that activity in the primary visual cortex (V1) correlates with lightness induction. However, such a correlation was not evident in extrastriate areas, V2, V3, and V4. These findings provide evidence for the involvement of V1 in the processing of context-dependent lightness.
Systematic characterization of site-specific proline hydroxylation using hydrophilic interaction chromatography and mass spectrometry
Authors: Jiang Hao , Druker Jimena , Wilson James W. , Bensaddek Dalila , Swedlow Jason R. , Rocha Sonia , Lamond Angus I.
Published: July 2023

To improve understanding of the role of site-specific proline hydroxylation in controlling protein function, we have developed a robust workflow for the identification of proline hydroxylation sites in proteins using a combination of hydrophilic interaction chromatography (HILIC) enrichment and high-resolution nano-Liquid Chromatography-Mass Spectrometry (LC-MS). Using this approach, together with refining and filtering parameters during data analysis, by combining the results from cell lines being treated with either the prolyl hydroxylase inhibitor Roxadustat (FG-4592, FG) or the proteasome inhibitor MG-132 (MG), or DMSO, a total of 4,993 and 3,247 proline hydroxylation sites were identified in HEK293 and RCC4 samples, respectively. A subset of 1,954 and 1,253 high confident proline hydroxylation sites (non-collagen) from HEK293 and RCC4 samples were inhibited by FG-4592 treatment. A set of features characteristic of proline hydroxylated peptides were identified in both datasets, which differ from either unmodified peptides, or oxidised peptides. Peptides containing hydroxyproline were enriched in the more hydrophilic HILIC fractions and showed characteristic differences in charge and mass distribution, as compared with unmodified or oxidised peptides. Furthermore, we discovered that the intensity of the diagnostic hydroxyproline immonium ion was greatly influenced by parameters including the MS collision energy setting, parent peptide concentration and the sequence of adjacent amino acids neighbouring the modified proline. We show using synthetic peptides that a combination of retention time in LC and optimised MS parameter settings allows reliable identification of proline hydroxylation sites in peptides, even when multiple prolines residues are present. By matching all the proline hydroxylated, non-collagen proteins to the Pfam database, the most common protein family domains identified in both HEK293 and RCC4 datasets were RNA recognition motif (RRM_1), WD40 repeat (WD40), and protein kinase domain (Pkinase). Sequence analysis of the hydroxylated peptides showed enrichment for the motif GxPGxx, including the Gxx repeats found in collagen proteins, as well as the protein kinase domain GTP motif. Glycine (G), serine (S) and glutamic acid (E) residues were found frequently in the sequence window from the hydroxylated peptides. Reactome pathway analysis for the proteins of these newly identified proline hydroxylation sites (FG inhibited), showed enrichment for proteins involved in metabolism of RNA, mRNA splicing and cell cycle regulation, potentially mediated by prolyl hydroxylase enzymes (PHDs).
Effect of the LSD1 Inhibitor RN-1 on γ-globin and Global Gene Expression during Erythroid Differentiation in Baboons (Papio anubis)
Authors: Ibanez Vinzon , Vaitkus Kestis , Ruiz Maria Armila , Lei Zhengdeng , Mannschein-Cline Mark , Arbieva Zarema , Lavelle Donald
Published: July 2023

Increased levels of Fetal Hemoglobin reduce the severity of symptoms of patients with sickle cell disease and decrease the risk of death. An affordable, small molecule drug that stimulates HbF expression in vivo would be ideally suited to treat the large numbers of SCD patients that exist worldwide. Our previous work showed that administration of the LSD1 (KDM1A) inhibitor RN-1 to normal baboons increased Fetal Hemoglobin (HbF) and was tolerated over a prolonged treatment period. HbF elevations were associated with changes in epigenetic modifications that included increased levels of H3K4 di-and tri-methyl lysine at the γ-globin promoter. While dramatic effects of the loss of LSD1 on hematopoietic differentiation have been observed in murine LSD1 gene deletion and silencing models, the effect of pharmacological inhibition of LSD1 in vivo on hematopoietic differentiation is unknown. The goal of these experiments was to investigate the in vivo mechanism of action of the LSD1 inhibitor RN-1 by determining its effect on γ-globin expression in highly purified subpopulations of bone marrow erythroid cells enriched for varying stages of erythroid differentiation isolated directly from baboons treated with RN-1 and also by investigating the effect of RN1 on the global transcriptome in a highly purified population of proerythroblasts. Our results show that RN-1 administered to baboons targets an early event during erythroid differentiation responsible for γ-globin repression and increases the expression of a limited number of genes including genes involved in erythroid differentiation such as GATA2, GFi-1B, and LYN.
Generation of porcine PK-15 cells lacking theIfnar1gene to optimize the efficiency of viral isolation
Authors: Shofa Maya , Saito Akatsuki
Published: July 2023

Because pigs are intermediate or amplifying hosts for several zoonotic viruses, the pig-derived PK-15 cell line is an indispensable tool for studying viral pathogenicity and developing treatments, vaccines, and preventive measures to mitigate the risk of disease outbreaks. However, we must consider the possibility of contamination by type I interferons (IFNs), such as IFNα and IFNβ, or IFN-inducing substances, such as virus-derived double-stranded RNA or bacterial lipopolysaccharides, in clinical samples, leading to lower rates of viral isolation. In this study, we aimed to generate a PK-15 cell line that can be used to isolate viruses from clinical samples carrying a risk of contamination by IFN-inducing substances. To this end, we depleted the IFN alpha and beta receptor subunit 1 (Ifnar1) gene in PK-15 cells using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 method. Treatment of PK-15 cells lackingIfnar1with IFNβ resulted in no inhibitory effects on viral infection by a lentiviral vector, influenza virus, and Akabane virus. These results demonstrate that PK-15 cells lackingIfnar1could represent a valuable and promising tool for viral isolation, vaccine production, and virological investigations.
Hallucination proneness alters sensory feedback processing in self-voice production
Authors: Duggirala Suvarnalata Xanthate , Schwartze Michael , Goller Lisa K. , Linden David E. J. , Pinheiro Ana P. , Kotz Sonja A.
Published: July 2023

Background

Sensory suppression occurs when hearing one’s self-generated voice, as opposed to passively listening to one’s own voice. Quality changes of sensory feedback to the self-generated voice can increase attentional control. These changes affect the self-other voice distinction and might lead to hearing non-existent voices in the absence of an external source (i.e., auditory verbal hallucinations (AVH)). However, it is unclear how changes in sensory feedback processing and attention allocation interact and how this interaction might relate to hallucination proneness (HP).

Study Design

Participants varying in HP self-generated and passively listened to their voice that varied in emotional quality and certainty of recognition — 100% neutral, 60-40% neutral-angry, 50-50% neutral-angry, 40-60% neutral-angry, 100% angry, during EEG recordings.

Study Results

The N1 auditory evoked potential was more suppressed for the self-generated than externally generated voices. Increased HP was associated with (i) an increased N1 response to the self-compared to externally generated voices, (ii) a reduced N1 response for angry compared to neutral voices, and (iii) a reduced N2 response to unexpected voice quality in sensory feedback (60-40% neutral-angry) compared to neutral voices.

Conclusions

The current study highlights an association between increased HP and systematic changes of the emotional quality and certainty in sensory feedback processing (N1) and attentional control (N2) in self-voice production in a non-clinical population. Considering that voice hearers also display these changes, these findings support the continuum hypothesis. However, additional research is needed to validate this conclusion.
Interaction of high-fat diet and brain trauma alters adipose tissue macrophages and brain microglia associated with exacerbated cognitive dysfunction
Authors: Henry Rebecca J. , Barrett James P. , Vaida Maria , Khan Niaz Z. , Makarevich Oleg , Ritzel Rodney M. , Faden Alan I. , Stoica Bogdan A.
Published: July 2023

Obesity increases the morbidity and mortality of traumatic brain injury (TBI). We performed a detailed analysis of transcriptomic changes in the brain and adipose tissue to examine the interactive effects between high-fat diet-induced obesity (DIO) and TBI in relation to central and peripheral inflammatory pathways, as well as neurological function. Adult male mice were fed a high-fat diet (HFD) for 12 weeks prior to experimental TBI and continuing after injury. Combined TBI and HFD resulted in additive dysfunction in the Y-Maze, novel object recognition (NOR), and Morris water maze (MWM) cognitive function tests. We also performed high-throughput transcriptomic analysis using Nanostring panels of cellular compartments in the brain and total visceral adipose tissue (VAT), followed by unsupervised clustering, principal component analysis, and IPA pathway analysis to determine shifts in gene expression programs and molecular pathway activity. Analysis of cellular populations in the cortex and hippocampus as well as in visceral adipose tissue during the chronic phase after combined TBI-HFD showed amplification of central and peripheral microglia/macrophage responses, including superadditive changes in select gene expression signatures and pathways. These data suggest that HFD-induced obesity and TBI can independently prime and support the development of altered states in brain microglia and visceral adipose tissue macrophages, including the disease-associated microglia/macrophage (DAM) phenotype observed in neurodegenerative disorders. The interaction between HFD and TBI promotes a shift toward chronic reactive microglia/macrophage transcriptomic signatures and associated pro-inflammatory disease-altered states that may, in part, underlie the exacerbation of cognitive deficits. Targeting of HFD-induced reactive cellular phenotypes, including in peripheral adipose tissue macrophages, may serve to reduce microglial maladaptive states after TBI, attenuating post-traumatic neurodegeneration and neurological dysfunction.
Sex, gender diversity, and brain structure in children ages 9 to 11 years old
Authors: Torgerson Carinna , Ahmadi Hedyeh , Choupan Jeiran , Fan Chun Chieh , Blosnich John R. , Herting Megan M.
Published: July 2023

There remains little consensus about the relationship between sex and brain structure, particularly in childhood. Moreover, few pediatric neuroimaging studies have analyzed both sex and gender as variables of interest - many of which included small sample sizes and relied on binary definitions of gender. The current study examined gender diversity with a continuous felt-gender score and categorized sex based on X and Y allele frequency in a large sample of children ages 9-11 years-old (N=7693). Then, a statistical model-building approach was employed to determine whether gender diversity and sex independently or jointly relate to brain morphology, including subcortical volume, cortical thickness, gyrification, and white matter microstructure. The model with sex, but not gender diversity, was the best-fitting model in 75% of gray matter regions and 79% of white matter regions examined. The addition of gender to the sex model explained significantly more variance than sex alone with regard to bilateral cerebellum volume, left precentral cortical thickness, as well as gyrification in the right superior frontal gyrus, right parahippocampal gyrus, and several regions in the left parietal lobe. For mean diffusivity in the left uncinate fasciculus, the model with sex, gender, and their interaction captured the most variance. Nonetheless, the magnitude of variance accounted for by sex was small in all cases and felt-gender score was not a significant predictor on its own for any white or gray matter regions examined. Overall, these findings demonstrate that at ages 9-11 years-old, sex accounts for a small proportion of variance in brain structure, while gender diversity is not directly associated with neurostructural diversity.

Highlights

Sex-related variance in regional human brain structure is widespread at ages 9-11

Together, sex and gender diversity accounted for more variance in only a few regions

Felt-gender diversity itself was not significantly related to any outcome at ages 9-11

Effect sizes for sex and felt-gender estimates were small
Distinct human stem cell subpopulations drive adipogenesis and fibrosis in musculoskeletal injury
Authors: Garcia Steven M. , Lau Justin , Diaz Agustin , Chi Hannah , Lizarraga Miguel , Wague Aboubacar , Montenegro Cristhian , Davies Michael R. , Liu Xuhui , Feeley Brian T.
Published: July 2023

Fibroadipogenic progenitors (FAPs) maintain healthy skeletal muscle in homeostasis but drive muscle degeneration in chronic injuries by promoting adipogenesis and fibrosis. To uncover how these stem cells switch from a pro-regenerative to pro-degenerative role we perform single-cell mRNA sequencing of human FAPs from healthy and injured human muscles across a spectrum of injury, focusing on rotator cuff tears. We identify multiple subpopulations with progenitor, adipogenic, or fibrogenic gene signatures. We utilize full spectrum flow cytometry to identify distinct FAP subpopulations based on highly multiplexed protein expression. Injury severity increases adipogenic commitment of FAP subpopulations and is driven by the downregulation of DLK1. Treatment of FAPs bothin vitroandin vivowith DLK1 reduces adipogenesis and fatty infiltration, suggesting that during injury, reduced DLK1 within a subpopulation of FAPs may drive degeneration. This work highlights how stem cells perform varied functions depending on tissue context, by dynamically regulating subpopulation fate commitment, which can be targeted improve patient outcomes after injury.
Cocaine Regulates Antiretroviral Therapy CNS Access Through Pregnane-X Receptor-Mediated Drug Transporter and Metabolizing Enzyme Modulation at the Blood Brain Barrier
Authors: Fridman Lisa B. , Knerler Stephen , Price Amira-Storm , Ortiz Rodnie Colón , Mercado Alicia , Wilkins Hannah , Flores Bianca R. , Orsburn Benjamin C. , Williams Dionna W.
Published: July 2023

Background

Appropriate interactions between antiretroviral therapies (ART) and drug transporters and metabolizing enzymes at the blood brain barrier (BBB) are critical to ensure adequate dosing of the brain to achieve HIV suppression. These proteins are modulated by demographic and lifestyle factors, including substance use. While understudied, illicit substances share drug transport and metabolism pathways with ART, increasing the potential for adverse drug:drug interactions. This is particularly important when considering the brain as it is relatively undertreated compared to peripheral organs and is vulnerable to substance use-mediated damage.

Methods

We used anin vitromodel of the human BBB to determine the extravasation of three first-line ART drugs, emtricitabine (FTC), tenofovir (TFV), and dolutegravir (DTG), in the presence and absence of cocaine, which served as our illicit substance model. The impact of cocaine on BBB integrity and permeability, drug transporters, metabolizing enzymes, and their master transcriptional regulators were evaluated to determine the mechanisms by which substance use impacted ART central nervous system (CNS) availability.

Results

We determined that cocaine had a selective impact on ART extravasation, where it increased FTC’s ability to cross the BBB while decreasing TFV. DTG concentrations that passed the BBB were below quantifiable limits. Interestingly, the potent neuroinflammatory modulator, lipopolysaccharide, had no effect on ART transport, suggesting a specificity for cocaine. Unexpectedly, cocaine did not breach the BBB, as permeability to albumin and tight junction proteins and adhesion molecules remained unchanged. Rather, cocaine selectively decreased the pregnane-x receptor (PXR), but not constitutive androstane receptor (CAR). Consequently, drug transporter expression and activity decreased in endothelial cells of the BBB, including p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 4 (MRP4). Further, cytochrome P450 3A4 (CYP3A4) enzymatic activity increased following cocaine treatment that coincided with decreased expression. Finally, cocaine modulated adenylate kinases are required to facilitate biotransformation of ART prodrugs to their phosphorylated, pharmacologically active counterparts.

Conclusion

Our findings indicate that additional considerations are needed in CNS HIV treatment strategies for people who use cocaine, as it may limit ART efficacy through regulation of drug transport and metabolizing pathways at the BBB.
Stimulus representation in human frontal cortex supports flexible control in working memory
Authors: Shao Zhujun , Zhang Mengya , Yu Qing
Published: July 2023

When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.
Cognitive Individuality and Underlying Creativity in Statistical Learning
Authors: Daikoku Tatsuya , KAMERMANS Kevin , Minatoya Maiko
Published: July 2023

Statistical learning starts at an early age and is intimately linked to brain development and the emergence of individuality. Through such a long period of statistical learning, the brain updates and constructs statistical models, with the model's individuality changing based on the type and degree of stimulation received. However, the detailed mechanisms underlying this process are unknown. This paper argues three main points of statistical learning, including 1) cognitive individuality based on reliability of prediction, 2) the construction of information hierarchy through chunking, and 3) the acquisition of 1-3Hz rhythm that is essential for early language and music learning. We developed a Hierarchical Bayesian Statistical Learning (HBSL) model that takes into account both reliability and hierarchy, mimicking the statistical learning processes of the brain. Using this model, we conducted a simulation experiment to visualize the temporal dynamics of perception and production processes through statistical learning. By modulating the sensitivity to sound stimuli, we simulated three cognitive models with different reliability on bottom-up sensory stimuli relative to top-down prior prediction: hypo-sensitive, normal-sensitive, and hyper-sensitive models. We suggested that statistical learning plays a crucial role in the acquisition of 1-3 Hz rhythm. Moreover, a hyper-sensitive model quickly learned the sensory statistics but became fixated on their internal model, making it difficult to generate new information, whereas a hypo-sensitive model has lower learning efficiency but may be more likely to generate new information. Various individual characteristics may not necessarily confer an overall advantage over others, as there may be a trade-off between learning efficiency and the ease of generating new information. This study has the potential to shed light on the heterogeneous nature of statistical learning, as well as the paradoxical phenomenon in which individuals with certain cognitive traits that impede specific types of perceptual abilities exhibit superior performance in creative contexts.
Theories, constructs and contexts in responsible leadership: a future research agenda
Authors: Pathak Priyanka , Jha Sumi
Published: July 2023

Purpose

The study explores the current research trends within the responsible leadership (RL) domain and proposes a future research agenda by conducting an extensive review of past research. The study aims to understand recent developments in theories, constructs and contexts in RL literature.

Design/methodology/approach

Scopus database is used for the data collection on RL and patterns from 1998–2022. In total, 138 articles were covered for a systematic literature review (SLR) of RL behaviors. Further, the search was extended, and 109 more articles were included for bibliometric analysis of RL using R software. In total, 247 papers were reviewed.

Findings

The results present the consequences and antecedents of RL behaviors with external and internal stakeholders. Literature also indicates that researchers are more attentive to empirical studies with internal stakeholders, such as responsible leaders' impact on employee outcomes. Among theories, stakeholder theory's normative integrative and instrumental perspectives are used with RL.

Research limitations/implications

The first limitation of the study is that this study collected data only from the Scopus database and the choice of language was English. Future studies may use other databases, languages and keywords. Instrumental and integrative RL behavioral styles would help balance organizations' financial and social goals.

Originality/value

This research enhances the literature on RL by combining content and bibliometric analysis to develop a more systematic and comprehensive understanding of integrative and instrumental leadership behaviors.
“Stay home, save SMEs”? The impact of a unique strict COVID-19 lockdown on small businesses
Authors: Mukherjee Abhishek , Scott Jonathan M. , Deakins David , McGlade Paul
Published: July 2023

Purpose

In exploring how small and medium-sized enterprises (SMEs) overcame COVID-19 restrictions by deploying their specific dynamic capabilities to pivot their business models, this article explains the novel approaches that SMEs take and how they have responded to the financial challenges that arose from the pandemic.

Design/methodology/approach

The article adopts a dynamic capabilities lens to explain: (1) the specific financial effects of the relatively “short” (seven week) COVID-19 lockdown during March and April 2020 on SMEs; (2) the barriers they faced; and (3) how they overcame these barriers. The data were collected via semi-structured interviews with the owner-manager or a senior manager in each surveyed SME. The interview data were analysed using NVivo.

Findings

Analysis of the findings revealed five key factors: (1) the capability of SMEs to access external resources, especially entrepreneurial finance; (2) their ability to reconfigure resources and plan for the longer term, yet retain flexibility; (3) how entrepreneurial learning provided the capability to deal with the “unplanned” events/uncertainty; (4) the importance of networking and sources of information; and (5) the remarkable optimism for a future recovery, despite the difficulties of the trading period.

Originality/value

This research fills a unique niche, as no previous studies have examined the resilience and dynamic capabilities of SMEs during a complete lockdown and business shutdown of this magnitude. This context, unprecedented in the history of modern economies, offers a new lens through which to understand the mechanisms of business survival and adaptation in times of severe disruptions. No previous studies have been conducted in unique circumstances during a time when SMEs were faced with such a strict lockdown with travel and business completely shut down.