bluuebunny/crossref_metadata_2025_split huggingface dataset:
TrkA+sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression
Authors: Qin Qizhi , Ramesh Sowmya , Li Zhao , Zhong Lingke , Cherief Masnsen , Archer Mary , Xing Xin , Thottappillil Neelima , Gomez-Salazar Mario , Xu Mingxin , Zhu Manyu , Chang Leslie , Uniyal Ankit , Mazhar Khadijah , Mittal Monisha , McCarthy Edward F. , Morris Carol D. , Levi Benjamin , Guan Yun , Clemens Thomas L. , Price Theodore J. , James Aaron W. 
Published: June 2024

AbstractBone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multi-omics analyses of human OS bone samples and human dorsal root ganglia neurons further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. In order to curb tumor-associated axonal ingrowth, we next leveraged FDA-approved bupivacaine liposomes leading to significant reductions in sarcoma growth, vascularity, as well as alleviation of pain. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition appears to disrupt calcitonin receptor signaling (CALCR) and VEGF signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of osteosarcoma represent a novel adjunctive therapy to improve clinical outcomes and survival.
Ketamine-Induced Unresponsiveness Shows a Harmonic Shift from Global to Localised Functional Organisation
Authors: Van Maldegem M. , Vohryzek J. , Atasoy S. , Alnagger N. , Cardone P. , Bonhomme V. , Vanhaudenhuyse A. , Demertzi A. , Jaquet O. , Bahri M. A. , Kringelbach M. L. , Stamatakis E. A. , Luppi A. I. 
Published: June 2024

AbstractKetamine is classified as a dissociative anaesthetic that, in sub-anaesthetic doses, can produce an altered state of consciousness characterised by dissociative symptoms, visual and auditory hallucinations, and perceptual distortions. Given the anaesthetic-like and psychedelic-like nature of this compound, it is expected to have different effects on brain dynamics in anaesthetic doses than in low, sub-anaesthetic doses. We investigated this question using connectome harmonic decomposition (CHD), a recently developed method to decompose brain activity in terms of the network organisation of the underlying human structural connectome. Previous research using this method has revealed connectome harmonic signatures of consciousness and responsiveness, with increased influence of global network structure in disorders of consciousness and propofol-induced sedation, and increased influence of localised patterns under the influence of classic psychedelics and sub-anaesthetic doses of ketamine, as compared to normal wakefulness. When we applied the CHD analytical framework to resting-state fMRI data of volunteers during ketamine-induced unresponsiveness, we found increased prevalence of localised harmonics, reminiscent of altered states of consciousness. This is different from traditional GABAergic sedation, where instead the prevalence of global rather than localised harmonics seems to increase with higher doses. In addition, we found that ketamine’s harmonic signature shows higher alignment with those seen in LSD- or psilocybin-induced psychedelic states than those seen in unconscious individuals, whether due to propofol sedation or brain injury. Together, the results indicate that ketamine-induced unresponsiveness, which does not necessarily suppress conscious experience, seems to influence the prevalence of connectome harmonics in the opposite way compared to GABAergic hypnotics. We conclude that the CHD framework offers the possibility to track alterations in conscious awareness (e.g., dreams, sensations) rather than behavioural responsiveness – a discovery made possible by ketamine’s unique property of decoupling these two facets.
Comprehensive assessment of recessive, pathogenicAARS1alleles in a humanized yeast model reveals loss-of-function and dominant-negative effects
Authors: Kuo Molly E. , Parish Maclaine , Jonatzke Kira E. , Antonellis Anthony 
Published: June 2024

ABSTRACTAlanyl-tRNA synthetase 1 (AARS1) encodes the enzyme that ligates tRNA molecules to alanine in the cytoplasm, which is required for protein translation. Variants inAARS1have been implicated in early-onset, multi-system recessive phenotypes and in later-onset dominant peripheral neuropathy; to date, no single variant has been associated with both dominant and recessive diseases raising questions about shared mechanisms between the two inheritance patterns.AARS1variants associated with recessive disease are predicted to result in null or hypomorphic alleles and this has been demonstrated, in part, via yeast complementation assays. However, pathogenic alleles have not been assessed in a side-by-side manner to carefully scrutinize the strengths and limitations of this model system. To address this, we employed a humanized yeast model to evaluate the functional consequences of allAARS1missense variants reported in recessive disease. The majority of variants showed variable loss-of-function effects, ranging from no growth to significantly reduced growth. These data deem yeast a reliable model to test the functional consequences of humanAARS1variants; however, our data indicate that this model is prone to false-negative results and is not informative for genotype-phenotype studies. We next tested missense variants associated with no growth for dominant-negative effects. Interestingly, K81TAARS1, a variant implicated in recessive disease, demonstrated loss-of-function and dominant-negative effects, indicating that certainAARS1variants may be capable of causing both dominant and recessive disease phenotypes.
Transcriptomic study of testicular hypoxia adaptation in Tibetan sheep
Authors: Yu Binyan , Yang Yanan , Li Yijian , Gao Rong , Ma Min , Wang Xinrong 
Published: June 2024

AbstractThe Tibetan sheep is a typical hypoxia-tolerant mammal, which lives on the plateau, an altitude of between 2,500 and 5,000 meters above sea level, the study of its hypoxic adaptation mechanism provides reference for exploring the hypoxic adaptation mechanism of other animals. To grope for the genetic mechanism of adaptation to hypoxic environment at the transcriptional level in Tibetan sheep testicular tissue, and to identify candidate genes and key pathways related to sheep adaptation. Histological observation of testicular tissues from two sheep breeds was carried out using hematoxylin-eosin (HE) conventional staining. A total of 277 differentially expressed genes (DEGs) were authenticated at high altitude Tibetan sheep (ZYH) and low altitude Tibetan sheep (ZYM) by RNA sequencing technology (RNA-Seq), which included 165 up-regulated genes and 112 down-regulated genes. Functional analyses revealed several terms and pathways, such as were closely related with testis adaptation to plateau. Several genes (includingGGT5, AGTR2, EDN1, LPAR3, CYP2C19, IGFBP3, APOC3andPKC1) were remarkably enriched in several pathways and terms, which may impact the Plateau adaptability of sheep by adjusting its reproductive activity and sexual maturation, and protecting Sertoli cells, various spermatocytes and spermatogenesis processes. The results make a reasonable case for a better understanding of the molecular mechanisms of adaptation to altitude in sheep.
MICROENDOSCOPIC CALCIUM IMAGING IN SUPPLEMENTARY MOTOR AREA AND PRIMARY MOTOR CORTEX OF RHESUS MACAQUES AT REST AND DURING ARM MOVEMENT
Authors: Martel Anne-Caroline , Pittard Damien , Devergnas Annaelle , Risk Benjamin , Nassi Jonathan J. , Yu Waylin , Downer Joshua D. , Wichmann Thomas , Galvan Adriana 
Published: June 2024

SUMMARYThe study of motor cortices in non-human primates is relevant to our understanding of human motor control, both in healthy conditions and in movement disorders. Calcium imaging and miniature microscopes allow the study of multiple genetically identified neurons with excellent spatial resolution. We used this method to examine activity patterns of projection neurons in deep layers of the supplementary motor (SMA) and primary motor areas (M1) in four rhesus macaques. We implanted gradient index lenses and expressed GCaMP6f to image calcium transients while the animals were at rest or engaged in an arm reaching task. We tracked the activity of SMA and M1 neurons across conditions, examined cell pairs for synchronous activity, and assessed whether SMA and M1 neuronal activation followed specific sequential activation patterns. We demonstrate the value ofin vivocalcium imaging for studying patterns of activity in groups of corticofugal neurons in SMA and M1.HIGHLIGHTSUse of one-photon miniature microscopes and microendoscopic calcium imaging to study the activity of cortical projection neurons in the supplementary motor area (SMA) and primary motor cortex (M1) of rhesus macaques at rest or performing simple arm reaches.Calcium transients were related to arm reaches and showed directional sensitivity in a proportion of cells in SMA and M1.Subsets of cell pairs showed coactivation in SMA and M1 during rest and reaching tasks. The strength of coactivity was not related to the distance between cells.SMA and M1 neurons displayed sequential activation patterns.We demonstrated that microendoscopic calcium imaging can be used to assess dynamic activity within genetically identified cell populations in deep layers of SMA and M1.
Identification and Functional Characterization of lncRNAs involved in Human Monocyte-to-Macrophage Differentiation
Authors: Montano Christy , Covarrubias Sergio , Malekos Eric , Katzman Sol , Carpenter Susan 
Published: June 2024

AbstractLong noncoding RNAs (lncRNAs) make up the largest portion of RNA produced from the human genome, but only a small fraction have any ascribed functions. Although the role of protein-coding genes in macrophage biology has been studied extensively, our understanding of the role played by lncRNAs in this context is still in its early stages. There are over 20,000 lncRNAs in the human genome therefore, attempting to select a lncRNA to characterize functionally can be a challenge. Here we describe two approaches to identify and functionally characterize lncRNAs involved in monocyte-to-macrophage differentiation. The first involves the use of RNA-seq to infer possible functions and the second involves a high throughput functional screen. We examine the advantages and disadvantages of these methodologies and the pipelines for validation that assist in determining functional lncRNAs.
Mature and migratory dendritic cells promote immune infiltration and response to anti-PD-1 checkpoint blockade in metastatic melanoma
Authors: Yang Jiekun , Wang Cassia , Fu Doris , Ho Li-Lun , Galani Kyriakitsa , Chen Lee , Frederick Dennie T , He Liang , Huang Amy Y. , Robitschek Emily J. , Yadav Sandeep K. , Deng Wentao , Tacke Rahul , Burke Kelly P. , Sharova Tatyana , Rai Kunal , Liu David , Boland Genevieve M. , Kellis Manolis 
Published: June 2024

AbstractImmune checkpoint inhibitors (ICIs) have heralded a remarkable shift in cancer care, significantly extending survival for advanced cancer patients. However, despite their remarkable clinical successes, a substantial majority of patients fail to achieve a lasting response to ICIs. To address this challenge and gain insights into the complex landscape of the tumor microenvironment (TME), we conducted an extensive analysis using single-cell RNA sequencing (scRNA; ∼216K cells across 39 samples) and single-nucleus transposase-accessible chromatin sequencing (snATAC; ∼43K cells from 15 samples) in a metastatic melanoma cohort. This systematic approach delineates 14 distinct cell types and 55 cell subtypes, including the identification of 15 transcriptional hallmarks of malignant cells. Through correlation analysis of cell subtype proportions, we unveiled six distinct clusters associated with varying tumor responses. Particularly intriguing was the identification of the mature DC enriched in immunoregulatory molecules (mregDC) subtype exhibiting correlations with naive T and B cells, forming an anti-tumor program that underscores the importance of multiple immune cell types in mediating anti-tumor immunity. Notably, we found that mregDC abundance represents a good prognostic predictor of progression-free survival (PFS) in the context of ICI treatment, and when combined with the TCF7+/- CD8 T cell ratio, it reliably predicts patient PFS across treatments beyond ICI. We validated our findings using an independent cohort of 274 ICI-treated melanoma samples analyzed using tissue-level expression. We next compared mregDCs and conventional dendritic cell types 1 and 2 (cDC1 and cDC2) using transcriptome signature, differentiation trajectory, interactome, cytokine milieu, and epigenome landscape analyses. This comparative analysis shed light on the unique attributes of mregDCs within the TME. Finally, we investigated cell type/subtype-specific genes, pathways, immune response enrichment, and ligand-receptor interactions closely associated with the proportions of mregDCs within the TME. These molecular and cellular insights, with their critical roles in enhancing the immune response against cancer, offer valuable prospects for predicting the efficacy of ICI regimens, and potentially guiding the selection of rational combinatorial therapies.
Assessing mechanisms driving phenol isopropylated phosphate (IPP)-induced larval photomotor response deficits in zebrafish
Authors: Sharma Sunil , Rojas Alfredo , Serradimigni Rosemaria , Leong Connor , Dasgupta Subham 
Published: June 2024

AbstractPhenol isopropylated phosphates (IPP) are an additive organophosphate flame retardant (OPFR) which has been extensively used in furniture, electronics, automobiles, plastics, and children’s products to slow down the spread of fire. The processing and distribution of IPP-containing products have been prohibited but its continuous leaching from end use products has retained the concern of its toxicity. The present study was designed to evaluate IPP-induced developmental toxicity using zebrafish embryos. We first conducted range finding experiments with embryonic zebrafish exposures to 0-200 μM IPP from 6 to 120 h post fertilization and found significant morphological impacts like pericardial edema, yolk sac edema and spinal curvature at higher concentrations. For behavioral readouts, we performed larval photomotor response (LPR) assay at sublethal concentrations and observed hypoactive locomotory behavior in exposed larvae. Following this, relying on secondary analyses of our whole embryo mRNA-seq data, we conducted-1) retinoic acid receptor (RAR) signaling assay and 2) DNA methylation assays.In vitroassay for RA receptors indicate that IPP significantly inhibits RARα, but not RARβ and RARγ. Whole-mount immunohistochemistry for 5-methylcytosine and global DNA methylation assay showed significant IPP-induced hypermethylationin situ. We conducted IPP co-exposure studies with a methylome modifier 5-azacytidine (Aza-c a methylation inhibitor) or retinoic acid signaling activators to assess if LPR phenotypes were mitigated by co-exposures. Data showed that Aza-c co-exposures partially reversed IPP-induced LPR hypoactivity and DNA hypermethylation, co-exposure with retinoic acid as well as AM580 (an RARα activator) were not able to reverse IPP-induced hypoactivity. Finally, based on RNA-seq data, we hypothesized that IPP affects the development of brain and eyes. Firstly, we performed global DNA methylation in brain and eyes, but did not find any significant effects. Then, we conducted mRNA sequencing on dissected brains and eyes, and found 2 and 135 differentially expressed genes, respectively. Gene ontology revealed that IPP affect phototransduction, voltage gated ion channels, synaptic and neurotransmitter signaling. Collectively, our data shows that IPP induces morphological abnormalities and disrupts larval photo motor response, potentially through methylomic regulation. Finally, we observed that IPP affects gene expression within the developing eye, establishing synaptic transmission, vision and muscle contraction as a potential causative factor for LPR responses.
Integrating neurophysiological insights into effective bird deterrence using flickering light
Authors: Hondaa Takeshi , Tominaga Hiroki , Shimizu Akio 
Published: June 2024

AbstractThere are few effective methods to mitigate the economic or health-related disadvantages caused by birds. Traditional countermeasures employing sound and light have been utilized for mitigating crop damage, but their efficacy is insufficient, and human-avian conflicts persist. This study explores a fundamentally different approach to resolving these conflicts. Flashing lights that alternate between red and blue are known to stimulate the human brain and can potentially cause photosensitive epilepsy in one in 100,000 people, though very rarely. A 15 Hz flashing stimulus is known to elicit a significant response in humans; however, the optimal flashing pattern for birds remained unclear. We investigated the effect of different flickering patterns, specifically 12.5, 15, and 20 Hz, on crows when illuminated from a distance within 200 meters. The flashlight used was a long-range model and the Light Emitting Diodes (LEDs) consumed about 9 watts of power. The power was supplied by 21700 type lithium-ion batteries. Using a long-range flashlight during daylight, we determined that a 15 Hz flashing stimulus was most effective. This finding suggests that the most intense stimulus identified in human physiology can be equally effective when applied to birds. Survival analysis estimated that by projecting this pattern from a distance of 100 meters, crows fled within 8.1 seconds. Unlike traditional bird damage control techniques that rely on neophobia, this study utilizes physiological aversion. In this regard, our approach is fundamentally different from traditional techniques. The method of using flashing light to stimulate the brain, rather than the eyes, is based on insights from human medical and physiological studies. These findings elucidate the principle of a novel aversive stimulus using flashing light, which holds potential for widespread application in mitigating bird-related issues.
BGMDB: A curated database linking gut microbiota dysbiosis to brain disorders
Authors: Shi Kai , Zhao Pengyang , Li lin , Liu Qiaohui , Wu Zhengxia , He Qisheng , Yu Juehua 
Published: June 2024

AbstractThe gut microbiota plays a pivotal role in human health by modulating physiological homeostasis and influencing the pathogenesis of various diseases. Recent studies have underscored the close relationship between neurotransmitters, which act as communication mediators between the gut and brain, and the development and treatment of multiple brain disorders. Despite these advances, the intricate interactions between gut microbiota and brain diseases remain largely unexplored in the extensive biomedical literature. There is a notable absence of a structured database focusing on gut microbiota-brain disease associations. Introducing BGMDB (Brain Disease Gut Microbiota Database), a meticulously curated database designed to provide experimentally supported connections between gut microbiota and brain diseases. The current version of BGMDB extensively covers 1,419 associations involving 609 gut microbiota and 43 brain diseases, including 184 specific association triplets linking brain diseases, neurotransmitters, and gut microbiota among six neurotransmitters. Noteworthy is that BGMDB integrates gene data related to gut microbiota from the gutMGene database. Brain region and disease microbial networks are introduced to investigate potential common genetic relationships between brain diseases and brain region changes. Each entry in BGMDB offers detailed insights into specific associations, including the particular brain disease implicated, the involved gut microbiota, neurotransmitter, and a concise description of the relationship supported by relevant literature references. To facilitate easier access to relevant information for specific brain diseases, BGMDB provides enhanced graphical query options to address various biologically pertinent inquiries. Additionally, a user-friendly interface allows users to browse, retrieve, and download entries conveniently. BGMDB serves as a valuable resource for investigating microbes associated with human brain disorders. Access BGMDB throughhttp://43.139.38.118:8080/demo02/.
Analysis of spatial and temporal risk of Peste des Petits Ruminants Virus (PPRV) outbreaks in endemic settings: A scoping review
Authors: Mwanandota Julius , Hakizimana Jean , Machuka Eunice , Mdetele Daniel , Okoth Edward , Omondi George , Chengula Augustino , Kimera Sharadhuli , Muunda Emmanuel , Misizo Gerald 
Published: June 2024

AbstractBackgroundSustained Peste des petits ruminants (PPR) circulation, as evidenced by surveillance, shows PPR endemicity in Africa and Asia. Regional transmission of PPR is enabled by joining numerous epidemiological factors. Spatial, spatiotemporal and transmission dynamics analytical methods have been used to explore the risk of PPR transmission. The dearth of information on the risk factors associated with spatiotemporal distribution and transmission dynamics of PPR at a regional scale is high. Through a thorough analysis of peer-reviewed literature, this study sought to evaluate the risks of Peste des Petit ruminant virus (PPRV) epidemics by noting distinctions of geographical and spatial-temporal approaches applied in endemic settings.MethodsA scoping literature review of PPR research publications that used spatial and spatiotemporal approaches to assess PPR risks in endemic areas was carried out using PubMed and Google Scholar data base.ResultsOut of 42 papers selected 19 focused on Asia, 15 on Africa, and 8 had a global view. 61.9% used clustering analysis while 35.7% used spatial autocorrelation. Temporal trends were described by most studies at about 71.2% while modeling approaches were used by 13 articles (30%). Five risk factors evaluated include demographics and livestock–wildlife interactions (n = 20), spatial accessibility (n = 19), trade and commerce (n = 17), environment and ecology (n = 12), and socioeconomic aspects (n=9). Transmission dynamics of PPR was covered in almost all articles except 2 articles but it has linked all the risk factors.ConclusionsThe review has contributed to the shifting and improvement of our understanding on PPR outbreaks in endemic settings and support evidence-based decision-making to mitigate the impact of the virus on small ruminant populations. Linkage of other risk factors to livestock trade which is the major driver of livestock movement has been shown to pose a significant risk of PPR epidemics in endemic settings. With many studies being found in Asia compared to Africa, future development of predictive models to evaluate possible eradication strategies at national and regional levels should also consider Africa.