bluuebunny/crossref_metadata_2025 huggingface dataset:
Knee Contact Forces of Individuals With Osteoarthritis and Those With Lower Limb Amputation
Authors: Andrag Lizanne , Kunorozva Lovemore , Derman Wayne , Runciman Phoebe
Published: June 2024

Objective

Osteoarthritis is a major cause of impairment. Research has shown that individuals with unilateral lower limb amputation are 17 times more likely to develop osteoarthritis on their sound side limb. Therefore, this review aimed to describe similarities and differences in the biomechanical loading variables of individuals with osteoarthritis and those with unilateral lower limb amputation.

Design

Researchers systematically searched PubMed-Medline, EBSCOhost, and Web of Science for articles published between January 1990 and February 2022. Included studies investigated the biomechanical profiles (peak external knee adduction moment; peak external knee flexion moment; ground reaction force; external knee adduction moment loading rate; external knee adduction moment impulse) of both population groups.

Results

A total of 31 articles were included in this review. Only knee adduction moment and knee flexion moment presented similar profiles in both groups, while all other variables were dissimilar. The use of advanced prostheses reduced the loading on the sound side of individuals with unilateral lower limb amputation.

Conclusions

As both knee adduction moment and knee flexion moment are surrogate measures for knee contact forces, interventions need to target these variables to help manage and prevent the development of osteoarthritis. Interventions, particularly for addressing these variables in individuals with unilateral lower limb amputation, should be further investigated in future research.
Mapping the role of sexuality in adolescent mental health and substance use
Authors: Andrews Jack L. , Astle Duncan E. , Jones Jonathan S. , Blakemore Sarah-Jayne
Published: June 2024

Individuals who belong to a sexual minority are at greater risk of adverse health and social outcomes. These effects are observed during adolescence when many mental health problems, such as depression, first emerge. Here, we used a network analytic approach to better understand the role that sexual minority status plays in the association between depression, interpersonal difficulties and substance use in a large sample of mid-adolescents. In doing so, we used data from 8017 fourteen year olds from the UK’s Millennium Cohort Study, of which 490 self-identified as belonging to a sexual minority. We found that sexual minority status was highly central in the network and connected to multiple adverse outcomes, sometimes directly and sometimes indirectly. The largest single association was between sexual minority status and depression, and this link mediated multiple negative associations with being in a sexual minority. The shortest path to drinking, poor social support and closeness with parents and victimization occurred via depression. The shortest path to smoking and drug use occurred via conduct problems. We also identified three distinct profiles of adverse outcomes among those belonging to a sexual minority, highlighting the heterogeneous nature of this group.
Biodiversity as a firewall to engineered microbiomes for restoration and conservation
Authors: Maull Victor , Solé Ricard
Published: June 2024

The possibility of abrupt transitions threatens to poise ecosystems into irreversibly degraded states. Synthetic biology has recently been proposed to prevent them from crossing tipping points. However, there is little understanding of the impact of such intervention on the resident communities. Can such modification have ‘unintended consequences’, such as loss of species? Here, we address this problem by using a mathematical model that allows us to simulate this intervention scenario explicitly. We show how the indirect effect of damping the decay of shared resources results in biodiversity increase, and last but not least, the successful incorporation of the synthetic within the ecological network and very small-positive changes in the population size of the resident community. Furthermore, extensions and implications for future restoration and terraformation strategies are discussed.
Fish (eggs) out of water: evolutionary divergence in terrestrial embryonic plasticity in Trinidadian killifish
Authors: Walsh Matthew R. , Roden Christopher
Published: June 2024

Externally laid eggs are often responsive to environmental cues; however, it is unclear how such plasticity evolves. In Trinidad, the killifish (
Anablepsoides hartii
) is found in communities with and without predators. Here, killifish inhabit shallower, ephemeral habitats in sites with predators. Such shifts may increase the exposure of eggs to air and lead to possible desiccation. We compared egg-hatching plasticity between communities by rearing eggs terrestrially on peat moss or in water. The timing of hatching did not differ between communities when eggs were reared in water. Eggs from sites with predators responded to terrestrial incubation by hatching significantly earlier compared with water-reared eggs. These responses were weaker in sites with no predators. Such divergent trends show that the presence of predators is associated with evolutionary shifts in hatching plasticity. Our results provide evidence for local adaptation in embryonic plasticity at the population scale.
Stratifying macrophages based on their infectious burden identifies novel host targets for intervention during Crohn’s disease associated adherent-invasive Escherichia coli infection
Authors: Li Xiang , Cole John , Vaughan Diane , Xiao Yinbo , Walker Daniel , Wall Daniel M.
Published: June 2024

Bacterial infection is a dynamic process resulting in a heterogenous population of infected and uninfected cells. These cells respond differently based on their bacterial load and duration of infection. In the case of infection of macrophages with Crohn’s disease (CD) associated adherent-invasive Escherichia coli (AIEC), understanding the drivers of pathogen success may allow targeting of cells where AIEC replicate to high levels. Here we show that stratifying immune cells based on their bacterial load identifies novel pathways and therapeutic targets not previously associated with AIEC when using a traditional homogeneous infected population approach. Using flow cytometry-based cell sorting we stratified cells into those with low or high intracellular pathogen loads, or those which were bystanders to infection. Immune cells transcriptomics revealed a diverse response to the varying levels of infection while pathway analysis identified novel intervention targets that were directly related to increasing intracellular AIEC numbers. Chemical inhibition of identified targets reduced AIEC intracellular replication or inhibited secretion of tumour necrosis factor alpha (TNFα), a key cytokine associated with AIEC infection. Our results have identified new avenues of intervention in AIEC infection that may also be applicable to CD through the repurposing of already available inhibitors. Additionally, they highlight the applicability of immune cell stratification post-infection as an effective approach for the study of microbial pathogens.
STHD: probabilistic cell typing of single Spots in whole Transcriptome spatial data with High Definition
Authors: Sun Chuhanwen , Zhang Yi
Published: June 2024

Recent spatial transcriptomics (ST) technologies have enabled single- and sub-cellular resolution profiling of gene expression across the whole transcriptome. However, the transition to high-definition ST significantly increased data sparsity and dimensionality, posing computational challenges in identifying cell types, deciphering neighborhood structure, and detecting differential expression - all are crucial steps to study normal and disease ST samples. Here we present STHD, a novel machine learning method for probabilistic cell typing of single spots in whole-transcriptome, high-resolution ST data. Unlike the current binning-aggregation-deconvolution strategy, STHD directly models gene expression at single-spot level to infer cell type identities without cell segmentation or spot aggregation. STHD addresses sparsity by modeling count statistics, incorporating neighbor similarities, and leveraging reference single-cell RNA-seq data. We show in VisiumHD data that STHD accurately predicts cell type identities at single-spot level, which achieves precise segmentation of both global tissue architecture and local multicellular neighborhoods. The high-resolution labels facilitate various downstream analyses, including cell type-stratified bin aggregation, spatial compositional comparisons, and cell type-specific differential expression analyses. Moreover, STHD labels further reveal frontlines of inter-cell type interactions at immune hubs in cancer samples. STHD is scalable and generalizable across diverse samples, tissues, and diseases, facilitating genome-wide analyses in various spatial organization contexts. Overall, computational modeling of individual spots with STHD facilitates discoveries in cellular interactions and molecular mechanisms in whole-genome spatial technologies with high resolution. STHD is available athttps://github.com/yi-zhang/STHD.
Predicting biological activity from biosynthetic gene clusters using neural networks
Authors: Goyat Hemant , Singh Dalwinder , Paliyal Sunaina , Mantri Shrikant
Published: June 2024

Microorganisms like bacteria and fungi have been used for natural products that translate to drugs. However, assessing the bioactivity of extract from culture to identify novel natural molecules remains a strenuous process due to the cumbersome order of production, purification, and assaying. Thus, extensive genome mining of microbiomes is underway to identify biosynthetic gene clusters or BGCs that can be profiled as particular natural products, and computational methods have been developed to address this problem using machine learning. However, existing tools are ineffective due to a small training dataset, dependence on old genome mining tools, lack of relevant genomic descriptors, and prevalent class imbalance. This work presents a new tool, NPBdetect, that can detect multiple bioactivities and has been designed through rigorous experiments. Firstly, we composed a larger training set using MIBiG database and a test set through literature mining to build and assess the model respectively. Secondly, the latest antiSMASH genome mining tool was used to obtain BGC and introduced new sequence-based descriptors. Thirdly, neural networks are used to build the model by dealing with class imbalance issues through the class weighting technique. Finally, we compared the NPBdetect tool with an existing tool to show its efficacy and real-world utility in detecting several bioactivities with high confidence.
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

Bone 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

Ketamine 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

Alanyl-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

The 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

The 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.

HIGHLIGHTS

Use 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

Long 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.
RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice
Authors: Weiss Alexandra , Gilbert James W , Flores Iris Valeria Rivera , Belgrad Jillian , Ferguson Chantal , Dogan Elif O , Wightman Nicholas , Mocarski Kit , Echeverria Dimas , Summers Ashley , Bramato Brianna , McHugh Nicholas , Furgal Raymond , Yamada Nozomi , Cooper David , Monopoli Kathryn , Godinho Bruno M.D.C. , Hassler Matthew R , Yamada Ken , Greer Paul L , Henninger Nils , Brown Robert H , Khvorova Anastasia
Published: June 2024

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNASOD1extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.
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

Immune 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.
Probing Individual Differences in the Topological Landscape of Naturalistic Brain Dynamics
Authors: Xian Junxing , He Yini , Yan Yan , Tian Xiaohan , Peng Yingjie , Lou Jing , Liu Xiya , Wang Qi , Gao Tian , Wang Qi , Sun Yuqing , Li Puze , Wang Yue , Huang Shangzheng , Li Kaixin , Hu Ke , Ding Chaoyue , Li Dazheng , Wang Meng , Liu Bing , Li Ang
Published: June 2024

Psychiatry seeks to unravel brain dysfunction and individual differences in real-world contexts. Naturalistic stimuli, like movie watching, are increasingly recognized for eliciting complex, context-dependent neural activity with high ecological validity. Yet, current methods often rely on standard paradigms that average data across time, limiting the full potential of such stimuli. Here, we present STIM, a Topological Data Analysis-based framework designed to dynamically track how individuals integrate complex contexts in real time. Applied to large-sample fMRI data from movie watching, STIM constructs a robust low-dimensional dynamical landscape that reflects group consensus while probing individual variations at both global (spanning narratives) and local (within specific narratives) levels. At the global level, individual differences emerge along a center-periphery gradient in the dynamical landscape, which significantly predicts fluid intelligence, underscoring the importance of neural adaptability and diversity. At finer scales, local geometric features correlate with context-specific psychological traits beyond cognition. STIM also captures developmental changes in the dynamical landscape and reveals abnormalities in conditions such as autism. These findings demonstrate that STIM leverages the rich information from movie stimuli and fMRI recordings as neural probes to assess individual differences in cognition and mental health.
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

Phenol 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

There 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.
When your heart isn't in it anymore: Cardiac correlates of task disengagement
Authors: Corcoran Andrew W , Hohwy Jakob , Andrillon Thomas
Published: June 2024

Neuroscience is beginning to uncover the role of interoceptive feedback in perception, learning, and decision-making; however, the relation between spontaneous visceral and cognitive dynamics has received surprisingly little scrutiny. Here, we investigate how subjective, physiological, and behavioural indicators of arousal and attentional state vary as a function of cardiac activity and brain-heart coupling. Combined electroencephalogram, electrocardiogram, and pupillometric records were obtained from 25 healthy human adults during the performance of a sustained attention to response task (SART). Thought-probes were intermittently administered during the SART to collect subjective reports of attentional state (i.e., on-task, mind-wandering, mind-blanking) and vigilance level (i.e., alertness). Mind-wandering and mind-blanking reports increased in frequency with time-on-task, but were associated with distinct behavioural profiles. Mind-blanking was further characterised by more profound decreases in heart-rate and pupil size than mind-wandering, and late modulation of the heartbeat-evoked potential. Besides attentional state, lower heart-rate predicted decreased vigilance and pupil size, while heart-rate variability predicted more impulsive behaviour and pupil dilation. Together, these findings reveal that cardiac parameters afford complementary information about arousal states and attentional dynamics, illustrating the complexity of task disengagement from a cognitive and physiological perspective.
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

The 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

Background

Sustained 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.

Methods

A 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.

Results

Out 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.

Conclusions

The 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.
Targeted engineering of the phase separating PARCL protein
Authors: Veevers Ruth , Ostendorp Steffen , Ostendorp Anna , Kehr Julia , Morris Richard J.
Published: June 2024

PARCL is a plant-specific RNA-binding protein (RBP) that exhibits chaperone activity, is abundant in the phloem, intrinsically disordered, and contains a prion-like domain (PLD). PARCL proteins have been observed to form large biomolecular condensatesin vivoandin vitro. Biomolecular condensates are membraneless compartments, wherein biomolecules become partitioned from their surrounding liquid environment into liquid droplets with their own composition, dynamics, and function. Which molecular properties drive phase separation is of great interest for targeted engineering efforts. Here, we present results on residue interactions derived from simulations of PARCL using course-grained molecular dynamics with the HPS-Urry model. We adjust the parameters of the simulations to allow the inclusion of folded eYFP tags, since fluorescent tags are often used in phase separation experiments for visualising droplets, yet have not been included in simulations to date. While still simulating phase separation, these trajectories suggest minor changes to droplet and network structure when proteins contain eYFP. By analysing the residues of the PARCL molecules that come within contact distance in the simulations, we identify which individual residues drive phase separation. To experimentally validate these findings, we introduced mutations of the most contacted residues and could indeed confirm that these mutations prevent the formation of condensate droplets. To investigate the RNA-binding of PARCL, we added microRNA to the simulation and find a short region of PARCL consistently making contact with the miRNA, which is also in agreement with predictions and experiments. We discuss the implications of our findings in terms of model-guided engineering of biomolecular condensates.
MetaKSSD: Boosting the Scalability of Reference Taxonomic Marker Database and the Performance of Metagenomic Profiling Using Sketch Operations
Authors: Yi Huiguang , Lu Xiaoxin , Chang Qing
Published: June 2024

The rapid increase in genomes and metagenomic data presents major scalability and efficiency challenges for current metagenomic profilers. In response, we introduce MetaKSSD, which redefines reference taxonomic marker database (MarkerDB) construction and metagenomic profiling using sketch operations, offering efficiency improvements by orders of magnitude. MetaKSSD encompasses 85,202 species in its MarkerDB using just 0.17GB of storage and profiles 10GB of data within seconds, utilizing only 0.5GB of memory. Extensive benchmarking experiments demonstrated that MetaKSSD is among the top-performing profilers across various metrics. In a microbiome-phenotype association study, MetaKSSD identified significantly more effective associations than MetaPhlAn4. We profiled 382,016 metagenomic runs using MetaKSSD, conducted extensive sample clustering analyses, and suggested potential yet-to-be-discovered niches. Additionally, we developed functionality in MetaKSSD for instantaneous searching among large-scale profiles. The client-server architecture of MetaKSSD allows the swift transmission of metagenome sketches over the network and enables real-time online metagenomic analysis, facilitating use by non-expert users.
Molecular Architecture of Monkeypox Mature Virus
Authors: Hong Ye , Huang Baoying , Zhang Junxia , Peng Cheng , Kong Weizheng , Tan Wenjie , Li Sai
Published: June 2024

Since the 2022 mpox outbreak, MPXV has caused ∼100,000 infected cases with ∼200 deaths across 117 countries. and was declared a public health emergency of international concern by the WHO. The causative pathogen, monkeypox virus (MPXV), is a zoonotic double-stranded DNA orthopoxvirus. To investigate the structures and replication mechanism of MPXV, the MPXV recombinant proteins and vaccinia virus (VACV) particles have been studied by cryo-EM, however,in situstructural insights into major structural proteins and assembly of the authentic MPXV particles are missing. In this work, we isolated two MPXV strains from the first imported mpox case and the first local mpox case in mainland China. From the two strains, we propagated and purified mature viruses, and applied cryo-electron tomography (cryo-ET) and sub-tomogram averaging (STA) to unveil the architecture of intact MPXV virus. Interestingly, we also discovered irregularly-shaped mature virions with distorted core walls. To our knowledge, these in situ structural insights in MPXV have not been reported before.
Disruption of liquid/liquid phase separation in asymmetric GUVs prepared by hemifusion
Authors: Kennison-Cook Kristen B. , Heberle Frederick A.
Published: June 2024

Model asymmetric bilayers are useful for studying the coupling between lateral and transverse lipid organization. Here, we used calcium-induced hemifusion to create asymmetric giant unilamellar vesicles (aGUVs) for exploring the phase behavior of 16:0-PC/16:1-PC/Cholesterol, a simplified model for the mammalian plasma membrane. Symmetric GUVs (sGUVs) were first prepared using a composition that produced coexisting liquid-disordered and liquid-ordered phases visible by confocal fluorescence microscopy. The sGUVs were then hemifused to a supported lipid bilayer (SLB) composed of uniformly mixed 16:1-PC/Cholesterol. The extent of outer leaflet exchange was quantified in aGUVs in two ways: (1) from the reduction in fluorescence intensity of a lipid probe initially in the sGUV (“probe exit”); or (2) from the gain in intensity of a probe initially in the SLB (“probe entry”). These measurements revealed a large variability in the extent of outer leaflet exchange in aGUVs within a given preparation, and two populations with respect to their phase behavior: a subset of vesicles that remained phase separated, and a second subset that appeared uniformly mixed. Moreover, a correlation between phase behavior and extent of asymmetry was observed, with more strongly asymmetric vesicles having a greater probability of being uniformly mixed. We also observed substantial overlap between these populations, an indication that the uncertainty in measured exchange fraction is high. We developed models to determine the position of the phase boundary (i.e., the fraction of outer leaflet exchange above which domain formation is suppressed) and found that the phase boundaries determined separately from probe-entry and probe-exit data are in good agreement. Our models also provide improved estimates of the compositional uncertainty of individual aGUVs. We discuss several potential sources of uncertainty in the determination of lipid exchange from fluorescence measurements.

Statement of Significance

We used calcium-induced hemifusion to create an asymmetric lipid distribution in giant unilamellar vesicles that are models for the mammalian plasma membrane. Confocal fluorescence micrographs of asymmetric vesicles showed that coexisting liquid-ordered and liquid-disordered domains initially present in symmetric vesicles were disrupted after 75% of the saturated lipid in their outer leaflets was replaced with unsaturated lipid. We developed quantitative models for extracting valuable information from the data, including the location of the phase boundary and the compositional uncertainty of individual asymmetric vesicles. The methodology we describe can help reveal the molecular determinants of interleaflet coupling of phase behavior and thus contribute to a better understanding of lipid raft phenomena.