bluuebunny/crossref_metadata_2025 huggingface dataset:
Harmonic representations of regions and interactions in spatial transcriptomics
Authors: Maher Kamal , Wang Xiao
Published: August 2024

Spatial transcriptomics technologies enable unbiased measurement of the cell-cell interactions underlying tissue structure and function. However, most unsupervised methods instead focus on identifying tissue regions, representing them as positively covarying low-frequency spatial patterns of gene expression over the tissue. Here, we extend this frequency-based (i.e. harmonic) approach to show that negatively covarying high frequencies represent interactions. Similarly, combinations of low and high frequencies represent interactions along large length scales, or, equivalently, region boundaries. The resulting equations further reveal a duality in which regions and interactions are complementary representations of the same underlying information, each with unique strengths and weaknesses. We demonstrate these concepts in multiple datasets from human lymph node, human tonsil, and mouse models of Alzheimer's disease. Altogether, this work offers a conceptually consistent quantitative framework for spatial transcriptomics.
Finding the E-Channel Proton Loading Sites by Calculating the Ensemble of Protonation Microstates
Authors: Uddin Md. Raihan , Khaniya Umesh , Gupta Chitrak , Mao Junjun , Ranepura Gehan , Wei Rongmei , Soto Jose Ortiz , Singharoy Abhishek , Gunner Marilyn
Published: August 2024

The aerobic electron transfer chain builds a proton gradient by proton coupled electron transfer reactions through multiple proteins. Complex I is the first enzyme in this chain. On transfer of two electrons from NADH to quinone four protons are pumped from the N- (negative, higher pH) to the P- (positive, lower) side. Protons move pthrough three linear antiporter paths, with a few amino acids and waters providing the route and the E-channel, which is a complex of competing paths, with clusters of interconnected protonatable residues. Proton loading sites (PLS) are residues that transiently bind protons as they are transported from N- to P-compartments. PLS can be individual residues or extended clusters. The program MCCE uses Monte Carlos sampling to analyze the E-channel proton binding in equilibrium with individual Molecular Dynamics snapshots from trajectories of Thrmus thermuphillus Complex I in the apo, quinone or quinol bound states. At pH 7, the five E-channel subunits (Nqo4, Nqo7, Nqo8, Nqo10, and Nqo11) have accepted >25,000 protonation microstates, each with different residues protonated. The microstate explosion is tamed by analyzing interconnected clusters of residues along the proton transfer paths. A proton is bound and released to five coupled residues in a cluster on the protein N-side and to six coupled residues in the protein center. Loaded microstates bind protons to sites closer to the P-side in the forward pumping direction. MCCE microstate analysis shows the strong coupling of proton binding amongst individual residues in the two PLS clusters.
Exercise-stimulated Resolvin Biosynthesis in Adipose Tissue is Abrogated by High Fat Diet-induced Adrenergic Deficiency
Authors: Pena Calderin Ernesto H , Zheng Jing-Juan , Boyd Nolan L , Lynch Will , Sansbury Brian E , Spite Matthew , Hill Bradford G. , Hellmann Jason
Published: August 2024

Objective: Diet-induced white adipose tissue inflammation is associated with insulin resistance and metabolic perturbations. Conversely, exercise (Exe) protects against the development of chronic inflammation and insulin resistance independent of changes in weight; however, the mechanisms remain largely unknown. We have recently shown that, through adrenergic stimulation of macrophages, exercise promotes resolution of acute peritoneal inflammation by enhancing the biosynthesis of specialized pro-resolving lipid mediators (SPMs). In this study, we sought to determine if exercise stimulates pro-resolving pathways in adipose tissue and whether this response is modified by diet. Specifically, we hypothesized that high fat diet feeding disrupts exercise-stimulated resolution by inhibiting adrenergic signaling, priming the development of chronic inflammation in adipose tissue (AT). Approach and Results: To explore the dietary dependence of the pro-resolving effects of Exe, mice were fed either a control or high-fat diet (HFD) for 2 weeks prior to, and throughout, a 4 wk period of daily treadmill running. Glucose handling, body weight and composition, and exercise performance were evaluated at the end of the feeding and exercise interventions. Likewise, catecholamines and their biosynthetic enzymes were measured along with AT SPM biosynthesis and macrophage phenotype and abundance. When compared with sedentary controls (Sed), macrophages isolated from mice exposed to 4 wk of exercise display elevated expression of the SPM biosynthetic enzyme Alox15, while whole AT SPM levels and anti-inflammatory CD301+ M2 macrophages increased. These changes were dependent upon diet as 6 wk of feeding with HFD abrogated the pro-resolving effect of exercise when compared with control diet-fed animals. Interestingly, exercise-induced epinephrine production was inhibited by HFD, which diminished expression of the epinephrine biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT) in adrenal glands. Conclusion: Taken together, these results suggest that a diet high in fat diminishes the pro-resolving effects of exercise in adipose tissue via decreasing the biosynthesis of catecholamines.
Dissecting the transcriptional regulation of infant and childhood acute myeloid leukemia
Authors: Godini Rasoul
Published: August 2024

Pediatric acute myeloid leukemia (AML) exhibits distinct characteristics between infants and children, manifested by variations in clinical features, cytogenetic abnormalities, and molecular aberrations. While most studies have focused on the associations between genomic abnormalities, age groups, and disease status, the transcriptional profiles and gene regulatory mechanisms underlying these differences remain underexplored. In this study, through differential gene expression analysis and Weighted Gene Co-expression Network Analysis, I have identified gene groups associated with AML and further categorized them by infant and childhood subgroups. The findings reveal three distinct gene groups with age- and tissue-specific expression patterns. Additionally, I propose a gene regulatory circuitry that elucidates the differences between infant and childhood AML. Several novel markers demonstrating significant expression changes in tumors were identified. Moreover, a comprehensive gene regulatory network for pediatric AML was constructed using differentially expressed transcription factors and protein-gene interaction data. This study highlights new gene regulation mechanisms in pediatric AML and offers potential avenues for developing novel biomarkers and therapeutic strategies.
Bioinformatics Copilot 2.0 for Transcriptomic Data Analysis
Authors: Wang Yongheng , Zhang Weidi , Wong Ian , Lin Siyu , Kumar Rohan , Wang Aijun
Published: August 2024

Large language models, when integrated into bioinformatics tools, offer valuable support for biologists in the analysis of single-cell transcriptomic data. Here, we introduce Bioinformatics Copilot 2.0, an advanced tool that builds upon its predecessor with four significant enhancements: 1) Internal server processing: users can now process large datasets on an internal server, thereby ensuring data privacy. 2) User-controlled analysis: users can take control of their data analysis when tasks exceed the copilot's capabilities. 3) Real-time information access: users can access up-to-date information from online resources, such as gene function queries and recent publications, thus enhancing data interpretation. 4) Data analysis and result documentation: the copilot now supports the generation of PDFs that include images and detailed analysis. These advancements represent a step towards building a bioinformatics autopilot. Demonstration videos showcasing these features are available at www.biochemml.com/tools.
Low-level features predict perceived similarity for naturalistic images
Authors: A-Izzeddin Emily J , Wallis Thomas SA , Mattingley Jason B , Harrison William J
Published: August 2024

The mechanisms by which humans perceptually organise individual regions of a visual scene to generate a coherent scene representation remain largely unknown. Our perception of statistical regularities has been relatively well-studied in simple stimuli, and explicit computational mechanisms that use low-level image features (e.g., luminance, contrast energy) to explain these perceptions have been described. Here, we investigate to what extent observers can effectively use such low-level information present in isolated naturalistic scene regions to facilitate associations between said regions. Across two experiments, participants were shown an isolated standard patch, then required to select which of two subsequently presented patches came from the same scene as the standard (2AFC). In Experiment 1, participants were consistently above chance when performing such association judgements. Additionally, participants’ responses were well-predicted by a generalised linear multilevel model (GLMM) employing predictors based on low-level feature similarity metrics (specifically, pixel-wise luminance and phase-invariant structure correlations). In Experiment 2, participants were presented with thresholded image regions, or regions reduced to only their edge content. Their performance was significantly poorer when they viewed unaltered image regions. Nonetheless, the model still correlated well with participants’ judgments. Our findings suggest that image region associations can be reduced to low-level feature correlations, providing evidence for the contribution of such basic features to judgements made on complex visual stimuli.
Primary culture of high grade serous ovarian cancer cells, selection and derivation of three cell lines
Authors: Brenton James D , Vias Maria , Sauer Carolin M , Funingana Gabriel , Piskorz Anna M , Moore Elizabeth , Chilamakuri Chandra , Hall Douglas , Goranova Teodora , Van Oudenhove Elke , Earl Helena M , Goldlust Ian
Published: August 2024

Cell line models for high grade serous ovarian cancer (HGSOC) are limited in number and are poorly clinically annotated. Consequently, existing models often fail to recapitulate common features of HGSOC, inhibiting mechanistic and therapeutic discovery. We generated and characterised three spontaneously immortalized continuous HGSOC cell lines named CIOV1, CIOV2, and CIOV3 and confirmed that each cell line retained the genomic and pathologic characteristics of its parental tumour. We show that subclonal cell populations present at initiation, expanded and contracted during the culturing process before converging on a stable immortalized line. These lines are new valuable models to study acquired chemoresistance of HGSOC.
Main compounds in sweat, such as squalene and fatty acids, should be promising pheromone components for humans
Authors: Zhang Yao-Hua , Du Yu-Feng , Zhang Jian-Xu
Published: August 2024

Pheromones are chemicals released outside the body by organisms to transmit information between individuals of the same species, thereby regulating behavior and physiology. Many biological and psychological studies have shown that human sweat does indeed contain chemical information related to gender, sex, emotion, etc., but there is no convincing answer to its chemical components. We conducted a GC-MS analysis of the chemical composition of adult and child sweat of Han Chinese, and found that the main components were squalene and fatty acids, and there were sex differences in adults, but not in children. Based on our long-term research on the coding rules of pheromones in a variety of animals, especially rodents, as well as men having more sweat glands and sebaceous glands, we speculate that squalene and many common fatty acids are likely to encode olfactory information such as sex and emotion in one component or a mix of components or in a dose-dependent manner. We also discussed that the main olfactory system and olfactory learning in social interactions should play an important role in human pheromone perception.
Eye-Opening Advances: Automated 3D Segmentation, Key Biomarkers Extraction, and the First Large-Scale MRI Eye Atlas.
Authors: Barranco Hernandez Jaime , Luyken Adrian , Kebiri Hamza , Stachs Philippe , Macias Gordaliza Pedro , Esteban Oscar , Aleman Gomez Yasser , Sznitman Raphael , Stachs Oliver , Langner Soenke , Franceschiello Benedetta , Bach Cuadra Meritxell
Published: August 2024

This study addresses the need for an automated and accurate 3D segmentation of the healthy human eye and orbit from Magnetic Resonance Images, to allow improved ophthalmic diagnostics and treatments. Past efforts primarily focused on small sample sizes and varied imaging modalities. Here, we leverage a large-scale dataset of T1-weighted MRI of 1245 subjects and the use of the deep learning-based nnU-Net for MR-Eye segmentation tasks. The results showcase robust and accurate segmentations of lens, globe, optic nerve, rectus muscles, and fat. We also present the automated estimation of key ophthalmic biomarkers such as AL and volumetry, while benchmarking correlations between body mass index (BMI) and eye structure volumes. Quality control protocols are introduced through the pipeline to ensure the reliability and clinical relevance of the segmented large-scale data, further enhancing the applicability of our algorithm.
Rapid and Sensitive Detection ofFusarium oxysporumf. sp.cubenseTropical Race 4 Using a RPA-DETECTR Assay
Authors: Venkatesh Jelli , Jankowicz-Cieslak Joanna , Mduma Hassan , Matijevic Mirta , Ali Adel , Balbin Isabel Cristina Calle , Soto-Suárez Mauricio , Zorrilla Cinthya , Mathur Pooja Bhatnagar-
Published: August 2024

Early and prompt detection of banana wilt pathogenFusarium oxysporumf. sp.cubense(Foc), tropical race 4 (Foc TR4), causing global banana crop losses is crucial to curtail the disease spread, minimize damage and implement quarantine measures. We report the first successfully developed DNA Endonuclease Targeted CRISPR Trans Reporter (DETECTR) assay for the highly sensitive and specific detection of Foc TR4, validated across several isolates. Notably, specific crRNA spacer sequences and recombinant polymerase amplification (RPA) primers designed and evaluated for the DETECTR assay exhibited exceptional sensitivity, detecting Foc TR4 with genomic DNA as low as 0.005 ng, and demonstrated a very high specificity, and reproducibility. The RPA-DETECTR assay was validated using a diverse panel of samples, including both target and non-target pathogens confirming its robustness and reliability across different types of samples, ensuring practical application under varied conditions. In terms of throughput, the RPA-DETECTR assays enabled faster detection of Foc TR4 than other molecular diagnostics including PCR, quantitative PCR (qPCR) and droplet digital PCR (ddPCR) analyses, making this assay suitable for point-of-care (POC) detection of Foc TR4, and facilitating rapid decision-making and immediate response. This rapid detection capability is crucial in restricting any potential transboundary movement as part of ongoing disease management efforts.
Combining Gamma Neuromodulation and Robotic Rehabilitation Restores Parvalbimin-mediated Gamma Function and Boosts Motor Recovery in Stroke Mice
Authors: Vignozzi Livia , Macchi Francesca , Montagni Elena , Pasquini Maria , Martello Alessandra , Minetti Antea , Coulomb Éléa , Allegra Mascaro Anna Letizia , Micera Silvestro , Caleo Matteo , Spalletti Cristina
Published: August 2024

Stroke is a leading cause of long-term disability, often characterized by compromised motor function. Gamma band is known to be related to Parvalbumin interneurons (PV-IN) synchronous discharge and it has been found to be affected after stroke in humans and animals. Both Gamma band and PV-IN also play a key role in motor function, thus representing a promising target for post-stroke neurorehabilitation. Non-Invasive neuromodulatory approaches are considered a safe intervention and can be used for this purpose. This study presents a novel, clinically relevant, non-invasive and well-tolerated sub-acute treatment combining robotic rehabilitation with advanced neuromodulation techniques, validated in a mouse model of ischemic injury. In the sub-acute phase after stroke, we scored profound deficits in motor-related Gamma band regulation on the perilesional cortex. Accordingly, both at the perilesional and at the whole-cortex levels, the damage results in impaired PV-IN activity, with reduced firing rate and increased functional connectivity levels. Therefore, we tested the therapeutic potential of coupling robotic rehabilitation with optogenetic PV-driven Gamma band stimulation in a subacute post-stroke phase during motor training to reinforce the efficacy of the treatment. Frequency-specific movement-related Gamma band stimulation, when combined with physical training, significantly improved forelimb motor function. More importantly, by pairing robotic rehabilitation with a clinical-like non-invasive 40 Hz transcranial Alternating Current Stimulation, we achieved similar motor improvements mediated by the effective restoring of movement-related Gamma band power and increased PV-IN connections in premotor cortex. Our research introduces a new understanding of the role of parvalbumin-interneurons in post-stroke impairment and recovery. These results highlight the synergistic potential of combining perilesional Gamma band stimulation with robotic rehabilitation as a promising and realistic therapeutic approach for stroke patients.

Stroke-induced motor deficits are accompanied by alteration of Gamma modulation and PV-interneurons activity and restored by a combination of non-invasive Gamma stimulation and robotic therapy.
Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer's disease mouse model
Authors: Dongre Prathamesh , Ramesh Madhu , Govindaraju Thimmaiah , Inamdar Maneesha S
Published: August 2024

Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate Aβ pathology in vivo is unclear. Methods: To explore the impact of Asrij on AD pathology, we deletedasrijin the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We used the Morris water maze and open field test to assess behavioral performance. Using immunohistochemistry and biochemical analyses, we evaluated Aβ plaque load, neuronal and synaptic damage, and gliosis. Further, we utilized confocal microscopy imaging, flow cytometry, and RNA sequencing analysis to comprehensively investigate changes in microglial responses to Aβ pathology upon Asrij depletion. Results: Asrij depletion ameliorates cognitive impairments, Aβ deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activation. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and impedes the acquisition of a pro-inflammatory disease-associated microglia (DAM) state. Reduced levels of proinflammatory cytokines and decreased STAT3 and NF-κB activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology. Conclusions: In summary, we show that Asrij depletion ameliorates Aβ pathology, neuronal and synaptic damage, gliosis, and improves behavioral performance in APP/PS1 mice. This supports that Asrij exacerbates the AD pathology. Mechanistically, Asrij is critical for the development of DAM and promotes neuroinflammatory signaling activation in microglia, thus restricting neuroprotective microglial responses. Hence, reducing Asrij in this context may help retard AD. Our work positions Asrij as a critical molecular regulator that links microglial dysfunction to AD pathogenesis.
Novel use of global occurrence data to indirectly predict suitable habitats for widely distributed marine species in data-scarce regions
Authors: De Wysiecki Agustín M. , Barnett Adam , Sánchez-Carnero Noela , Cortés Federico , Milessi Andrés C. , Trobbiani Gastón A. , Jaureguizar Andrés J.
Published: August 2024

This study addresses the challenge of advancing habitat use knowledge of widely distributed marine species populations when regional data is scarce. To achieve this, we use an innovative approach based on ecological niche models (ENMs) calibrated with global presence data to estimate the global niche of species, allowing for indirect predictions of suitable habitats and potential distribution in one or more regions of interest. The method leverages a range of global occurrence records, including scientific papers, government data, biodiversity repositories, and citizen science contributions, to overcome regional data scarcity, which are then integrated with environmental variables to predict habitat suitability. As a case study, we apply this method to predict suitable habitats of copper (Carcharhinus brachyurus) and sand tiger (Carcharias taurus) sharks in the Southwest Atlantic, two species of conservation concern in a region with limited data. Suitable habitats for both species were predicted, information required to guide conservation efforts. Environmental factors were key to shaping predicted distribution patterns of these large predatory sharks, aligning with previous knowledge and historical records of their latitudinal ranges. The results have significant implications for the conservation planning and sustainable management of shark populations in the Southwest Atlantic, contributing to broader efforts of marine biodiversity preservation. Additionally, the study highlights the potential of ENMs to identify essential habitats even in the absence of effort data, underscoring their value in marine conservation. This study not only advances the use of niche modelling in marine systems but also demonstrates its applicability for area-based conservation initiatives, particularly in data-poor regions.
The combined impact of climate change, pesticides and pharmaceuticals on life history and behaviour in killifish (Nothobranchius furzeri)
Authors: Kim Dongjin
Published: August 2024

Animals in nature are confronted simultaneously with multiple stressors of both natural and anthropogenic origin including temperature stress, pollutants, predators and parasites. The overall goal of this study was to assess the sensitivity of fish to climate change in combination with both classic pollutants (pesticides) and emerging contaminants (pharmaceuticals). Specifically, we exposed individuals of the model fish speciesNothobranchius furzerito combinations of temperature fluctuation, 3,4-DCA and FLX. Our results indicate that both traditional endpoints such as body size and fecundity as well as behavioural endpoints are affected by daily temperature variation and by the tested pollutants. The fact that certain effects were much more prominent when pollutants were combined illustrates the relevance of stressor combination studies. Also, while the tested concentrations of pollutants did not cause excess mortality, they did induce significant behavioural changes which may carry serious fitness consequences. Ultimately, our study provides an effective illustration of the need for performing stressor combination studies and for including behavioural endpoints in ecotoxicological testing.
Gut Microbiota and DTI Microstructural Brain Alterations in Rodents Due to Morphine Self-Administration
Authors: Brunetti Kaylee , Zhou Zicong , Shuchi Samia , Berry Raymond , Zhang Yan , Allen Michael S. , Yang Shaohua , Figueroa Johnny , Colon-Perez Luis
Published: August 2024

The opioid epidemic is an evolving health crisis in need of interventions that target all domains of maladaptive changes due to chronic use and abuse. Opioids are known for their effects on the opioid and dopaminergic systems, in addition to neurocircuitry changes that mediate changes in behavior; however, new research lines are looking at complementary changes in the brain and gut. The gut-brain axis (GBA) is a bidirectional signaling process that permits feedback between the brain and gut and is altered in subjects with opioid use disorders. In this work, we determine longitudinal, non-invasive, and in-vivo complementary changes in the brain and gut in rodents trained to self-administer morphine for two weeks using MRI and 16S rDNA analysis of fecal matter. We assess the changes occurring during both an acute phase (early in the self-administration process, after two days of self-administration) and a chronic phase (late in the self-administration process, after two weeks of self-administration), with all measurements benchmarked against baseline (naïve, non-drug state). Rats were surgically implanted with an intravenous jugular catheter for self-administration of morphine. Rats were allowed to choose between an active lever, which delivers a single infusion of morphine (0.4 mg/kg/infusion), or an inactive lever, which had no consequence upon pressing. Animals were scanned in a 7T MRI scanner three times (baseline, acute, and chronic), and before scanning, fecal matter was collected from each rat. After the last scan session, a subset of animals was euthanized, and brains were preserved for immunohistochemistry analysis. We found early changes in gut microbiota diversity and specific abundance as early as the acute phase that persisted into the chronic phase. In MRI, we identified alterations in diffusivity indices both within subjects and between groups, showing a main effect in the striatum, thalamus, and somatosensory cortex. Finally, immunohistochemistry analyses revealed increased neuroinflammatory markers in the thalamus of rats exposed to morphine. Overall, we demonstrate that morphine self-administration shapes the brain and gut microbiota. In conclusion, gut changes precede the anatomical effects observed in MRI features, with neuroinflammation emerging as a crucial link mediating communication between the gut and the brain. This highlights neuroinflammation as a potential target in addressing the impacts of opioid use.
Biological invasions forming intraguild predation communities in homogeneous and heterogeneous landscapes
Authors: Poloni Lyra Silas , Kraenkel Roberto Andre , Coutinho Renato Mendes
Published: August 2024

Intraguild predation (IGP) allows for coexistence between two consumers of a single resource, as long as the intraguild prey (IG prey) is competitively superior to the Intraguild Predator (IG predator) and resource population productivity is neither abundant or limiting. Here we explore biological invasions forming IGP community modules by either introducing IG prey or IG predator species to established Consumer-Resource populations in homogeneous and heterogeneous landscapes, using reaction-diffusion equations as our modeling framework. Our main methods of analysis are comparing numerical solutions to linearization techniques and homogenization approximations. We find that in homogeneous landscapes, speeds are linearly determinate, i.e., depend on low invader population densities at the leading edge. We also find traveling wave solutions and dynamical stabilization regimes. On heterogeneous landscapes, our results show that depending on habitat preferences of the three species involved, coexistence regimes can occur regardless of IG-Prey being least effective consumer, or be hindered even when IG-Prey remais as the dominant competitor. Our work asses how fast can organisms invade novel landscapes in presence of a established IG prey or IG predator, and also demonstrates how habitat fragmentation and species habitat preference can disrupt or facilitate coexistence in IGP communities.
Locus coeruleus activation 'resets' hippocampal event representations and separates adjacent memories
Authors: Clewett David Vaughn , Huang Ringo , Davachi Lila
Published: August 2024

Memories reflect the ebb and flow of experiences, capturing unique and meaningful events from our lives. Using a combination of functional magnetic resonance imaging (fMRI), neuromelanin imaging, and pupillometry, we show that arousal and locus coeruleus (LC) activation transform otherwise continuous experiences into distinct episodic memories. As sequences unfold, encountering a context shift, or event boundary, triggers arousal and LC processes that predict later memory separation. Boundaries furthermore promote temporal pattern separation within left hippocampal dentate gyrus, which correlates with heightened LC responses to those same transition points. We also find that a neurochemical index of prolonged LC activation correlates with diminished arousal responses at boundaries, suggesting a connection between elevated LC output and impaired event processing. These findings align with the idea that arousal processes initiate a neural and memory reset in response to significant changes, constructing the very episodes that define everyday memory.
Computational modeling of cancer cell metabolism along the catabolic-anabolic axes
Authors: Villela-Castrejon Javier , Levine Herbert , Onuchic José Nelson , George Jason T , Jia Dongya
Published: August 2024

Abnormal metabolism is a hallmark of cancer. Initially recognized through the observation of aerobic glycolysis in cancer nearly a century ago. Also, we now know that mitochondrial respiration is also used by cancer for progression and metastasis. However, it remains largely unclear the mechanisms by which cancer cells mix and match different metabolic modalities (oxidative/reductive) and leverage various metabolic ingredients (glucose, fatty acids, glutamine) to meet their bioenergetic and biosynthetic needs. Here, we formulate a phenotypic model for cancer metabolism by coupling master gene regulators (AMPK, HIF-1, Myc) with key metabolic substrates (glucose, fatty acid, and glutamine). The model predicts that cancer cells can acquire four metabolic phenotypes: a catabolic phenotype characterized by vigorous oxidative processes - O, an anabolic phenotype characterized by pronounced reductive activities - W, and two complementary hybrid metabolic states - one exhibiting both high catabolic and high anabolic activity - W/O, and the other relying mainly on glutamine oxidation - Q. Using this framework, we quantified gene and metabolic pathway activity respectively by developing scoring metrics based on gene expression. We validated the model-predicted gene-metabolic pathway association and the characterization of the four metabolic phenotypes by analyzing RNA-seq data of tumor samples from TCGA. Strikingly, carcinoma samples exhibiting hybrid metabolic phenotypes are often associated with the worst survival outcomes relative to other metabolic phenotypes. Our mathematical model and scoring metrics serve as a platform to quantify cancer metabolism and study how cancer cells adapt their metabolism upon perturbations, which ultimately could facilitate an effective treatment targeting cancer metabolic plasticity.
Function-first discovery of high affinity monoclonal antibodies using Nanovial-based plasma B cell screening
Authors: Challa Dilip , de Rutte Joseph , Konu Cassady , Udani Shreya , Liang Jesse , Krohl Patrick J , Rondon Ronald , Bondensgaard Kent , Di Carlo Dino , Watkins-Yoon Jennifer
Published: August 2024

Antibody discovery technologies, essential for research and therapeutic applications, have evolved significantly since the development of hybridoma technology. Various in vitro (display) and in vivo (animal immunization and B cell-sequencing) workflows have led to the discovery of antibodies against diverse antigens. Despite this success, standard display and B-cell sequencing-based technologies are limited to targets that can be produced in a soluble form. This limitation inhibits the screening of function-inducing antibodies, which require the target to be expressed in cells to monitor function or signaling, and antibodies targeting proteins that maintain their physiological structure only when expressed on cell membranes, such as G-protein coupled receptors (GPCRs). A high-throughput two-cell screening workflow, which localizes an antibody-secreting cell (ASC) and a cell expressing the target protein in a microenvironment, can overcome these challenges. To make function-first plasma cell-based antibody discovery accessible and scalable, we developed hydrogel Nanovials that can capture single plasma cells, target-expressing cells, and plasma cell secretions (antibodies). The detection and isolation of Nanovials harboring the antigen-specific plasma cells are then carried out using a flow cytometry cell sorter - an instrument that is available in most academic centers and biopharmaceutical companies. The antibody discovery workflow employing Nanovials was first validated in the context of two different cell membrane-associated antigens produced in recombinant form. We analyzed over 40,000 plasma cells over two campaigns and were able to identify a diversity of binders that i) exhibited high affinity (picomolar) binding, ii) targeted multiple non-overlapping epitopes and iii) demonstrated high developability scores. A campaign using the two-cell assay targeting the immune checkpoint membrane protein PD-1 yielded cell binders with similar EC50s to clinically used Pembrolizumab and Nivolumab. The highest selectivity for binders was observed for sorted events corresponding with the highest signal bound to target cells on Nanovials. Overall, Nanovials can provide a strong foundation for function-first antibody discovery, yielding direct cell binding information and quantitative data on prioritization of hits with flexibility for additional functional readouts in the future.
Sex differences and behaviour in the pace-of-life of rodents
Authors: Hughes Bryan , Mastromonaco Gaby , Bowman Jeff , Schulte-Hostedde Albrecht
Published: August 2024

Male and female rodents experience different selective pressures associated with reproductive costs. Thus, we may expect the expression of different Pace-of-life (POL) strategies between sexes. Further, the pace-of-life syndrome (POLS) hypothesis and anisogamy predict differences in the costs of gamete production, where variation in life history trait expression should follow a fast-slow continuum such that males and females might exist on opposite ends of the spectrum. However, males and females could express a similar POL strategy in systems where the reproductive costs are consistent between sexes or where selective pressures force a similar directionality of traits. We used standardized behavioural tests and fecal glucocorticoid metabolite (FGM) concentrations to measure potential differences in POL strategies among three rodent species in Algonquin Provincial Park. We hypothesized that differences in reproductive costs between males and females would result in differences in POL traits along the fast-slow continuum. We predicted that males would express more explorative behaviours and have a higher level FGMs than female counterparts. We found little support for the POLS hypothesis between sexes. Instead, we suggest that the species observed may express a similar directionality of selection for the observed behavioural traits, where both sexes express similar relationships in POL. Thus, some male rodents may be more explorative to accommodate the increase of energetic stress associated with mate acquisition, while females may share similar trait expressions to accommodate the increased metabolic demand for the care and development of young.
Ribosomal RNA transcription governs splicing through ribosomal protein RPL22
Authors: Fan Wenjun , Liu Hester , Stachelek Gregory C. , Begum Asma , Davis Catherine E. , Dorado Tony E. , Ernst Glen , Reinhold William C. , Ozbek Busra , Zheng Qizhi , De Marzo Angelo M. , Rajeshkumar N.V. , Barrow James C. , Laiho Marikki
Published: August 2024

Ribosome biosynthesis is a cancer vulnerability executed by targeting RNA polymerase I (Pol I) transcription. We developed advanced, specific Pol I inhibitors to identify drivers of this sensitivity. By integrating multi-omics features and drug sensitivity data from a large cancer cell panel, we discovered thatRPL22frameshift mutation conferred Pol I inhibitor sensitivity in microsatellite instable cancers. Mechanistically, RPL22 directly interacts with 28S rRNA and mRNA splice junctions, functioning as a splicing regulator. RPL22 deficiency, intensified by 28S rRNA sequestration, promoted the splicing of its paralog RPL22L1 and p53 negative regulator MDM4. Chemical and genetic inhibition of rRNA synthesis broadly remodeled mRNA splicing controlling hundreds of targets. Strikingly, RPL22-dependent alternative splicing was reversed by Pol I inhibition revealing a ribotoxic stress-initiated tumor suppressive pathway. We identify a mechanism that robustly connects rRNA synthesis activity to splicing and reveals their coordination by ribosomal protein RPL22.
Adolescent pregnancy prevalence, maternal characteristics, and perinatal outcomes
Authors: Toapanta-Pinta Paola Cristina , Rosero-Quintana Mercy Dolores , Chavez-Espinosa Soraya , Vasco-Toapanta Cristhian ,   Investigacion en Salud Infantil y Perinatal (ISIP), Vasco-Morales Santiago
Published: August 2024

Introduction: Adolescent pregnancy is a global public health issue with significant implications for maternal and neonatal health, particularly in regions with limited access to healthcare services. Objective: To investigate the prevalence of adolescent pregnancies and perinatal outcomes at the Isidro Ayora Gyneco-Obstetric Hospital during the period 2009-2022. Method: A cross-sectional study was conducted based on records from the Perinatal Information System. Adolescent women and their newborns were included. Multiple pregnancies and cases with incomplete data were excluded. The Chi-square test was applied, and multinomial logistic regression models were used. Ethical Approval: 009-DOC-FCM-2023 Results: Out of a total of 26,236 live births, 6,700 (25.53%) were born to adolescent mothers. Many of these mothers were of mestizo ethnicity (94.91%) and had secondary education (80.28%). Multivariate analyses indicated that younger adolescents (<14 years) belonged to minority ethnic groups, substance abuse during pregnancy, underwent episiotomy, and their neonates had a low Apgar score in the first minute of life. Conclusions: Adolescent pregnancy remains a public health issue in Ecuador, associated with adverse neonatal outcomes. It is crucial to implement health policies that address the socioeconomic and cultural determinants of adolescent pregnancy and to conduct prospective studies to better understand the factors involved in these perinatal outcomes.
Patterns of vascular access among chronic kidney disease patients on maintenance hemodialysis at Muhimbili National Hospital. A single centre cross-sectional study
Authors: Msilanga Daniel , Shoo Jacqueline , Mngumi Jonathan
Published: August 2024

Background: Hemodialysis access profoundly impacts the quality of care for chronic kidney disease (CKD) patients worldwide, with arteriovenous fistulas (AVFs) preferred for superior outcomes. Despite global guidelines, Sub-Saharan Africa, including Tanzania, faces challenges, as it relies heavily on nontunneled central venous catheters (CVCs) due to accessibility and financial constraints. We aimed to describe the pattern of vascular access use among CKD patients on maintenance hemodialysis at Muhimbili National Hospital. Methods: A cross-sectional study to describe the pattern of vascular access among patients with CKD on maintenance hemodialysis therapy. Descriptive statistics were used to summarize the baseline characteristics and patterns of vascular access. Results: We analysed 200 study participants, with a mean age of 53.3 (14.5) years. Almost all participants initiated hemodialysis with nontunneled central venous catheters (95.5%). A substantial portion continued to use nontunneled CVCs (25.5%), with some transitioning to tunneled CVCs (39.5%) or AVFs (35%). The mean (SD) duration to use nontunneled CVCs before transitioning to tunneled or AVF were 7.1 (2.1) months. Among patients with multiple nontunneled catheters, catheter dislodgement was the main indication for catheter replacement. Conclusion: Our study highlights the prevalent use of nontunneled central venous catheters (CVCs) as the primary vascular access method for CKD patients undergoing hemodialysis at Muhimbili National Hospital, Tanzania. These findings underscore the urgent need for analysis of the cost associated with nontunneled catheter reliance and interventions to improve access to AVFs and enhance vascular access management, ultimately optimizing patient outcomes in resource-limited settings.
Speckle contrast optical spectroscopy improves cuffless blood pressure estimation compared to photoplethysmography
Authors: Garrett Ariane , Kim Byungchan , Gurel Nil Z , Sie Edbert J , Wilson Benjamin K , Marsili Francesco , Forman John P , Hamburg Naomi M , Boas David A , Roblyer Darren
Published: August 2024

Continuous and non-invasive blood pressure (BP) monitoring has the potential to greatly improve hypertension diagnosis and management, along with enabling valuable personal health monitoring in the population at large. Existing methods rely on cuff-based sphygmomanometers, which are cumbersome and disrupt sleep. Despite extensive research utilizing photoplethysmography (PPG), which is integrated into many consumer wearables, errors in continuous BP estimation are generally considered unacceptable for general use. We developed a high-speed (390 Hz) Speckle Contrast Optical Spectroscopy (SCOS) system to measure the cardiac blood flow waveform simultaneously with the PPG signal at high temporal resolution. The system utilized high speed multiplexed detection of optical speckle patterns on the wrist and finger, enabling the extraction of novel features related to BP. In comparison to PPG alone, SCOS demonstrated a notable 31% improvement (p = 3.45 * 10-7) in systolic BP estimation when integrated into subject-specific machine-learning models. The resulting errors were remarkably low (systolic BP: 0.06+/- 2.88 mmHg, diastolic BP: 0.09 +/-2.14 mmHg) across a wide range of BP variations (range SBP: 89-284 mmHg). Importantly, this improvement was sustained several weeks later within a re-measured cohort, indicating highly robust BP predictions. Looking ahead, the use of SCOS for blood flow measurements holds the potential to substantially enhance BP estimations compared to conventional PPG-based methods.
Quantized multi-task learning for context-specific representations of gene network dynamics
Authors: Chen Han , Venkatesh Madhavan S , Gomez Ortega Javier , Mahesh Siddharth V , Nandi Tarak N , Madduri Ravi K , Pelka Karin , Theodoris Christina V
Published: August 2024

While often represented as static entities, gene networks are highly context-dependent. Here, we developed a multi-task learning strategy to yield context-specific representations of gene network dynamics. We assembled a corpus comprising ~103 million human single-cell transcriptomes from a broad range of tissues and diseases and performed a two stage pretraining, first with non-malignant cells to generate a foundational model and then with continual learning on cancer cells to tune the model to the cancer domain. We performed multi-task learning with the foundational model to learn context-specific representations of a broad range of cell types, tissues, developmental stages, and diseases. We then leveraged the cancer-tuned model to jointly learn cell states and predict tumor-restricting factors within the colorectal tumor microenvironment. Model quantization allowed resource-efficient fine-tuning and inference while preserving biological knowledge. Overall, multi-task learning enables context-specific disease modeling that can yield contextual predictions of candidate therapeutic targets for human disease.
Enhanced spatially resolved transcriptomics analysis by matching between expression profiles and spatial topology
Authors: Pang Yuxuan , Wang Chunxuan , Zhang Yao-zhong , Wang Zhuo , Imoto Seiya , Lee Tzong-Yi
Published: August 2024

Spatially resolved transcriptomics (SRT) quantifies gene expression covering contextual heterogeneity for the tissue section. Exploratory data analysis using SRT data sheds light on diverse biomedical research fields. We propose STForte, a pairwise graph autoencoding-based approach for SRT data analysis, which is capable of matching the information between expression profiles and spatial topology in the latent space. STForte benefits from the designed framework to provide encodings with justifiable spatial correlations for the downstream analysis of both homogeneous and heterogeneous SRT data. Moreover, STForte can unravel the biological patterns of unobserved locations or recover deficient measurements to enable spatial enhancement. Latent encodings generated by STForte can be used to perform spatial region identification or other downstream tasks to gain biological insights and elucidate biological processes. In this work, we presented various analyses to show that STForte is scalable for analyzing SRT data under different scenarios with considerable performance.
PanKB: An interactive microbial pangenome knowledgebase for research, biotechnological innovation, and knowledge mining
Authors: Sun B , Pashkova L , Pieters PA , Harke AS , Mohite OS , Palsson BO , Phaneuf PV
Published: August 2024

The exponential growth of microbial genome data presents unprecedented opportunities for mining the potential of microorganisms. The burgeoning field of pangenomics offers a framework for extracting insights from this big biological data. Recent advances in microbial pangenomic research have generated substantial data and literature, yielding valuable knowledge across diverse microbial species. PanKB (pankb.org), a knowledgebase designed for microbial pangenomics research and biotechnological applications, was built to capitalize on this wealth of information. PanKB currently includes 51 pangenomes on 8 industrially relevant microbial families, comprising 8, 402 genomes, over 500, 000 genes, and over 7M mutations. To describe this data, PanKB implements four main components: 1) Interactive pangenomic analytics to facilitate exploration, intuition, and potential discoveries; 2) Alleleomic analytics, a pangenomic- scale analysis of variants, providing insights into intra-species sequence variation and potential mutations for applications; 3) A global search function enabling broad and deep investigations across pangenomes to power research and bioengineering workflows; 4) A bibliome of 833 open- access pangenomic papers and an interface with an LLM that can answer in-depth questions using their knowledge. PanKB empowers researchers and bioengineers to harness the full potential of microbial pangenomics and serves as a valuable resource bridging the gap between pangenomic data and practical applications.

Graphical Abstract