bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of polygenic and gut metagenomic risk prediction for common diseases
Authors: Liu Yang , Ritchie Scott , Teo Shu Mei , Ruuskanen Matti Olavi , Kambur Oleg , Zhu Qiyun , Sanders Jon , Vazquez-Baeza Yoshiki , Verspoor Karin , Jousilahti Pekka , Lahti Leo , Niiranen Teemu , Salomaa Veikko , Havulinna Aki , Knight Rob , Méric Guillaume , Inouye Michael 
Published: August 2023

AbstractMulti-omics has opened new avenues for non-invasive risk profiling and early detection of complex diseases. Both polygenic risk scores (PRSs) and the human microbiome have shown promise in improving risk assessment of various common diseases. Here, in a prospective population-based cohort (FINRISK 2002; n=5,676) with ∼18 years of e-health record follow-up, we assess the incremental and combined value of PRSs and gut metagenomic sequencing as compared to conventional risk factors for predicting incident coronary artery disease (CAD), type 2 diabetes (T2D), Alzheimer’s disease (AD) and prostate cancer. We found that PRSs improved predictive capacity over conventional risk factors for all diseases (ΔC-indices between 0.010 – 0.027). In sex-stratified analyses, gut metagenomics improved predictive capacity over baseline age for CAD, T2D and prostate cancer; however, improvement over all conventional risk factors was only observed for T2D (ΔC-index 0.004) and prostate cancer (ΔC-index 0.005). Integrated risk models of PRSs, gut metagenomic scores and conventional risk factors achieved the highest predictive performance for all diseases studied as compared to models based on conventional risk factors alone. We make our integrated risk models available for the wider research community. This study demonstrates that integrated PRS and gut metagenomic risk models improve the predictive value over conventional risk factors for common chronic diseases.
LLIN Evaluation in Uganda Project (LLINEUP) –Plasmodiuminfection prevalence and genotypic markers of insecticide resistance inAnophelesvectors from 48 districts of Uganda
Authors: Lynd Amy , Gonahasa Samuel , Staedke Sarah G , Oruni Ambrose , Maiteki-Sebuguzi Catherine , Hancock Penny , Knight Erin , Dorsey Grant , Opigo Jimmy , Yeka Adoke , Katureebe Agaba , Kyohere Mary , Hemingway Janet , Kamya Moses R , McDermott Daniel , Lucas Eric R. , Donnelly Martin J 
Published: August 2023

AbstractBackgroundIn 2017-2019, we conducted a large-scale, cluster-randomised trial (LLINEUP) to evaluate long-lasting insecticidal nets (LLINs) treated with a pyrethroid insecticide plus the synergist piperonyl butoxide (PBO LLINs), as compared to conventional, pyrethroid-only LLINs across 104 health sub-districts (HSDs) in Uganda. In LLINEUP, and similar trials in Tanzania, PBO LLINs were found to provide greater protection against malaria than conventional LLINs, reducing parasitaemia and vector density. In the LLINEUP trial, cross-sectional entomological surveys were carried out at baseline and then every 6 months for two years. In each survey, ten households per HSD were randomly selected for indoor household entomological collections.ResultsOverall, 5395 female Anopheles mosquitoes were collected from 5046 households. The proportion of mosquitoes infected withPlasmodium falciparumdid not change significantly over time, while infection with non-falciparummalaria decreased inAn. gambiaes.s, but notAn. funestus. The frequency of genetic markers associated with pyrethroid resistance increased significantly over time, but the rate of change was not different between the two LLIN types. The knock-down resistance (kdr) mutationVgsc-995S declined over time asVgsc-995F, the alternative resistance mutation at this codon, increased.Vgsc-995F appears to be spreading into Uganda.ConclusionsDistribution of LLINs in Uganda was associated with reductions in parasite prevalence and vector density, but the proportion of infective mosquitoes remained stable, suggesting that the potential for transmission persisted. The increased frequency of markers of pyrethroid resistance indicates that LLIN distribution favoured the evolution of resistance within local vectors and highlights the potential benefits of resistance management strategies.Trial registration: This study is registered with ISRCTN,ISRCTN17516395. Registered 14 February 2017,http://www.isrctn.com/ISRCTN17516395
Racial/Ethnic Differences in COVID-19-Traumatic Symptoms, Sleep, Coping Outcomes in a Group of New-Yorkers
Authors: Blanc Judite , Seixas Azizi , Small Sean , Auguste Evan , Briggs Anthony , Antoine Yoann Sophie , Bubu Omonigho Michael , Jean-Louis Girardin 
Published: August 2023

AbstractBackgroundLittle research has examined within/between group predictors and mediators of race/ethnic differences or disparities in mental and sleep health outcomes arising from the experience of the COVID-19 pandemic.ObjectivesThis study sought to evaluate the effect of COVID-19 experiences on trauma-related symptoms and sleep quality among a multiracial/ethnic sample in New York.MethodThis is a cross-sectional study conducted online among multiethnic adults (n=541) who experienced the pandemic in New York from September to November 2020. Comparisons of characteristics and mean scores by race/ethnicity status were conducted using one-way ANOVA and independent samples t-tests for continuous variables and chi-square tests for categorical variables. Multilinear regression was used for associations between social determinants of health and/or SES, trauma-related symptoms, coping, and sleep.ResultsCompared to Whites [Mean (SD)= (24.1(7.6)] and other group [Mean (SD)=24.9(8.2), Blacks [Mean (SD)=(26.3(6.4)] and Hispanics [Mean(SD)=(27.2(8.2)] reported higher level of peritraumatic distress [df= 3; F=4273; p=0.005). The prevalence of clinically significant PTSD symptoms was 21.4%(n=113): [Whites=31(16.3%); Blacks=28(25.7%); Hispanics=24(25%); and other groups=30(22.4%); x2 =4.93; p=0.177]. This rate doubled [48.3%(257)] when it comes to the overall clinically significant depression level. Compared to all subcategories, [Blacks=52(47.7%); Hispanics =62(64.6%); other group=66(49.3%)], depression symptoms were lower among Whites [77(39.9%;x2 =15.71;p=0.001]. We found a prevalence of insufficient sleep <6 hours of 41%(198): [Whites=69(39.4%); Blacks=43(41.7%); Hispanics=46(52.3%); other groups=40(34.2%);x2=12.21;p=0.057]. Several unique demographic predictors of PTSD emerged for distinct racial/ethnic groups. Among Blacks, sex [β = −0.22; p < .01] and employment [β = −0.159; p < .05] emerged as significant predictors for PTSD, but for no other racial/ethnic group. Interestingly, among Hispanics [β = −0.144; p = .064] and Blacks [β = −0.174; p = .0.076], coping strategies did not mitigate PTSD or depressive symptoms.ConclusionAs New York and the rest of the world are trying to bounce back from the COVID-19 consequences, mental health outcomes are devastating, particularly among historically marginalized communities. This study provides insight into the emergency for policymakers to invest in racial justice programs and provide free access to culturally responsive mental health care for the most vulnerable groups.
Molecular pharmacology of selective Nav1.6 and dual Nav1.6 and Nav1.2 channel inhibitors that suppress excitatory neuronal activity ex vivo
Authors: Goodchild Samuel J. , Shuart Noah Gregory , Williams Aaron D. , Ye Wenlei , Parrish R. Ryley , Soriano Maegan , Thouta Samrat , Mezeyova Janette , Waldbrook Matthew , Dean Richard A. , Focken Thilo , Ghovanloo Mohammad-Reza , Ruben Peter C. , Scott Fiona , Cohen Charles J. , Empfield James R. , Johnson JP 
Published: August 2023

AbstractSodium channel inhibitors are used to treat neurological disorders of hyperexcitability. However, all currently available sodium channel targeting anti-seizure medications are non-selective among the NaVisoforms which potentially limits efficacy and therapeutic safety margins. XPC-7724 and XPC-5462 represent a new class of small molecule compounds. These compounds target inhibition of the NaV1.6 and NaV1.2 channels in excitatory pyramidal neurons and possess a molecular selectivity of >100 fold against NaV1.1 channels that are dominant in inhibitory cells. This profile will enable pharmacological dissection of the physiological roles of NaV1.2 and NaV1.6 and help to define the role of each channel in disease states. These compounds bind to and stabilize the inactivated-state of the channels, demonstrate higher potency with longer residency times, and slower off-rates than carbamazepine and phenytoin. These compounds possess cellular selectivity ex vivo in inhibiting action potential firing in cortical excitatory pyramidal neurons, whilst sparing fast spiking inhibitory interneurons. XPC-5462 also suppresses epileptiform activity in an ex vivo brain slice seizure model. This class of compounds provides a unique approach for treating neuronal excitability disorders by selectively down-regulating excitatory circuits.Graphical Abstract
Top dressed biochar increases tree seedling growth and decreases sodium leaching
Authors: Wagner Brian , Salisbury Allyson , Midgley Meghan G. 
Published: August 2023

ABSTRACTDe-icing salts on roadways are nearly ubiquitous in northern cities during winter months, leading to contamination of soils adjacent to roadways. Sodium chloride salts often have detrimental impacts on water and trees, though some species are more sensitive than others. Biochar has the potential to mitigate sodium’s harmful effects due to its large surface area:volume ratio and subsequent ability to sorb ions from solution. We conducted a four-month greenhouse experiment to test if biochar applied as either a top dressing or incorporated into the growing medium reduced sodium leaching and buffered tree responses to sodium stress. We also evaluated the effects of salt addition and biochar on four tree species that vary in salt tolerance:Catalpa speciosa(tolerant),Gleditsia triacanthos(tolerant),Acer saccharum(intolerant), andQuercus rubra(intolerant). We found no interactive effects of sodium addition and biochar on sodium leaching or tree growth and physiology. However, we did find that top dressed biochar broadly decreased sodium leaching, likely via positive effects of top dressed biochar on tree seedling growth,Catalpa speciosain particular. Incorporated biochar, on the other hand, had positive or neutral effects on sodium leaching and negative effects on the production of new shoots and fine roots. Given that biochar is a relatively expensive amendment, it should be used sparingly to improve urban tree growth and health. Overall, this study shows that biochar application decisions have implications for tree growth and soil management.
Parameters of Cable Theory Are Mostly Unaffected by the Geometry of Dendritic Spines
Authors: Eberhardt Florian 
Published: August 2023

AbstractDendritic spines are extremely small and experimentally difficult to access. Therefore, it is still uncertain whether all assumptions of basic neuroscientific theories, such as cable theory, are valid there. Previous theoretical work suggests that electroneutrality could be violated in dendritic spines. If this were true, new theories would be required. Unfortunately, these results were based on a greatly simplified model system with unrealistic ion concentrations.Inspired by these studies, we apply Poison-Nernst-Planck (PNP) equations to study the profiles of ion concentrations and the membrane potential in dendritic spines in a physiologically relevant regime. We find that, for realistic ion concentrations and in contrast to previous results, electroneutrality is a valid assumption for all tested geometries, irrespective of size and shape. However, the surface charge causes an accumulation of counter ions and a strong electric field near the surface of the membrane in the intra- and extracellular space.Still, a plate capacitor model accurately describes the capacitance of the membrane. Most importantly, the two cable parameters - the specific capacitance and the intracellular resistivity - are constants over a wide range of parameters. These results justify the application of models based on cable theory to dendritic spines.
Conformational diversity and protein-protein interface clusters help drug repurposing in Ras/Raf/MEK/ERK signaling pathway
Authors: Sayin Ahenk Zeynep , Abali Zeynep , Senyuz Simge , Cankara Fatma , Gursoy Attila , Keskin Ozlem 
Published: August 2023

ABSTRACTRas/Raf/MEK/ERK signaling pathway regulates cell growth, division, and differentiation. In this work, we focus on drug repurposing in the Ras/Raf/MEK/ERK signaling pathway, considering structural similarities of protein-protein interfaces. The complexes in this pathway are extracted from literature and interfaces formed by physically interacting proteins are found via PRISM (PRotein Interaction by Structural Matching) if not available in Protein Data Bank. As a result, the structural coverage of these interactions has been increased from 21% to 92% using PRISM. Multiple conformations of each protein are used to include protein dynamics and diversity. Next, we find FDA-approved drugs bound to additional structurally similar protein-protein interfaces. The results suggest that HIV protease inhibitors tipranavir, indinavir and saquinavir may bind to Epidermal Growth Factor Receptor (EGFR) and Receptor Tyrosine-Protein Kinase ErbB-3 (ERBB3/HER3) interface. Tipranavir and indinavir may also bind to EGFR and Receptor Tyrosine-Protein Kinase ErbB-2 (ERBB2/HER2) interface. Additionally, a drug used in Alzheimer’s disease (galantamine) and an antinauseant for cancer chemotherapy patients (granisetron) can bind to RAF proto-oncogene serine/threonine-protein kinase (RAF1) and Serine/threonine-protein kinase B-Raf (BRAF) interface. Hence, we propose an algorithm to find drugs to be potentially used for cancer. As a summary, we propose a new strategy of using a dataset of structurally similar protein-protein interface clusters rather than pockets in a systematic way.Significance statementThis work focuses on drug repurposing in the Ras/Raf/MEK/ERK signaling pathway based on structural similarities of protein-protein interfaces. The Food and Drug Administration approved drugs bound to the protein-protein interfaces are proposed for the other interfaces using protein-protein interface clusters based on structural similarities. Moreover, the structural coverage of protein complexes of physical interactions in the pathway has been increased from 21% to 92% using multiple conformations of each protein to include protein dynamics.
TWISP: A Transgenic Worm for Interrogating Signal Propagation inC. elegans
Authors: Sharma Anuj Kumar , Randi Francesco , Kumar Sandeep , Dvali Sophie , Leifer Andrew M 
Published: August 2023

ABSTRACTGenetically encoded optical indicators and actuators of neural activity allow for all-optical investigations of signaling in the nervous system. But commonly used indicators, actuators and expression strategies are poorly suited for systematic measurements of signal propagation at brain scale and cellular resolution. Large scale measurements of the brain require indicators and actuators with compatible excitation spectra to avoid optical crosstalk. They must be highly expressed in every neuron but at the same time avoid lethality and permit the animal to reach adulthood. And finally, their expression must be compatible with additional fluorescent labels to locate and identify neurons, such as those in the NeuroPAL cell identification system. We present TWISP, a Transgenic Worm for Interrogating Signal Propagation, that address these needs and enables optical measurements of evoked calcium activity at brain scale and cellular resolution in the nervous system of the nematodeCaenorhabditis elegans. We express in every neuron a non-conventional optical actuator, the gustatory receptor homolog GUR-3+PRDX-2 under the control of a drug-inducible system QF+hGR, and calcium indicator GCAMP6s, in a background with additional fluorophores of the NeuroPAL cell ID system. We show that this combination, but not others tested, avoids optical-crosstalk, creates strong expression in the adult, and generates stable transgenic lines for systematic measurements of signal propagation in the worm brain.
Compound activity prediction with dose-dependent transcriptomic profiles and deep learning
Authors: Godinez William J. , Trifonov Vladimir , Fang Bin , Kuzu Guray , Pei Luying , Guiguemde W. Armand , Martin Eric J. , King Frederick J. , Jenkins Jeremy L. , Skewes-Cox Peter 
Published: August 2023

AbstractPredicting compound activity in assays is a long-standing challenge in drug discovery. Computational models based on compound-induced gene-expression signatures from a single profiling assay have shown promise towards predicting compound activity in other, seemingly unrelated, assays. Applications of such models include predicting mechanisms-of-action (MoA) for phenotypic hits, identifying off-target activities, and identifying polypharmacologies. Here, we introduce Transcriptomics-to-Activity Transformer (TAT) models that leverage gene-expression profiles observed over compound treatment at multiple concentrations to predict compound activity in other biochemical or cellular assays. We built TAT models based on gene-expression data from a RASL-Seq assay to predict the activity of 2,692 compounds in 262 dose response assays. We obtained useful models for 51% of the assays as determined through a realistic held-out set. Prospectively, we experimentally validated the activity predictions of a TAT model in a malaria inhibition assay. With a 63% hit rate, TAT successfully identified several sub-micromolar malaria inhibitors. Our results thus demonstrate the potential of transcriptomic responses over compound concentration and the TAT modeling framework as a cost-efficient way to identify the bioactivities of promising compounds across many assays.
A computational pipeline for spatial mechano-transcriptomics
Authors: Hallou Adrien , He Ruiyang , Simons Benjamin D. , Dumitrascu Bianca 
Published: August 2023

AbstractAdvances in spatial profiling technologies are providing insights into how molecular programs are influenced by local signaling and environmental cues. However, cell fate specification and tissue patterning involve the interplay of biochemical and mechanical feedback. Here, we develop a computational framework that enables the joint statistical analysis of transcriptional and mechanical signals in the context of spatial transcriptomics. To illustrate the application and utility of the approach, we use spatial transcriptomics data from the developing mouse embryo to infer the forces acting on individual cells, and use these results to identify mechanical, morphometric, and gene expression signatures that are predictive of tissue compartment boundaries. In addition, we use geoadditive structural equation modeling to identify gene modules that predict the mechanical behavior of cells in an unbiased manner. This computational framework is easily generalized to other spatial profiling contexts, providing a generic scheme for exploring the interplay of biomolecular and mechanical cues in tissues.
Predicting Molecular Docking Affinity of Per- and Polyfluoroalkyl Substances (PFAs) Towards Human Blood Proteins Using Generative AI Algorithm DiffDock
Authors: Fortela Dhan Lord B. , Mikolajczyk Ashley P. , Carnes Miranda R. , Sharp Wayne , Revellame Emmanuel , Hernandez Rafael , Holmes William , Zappi Mark 
Published: August 2023

AbstractThis study computationally evaluates the molecular docking affinity of various perfluoroalkyl and polyfluoroalkyl substances (PFAs) using a generative machine learning algorithm, DiffDock, specialized in protein-ligand blind-docking learning and prediction. Concerns about the chemical pathways and accumulation of PFAs in the environment and eventually in human body has been rising due to empirical findings that levels of PFAs in human blood has been rising. Though there is currently a heightened need to understand the pathways of PFAs, empirical studies on PFAs have been relatively slow due to the time-scale and cost of standard chemical analysis such as those in blood samples. The current study demonstrates the implementation of DiffDock and assesses the prediction results in relation to empirical findings. The capability of an advanced generative artificial intelligence (AI) algorithm designed for protein-ligand docking such as DiffDock offers a fast approach in determining the potential molecular pathways of PFAs in human body.
Glioma-neuronal circuit remodeling induces regional immunosuppression
Authors: Nejo Takahide , Krishna Saritha , Jimenez Christian , Yamamichi Akane , Young Jacob S. , Lakshmanachetty Senthilnath , Chen Tiffany , Phyu Su Su Sabai , Ogino Hirokazu , Watchmaker Payal , Diebold David , Choudhury Abrar , Daniel Andy G. S. , Raleigh David R. , Hervey-Jumper Shawn L. , Okada Hideho 
Published: August 2023

SummaryNeuronal activity-driven mechanisms impact glioblastoma cell proliferation and invasion1–7, and glioblastoma remodels neuronal circuits8,9. Distinct intratumoral regions maintain functional connectivity via a subpopulation of malignant cells that mediate tumor-intrinsic neuronal connectivity and synaptogenesis through their transcriptional programs8. However, the effects of tumor-intrinsic neuronal activity on other cells, such as immune cells, remain unknown. Here we show that regions within glioblastomas with elevated connectivity are characterized by regional immunosuppression. This was accompanied by different cell compositions and inflammatory status of tumor-associated macrophages (TAMs) in the tumor microenvironment. In preclinical intracerebral syngeneic glioblastoma models, CRISPR/Cas9 gene knockout of Thrombospondin-1 (TSP-1/Thbs1), a synaptogenic factor critical for glioma-induced neuronal circuit remodeling, in glioblastoma cells suppressed synaptogenesis and glutamatergic neuronal hyperexcitability, while simultaneously restoring antigen-presentation and pro-inflammatory responses. Moreover, TSP-1 knockout prolonged survival of immunocompetent mice harboring intracerebral syngeneic glioblastoma, but not of immunocompromised mice, and promoted infiltrations of pro-inflammatory TAMs and CD8+ T-cells in the tumor microenvironment. Notably, pharmacological inhibition of glutamatergic excitatory signals redirected tumor-associated macrophages toward a less immunosuppressive phenotype, resulting in prolonged survival. Altogether, our results demonstrate previously unrecognized immunosuppression mechanisms resulting from glioma-neuronal circuit remodeling and suggest future strategies targeting glioma-neuron-immune crosstalk may open up new avenues for immunotherapy.