bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking fluid-axons interactions to the macroscopic fluid transport properties of the brain
Authors: Yuan Tian , Zhan Wenbo , Dini Daniele 
Published: January 2023

ABSTRACTMany brain disorders, including Alzheimer’s Disease and Parkinson’s Disease, and drug delivery procedures are linked to fluid transport in the brain; yet, while neurons are extremely soft and can be easily deformed, how the microscale channel flow interacts with the neuronal structures (especially axons) deformation and how this interactions affect the macroscale tissue function and transport properties is poorly understood. Misrepresenting these relationships may lead to the erroneous prediction of e.g. disease spread, drug delivery, and nerve injury in the brain. However, understanding fluid-neuron interactions is an outstanding challenge because the behaviours of both phases are not only dynamic but also occur at an extremely small length scale (the width of flow channel is ∼100 nm), which cannot be captured by the state-of-the-art experimental techniques. Here, by explicitly simulating dynamics of the flow and axons at the microstructural level, we, for the first time, establish the link between micromechanical tissue response to the physical laws governing the macroscopic transport property of the brain white matter. We found that interactions between axons and the interstitial flow is very strong, thus playing an essential role in the brain fluid/mass transport. Furthermore, we proposed the first anisotropic pressure-dependent permeability tensor informed by microstructural dynamics for more accurate brain modelling at the macroscale, and analysed the effect of the variation of the microstructural parameters that influence such tensor. These findings will sheds light on some unsolved issues linked to brain functions and medical treatments relying on intracerebral transport, and the mathematical model provides a framework to more realistically model the brain and design the brain-tissue-like biomaterials.Statement of significanceThis study reveals how neurons interact with the fluid flowing around them and how these microscale interactions affect macroscale transport behaviour of the brain tissue. The findings provide unprecedented insights into some unsolved issues linked to brain functions and medical treatments relying on intracerebral fluid transport. Furthermore, we, for the first time, established a microstructure-informed permeability tensor as a function of local hydraulic pressure and pressure gradient for the brain tissue, which inherently captures the dynamic transport property of the brain. This study is a cornerstone to advance the predicting accuracy of brain tissue transport property and neural tissue engineering.
Hand preference predicts behavioral responses to threats in Barbary macaques
Authors: van Dijk Eva S.J. , Bhattacharjee Debottam , Belli Elena , Massen Jorg J.M. 
Published: January 2023

AbstractThe structure and functioning of the brain are lateralized – the right hemisphere processes unexpected stimuli and controls spontaneous behavior, while the left deals with familiar stimuli and routine responses. Hemispheric dominance, the predisposition of an individual using one hemisphere over the other, may lead to behavioral differences; particularly, an individual may be programmed to act in a certain way concerning hemispheric dominance. Hand preference is a robust estimator of hemispheric dominance in primates, as each brain hemisphere controls the opposing side of the body. Studies have found links between hand preference and the exhibition of different behaviors in contexts such as exploring and manipulating objects. However, little is known about whether hand preference can predict behavioral variations in other ecologically relevant contexts like, for example, predation. We investigated the relationship between hand preference and the behavioral responses to two types of predator models in captive Barbary macaques (Macaca sylvanus) (n=22). Hand preference was determined by observing unimanual foraging, whereas focus and tension behaviors were quantified during experimental exposure to predator models. We found 91% of the macaques to be lateralized with no group-level bias. In contrast to their right-hand counterparts, individuals with a strong left-hand preference elicited frequent focus and tension behavior. Additionally, the behavioral response varied with predator type. We also found an interaction effect between hand preference and the predator type. Our study suggests that hand preference can reliably predict behavioral variations in the context of potential predation. While these results are consistent with the lateralized brain function, indicating lateralization as a potential neural mechanism of behavioral variation, the interaction effect between hand preference and predator type elucidates the importance of context-specificity when investigating laterality non-invasively. Future research on other non-human primates using the current framework may shed light on the evolution of laterality and underlying behavioral predispositions.
Long-Read Genome Assembly and Gene Model Annotations for the Rodent Malaria ParasitePlasmodium yoelii17XNL
Authors: Godin Mitchell J. , Sebastian Aswathy , Albert Istvan , Lindner Scott E. 
Published: January 2023

AbstractMalaria causes over 200 million infections and over 600 thousand fatalities each year, with most cases attributed to a human-infectiousPlasmodiumspecies,Plasmodium falciparum. Many rodent-infectiousPlasmodiumspecies, likePlasmodium berghei, Plasmodium chabaudi, andPlasmodium yoelii, have been used as genetically tractable model species that can expedite studies of this pathogen. In particular,P. yoeliiis an especially good model for investigating the mosquito and liver stages of parasite development because key attributes closely resemble those ofP. falciparum. Because of its importance to malaria research, in 2002 the 17XNL strain ofP. yoeliiwas the first rodent malaria parasite to be sequenced. While sequencing and assembling this genome was a breakthrough effort, the final assembly consisted of >5000 contiguous sequences that impacted the creation of annotated gene models. While other important rodent malaria parasite genomes have been sequenced and annotated since then, including the relatedP. yoelii17X strain, the 17XNL strain has not. As a result, genomic data for 17X has become thede factoreference genome for the 17XNL strain while leaving open questions surrounding possible differences between the 17XNL and 17X genomes. In this work, we present a high-quality genome assembly forP. yoelii17XNL using HiFi PacBio long-read DNA sequencing. In addition, we use Nanopore long-read direct RNA-seq and Illumina short-read sequencing of mixed blood stages to create complete gene models that include not only coding sequences but also alternate transcript isoforms, and 5’ and 3’ UTR designations. A comparison of the 17X and this new 17XNL assembly revealed biologically meaningful differences between the strains due to the presence of coding sequence variants. Taken together, our work provides a new genomic and gene expression framework for studies with this commonly used rodent malaria model species.
Unmixing Biological Fluorescence Image Data with Sparse and Low-Rank Poisson Regression
Authors: Wang Ruogu , Lemus Alex A. , Henneberry Colin M. , Ying Yiming , Feng Yunlong , Valm Alex M. 
Published: January 2023

AbstractMultispectral biological fluorescence microscopy has enabled the identification of multiple targets in complex samples. The accuracy in the unmixing result degrades (1) as the number of fluorophores used in any experiment increases and (2) as the signal-to-noise ratio in the recorded images decreases. Further, the availability of prior knowledge regarding the expected spatial distributions of fluorophores in images of labeled cells provides an opportunity to improve the accuracy of fluorophore identification and abundance. We propose a regularized sparse and low-rank Poisson unmixing approach (SL-PRU) to deconvolve spectral images labeled with highly overlapping fluorophores which are recorded in low signal-to-noise regimes. Firstly, SL-PRU implements multi-penalty terms when pursuing sparseness and spatial correlation of the resulting abundances in small neighborhoods simultaneously. Secondly, SL-PRU makes use of Poisson regression for unmixing instead of least squares regression to better estimate photon abundance. Thirdly, we propose a method to tune the SL-PRU parameters involved in the unmixing procedure in the absence of knowledge of the ground truth abundance information in a recorded image. By validating on simulated and real-world images, we show that our proposed method leads to improved accuracy in unmixing fluorophores with highly overlapping spectra.
EnsDTI-kinase: Web-server for Predicting Kinase-Inhibitor Interactions with Ensemble Computational Methods and Its Applications
Authors: Lu Yijingxiu , Lim Sangsoo , Park Sungjoon , Choi MinGyu , Cho Changyun , Kang Soosung , Kim Sun 
Published: January 2023

AbstractMotivationKinase inhibitors are a major category of drugs. Experimental panel assay protocols are routinely used as a standard procedure to evaluate the efficiency and selectivity of a drug candidate to target kinase. However, current kinase panel assays are time-consuming and expensive. In addition, the panel assay protocols neither provide insights on binding sites nor allow experiments on mutated sequences or newly-characterized kinases. Existing virtual screening or docking simulation technologies require extensive computational resources, thus it is not practical to use them for the panel of kinases. With rapid advances in machine learning and deep learning technologies, a number of DTI tools have been developed over the years. However, these methods are yet to achieve prediction accuracies at the level of practical use. In addition, the performances of current DTI tools vary significantly depending on test sets. In this case, an ensemble model can be used to improve and stabilize DTI prediction accuracies.ResultsIn this work, we propose an ensemble model, EnsDTI-kinase, that integrates eight existing machine learning and deep learning models into a unified model deployed as a web-server. Upon submission of a compound SMILES string, potential target kinases are automatically predicted and evaluated on the web-server. Importantly, EnsDTI-kinase is a computational platform where newly developed DTI tools can be easily incorporated without modifying core components so that its DTI prediction quality can improve over time. Besides, many useful functionalities are provided on our platform for users to further investigate predicted DTI: it allows confidence experiments by changing the amino acid (AA) at a specific position in a kinase sequence, namedin silicomutagenesis, to investigate the effect of AA changes in binding affinity; it predicts kinase sequential regions where the query compound likely binds to by slidingly masking the sequence of selected kinases so that confidence in the predicted binding sites can be evaluated. Our model was evaluated in three experimental settings using four independent datasets, and showed accuracy of 0.82 compared to the average accuracy of 0.69 from five deep learning methods on the ChEMBL dataset. It achieved average selectivity of 0.95 within kinase families such as TK, CAMK and STE. For 8 out of 17 recent drugs, our model successfully predicted their interactions with 404 proteins at average accuracy of 0.82.Availabilityhttp://biohealth.snu.ac.kr/software/ensdtiContactsunkim.bioinfo@snu.ac.kr
Gaudichaudione H inhibits Herpes Simplex Virus-1 replication by regulating cellular nuclear factor-κB in an interferon-γ-inde-pendent manner
Authors: Feng Jiling , Tang Yuexun , Fu Wenwei , Xu Hongxi 
Published: January 2023

AbstractThe highly prevalent herpes simplex virus type 1 (HSV-1) causes keratoconjunctivitis and encephalitis. Viral DNA polymerase-inhibiting nucleoside analogs (such as acyclovir) are standard treatment agents against HSV infections but are limited by severe drug resistance issues. Thus, new antiviral agents with novel targets are urgently needed. Earlier, we investigated the anti-cancer, anti-inflammatory, and antibacterial bioactivities ofGarcinia sp. Here, we report that non-cytotoxic concentrations (< 500 nM) of Gaudichaudione H (GH, isolated fromGarcinia oligantha Merr.) potently inhibits HSV-1 replicationin vitrowithout affecting viral entry or attachment. GH inhibits the expression of the viral proteins ICP0, ICP4, and ICP27 without affecting their mRNA levels. In Vero cells, GH enhanced STAT1 and 3 phosphorylation, which occurs downstream to interferon (IFN)-γ activation during viral infections. However, pharmacological/genetic inhibition of IFN-γ failed to suppress the GH-mediated inhibition of HSV-1 replication, indicating that GH exerts antiviral effects independent of IFN. Further mechanistic studies suggest that GH inhibits HSV-1 replication, at least partially by inhibiting cellular NF-κB activation. Moreover, GH prolonged the survival rate of KOS-infected mice by 25% (n = 5). In conclusion, GH treatment inhibits HSV-1 replication bothin vitroandin vivo; therefore, it can be developed as an antiviral.ImportanceVery few therapeutic drug options are available to treat herpes simplex virus-1/2 which cause myriad debilitating diseases. We screened eightGarciniacompounds and found Gaudichaudione H was the most effective compound at non-cytotoxic concentrations. Further mechanism study illustrates that GH inhibits HSV-1 replication, at least partially by inhibiting cellular NF-κB activation. Natural compound is a promising resource of new antiviral agents with different targets that has ability to treat resistant viral strains.
EhrlichiaNotch signaling induction promotes XIAP stability and inhibits apoptosis
Authors: Patterson LaNisha L. , Byerly Caitlan D. , Solomon Regina , Pittner Nicholas , Bui Duc Cuong , Patel Jignesh , McBride Jere W. 
Published: January 2023

AbstractEhrlichia chaffeensishas evolved multiple strategies to evade innate defenses of the mononuclear phagocyte. Recently, we reported theE. chaffeensisTRP120 effector functions as a Notch ligand mimetic and a ubiquitin ligase that degrades the nuclear tumor suppressor, F-box and WD repeat domain-containing 7 (FBW7), a negative regulator of Notch. The Notch receptor intracellular domain (NICD) is known to inhibit apoptosis primarily by interacting with X-linked inhibitor of apoptosis protein (XIAP) to prevent degradation. In this study, we determinedE. chaffeensisactivation of Notch signaling increases XIAP levels, thereby inhibiting intrinsic apoptosis. Increased NICD and XIAP levels were detected duringE. chaffeensisinfection and after TRP120 Notch ligand mimetic peptide treatment. Conversely, XIAP levels were reduced in the presence of Notch inhibitor DAPT. Cytoplasmic colocalization of NICD and XIAP was observed during infection and a direct interaction was confirmed by co-immunoprecipitation. Procaspase levels increased temporally during infection, consistent with increased XIAP levels; however, knockdown of XIAP during infection significantly increased apoptosis and Caspase-3, −7 and −9 levels. Further, treatment with SM-164, a second mitochondrial activator of caspases (Smac/DIABLO) antagonist, resulted in decreased procaspase levels and increased caspase activation, induced apoptosis, and significantly decreased infection. In addition, iRNA knockdown of XIAP also decreased infection and significantly increased apoptosis. Moreover, ectopic expression of TRP120 HECT Ub ligase catalytically defective mutant in HeLa cells decreased NICD and XIAP levels and increased caspase activation compared to WT. This investigation reveals a mechanism wherebyE. chaffeensisrepurposes Notch signaling to stabilize XIAP and inhibit apoptosis.Author SummaryEhrlichia chaffeensisis a tick-borne, obligately intracellular bacterium that exhibits tropism for mononuclear phagocytes.E. chaffeensissurvives by mobilizing various molecular strategies to promote cell survival, including modulation of apoptosis. This investigation reveals anE. chaffeensisinitiated, Notch signaling regulated, antiapoptotic mechanism involving inhibitor of apoptosis proteins (IAPs). Herein, we demonstrate thatE. chaffeensisinduced Notch activation results in Notch intracellular domain stabilization of X-linked inhibitor of apoptosis protein (XIAP) to inhibit intrinsic apoptosis. This study highlights a novel mechanistic strategy whereby intracellular pathogens repurpose evolutionarily conserved eukaryotic signaling pathways to engage an antiapoptotic program for intracellular survival.
Differential impact of the COVID-19 pandemic on excess mortality and life expectancy loss within the Hispanic population
Authors: Arias Elizabeth , Tejada-Vera Betzaida 
Published: January 2023

AbstractBackgroundThe impact of the COVID-19 pandemic on the Hispanic population resulted in the almost complete elimination of the longstanding Hispanic mortality advantage relative to the non-Hispanic White population. However, it is unknown how COVID-19 mortality affected the diverse Hispanic sub-populations.ObjectiveWe estimate life expectancy at birth in 2019 and 2020 by Hispanic sub-group and explore how changes in age-specific all-cause and COVID-19 mortality affected changes in life expectancy between 2019 and 2020 for each group.MethodsWe use final 2019 and 2020 mortality data from the National Center for Health Statistics and population estimates based on the 2019 and 2020 American Community Survey. We calculate life tables and apply decomposition techniques to explore the effects of changes in age- and cause-specific mortality on life expectancy.ResultsPatterns of age- and cause-specific excess deaths and their impact on declines in life expectancy due to the COVID-19 pandemic differed substantially by Hispanic sub-group. Life expectancy losses ranged from 0.6 to 6.7 years among males and 0.6 to 3.6 years among females.ConclusionsOur findings highlight the heterogeneous impact of the COVID-19 pandemic within the Hispanic population.ContributionsOur findings contribute new information that will assist future research identify the causes of the disproportionately severe impact of the COVID-19 pandemic on the Hispanic population. Our study underscores the importance of population disaggregation in endeavors to identify the multiple pathways by which the pandemic affected the Hispanic population.
Cytokinins regulate spatially-specific ethylene production to control root growth inArabidopsis
Authors: Yamoune Amel , Zdarska Marketa , Depaepe Thomas , Korytarova Anna , Skalak Jan , Berendzen Kenneth Wayne , Mira-Rodado Virtudes , Tarr Paul , Spackova Eliska , Badurova Lucia , Parizkova Barbora , Franczyk Abigail , Kovacova Ingrid , Pernisova Marketa , Novak Ondrej , Meyerowitz Elliot , Harter Klaus , Van Der Straeten Dominique , Hejatko Jan 
Published: January 2023

AbstractThe two principal growth regulators cytokinins and ethylene are known to interact in the regulation of plant growth. However, information about underlying molecular mechanism and positional specificity of the cytokinin/ethylene crosstalk in root growth control is scarce. We have identified spatial specificity of cytokinin-regulated root elongation and root apical meristem (RAM) size, both of which we demonstrate to be ethylene biosynthesis-dependent. Upregulation of the cytokinin biosynthetic geneISOPENTENYLTRANSFERASE(IPT) in proximal and peripheral tissues leads to both root and RAM shortening. In contrast,IPTactivation in distal and inner tissues reduces RAM size while leaving the root length comparable to mock-treated controls. We show that cytokinins regulate two steps specific to ethylene biosynthesis, the production of ACC by ACC SYNTHASEs (ACSs), and its conversion to ethylene by ACC OXIDASEs (ACOs). We describe cytokinin- and ethylene-specific regulation controlling the activity ofACSsandACOsthat are spatially discrete along both proximo/distal and radial root axes. Using direct ethylene measurements, we identifyACO2, ACO3andACO4as being responsible for ethylene biosynthesis and the ethylene-regulated root and RAM shortening in cytokinin-treatedArabidopsis. Finally, we describe the tight cooperation between cytokinin and ethylene signaling in cytokinin-induced, ethylene-regulated control ofACO4due to the direct interaction between ARABIDOPSIS RESPONSE REGULATOR 2 (ARR2), a member of the multistep phosphorelay cascade and the C-terminal portion of ETHYLENE INSENSITIVE 2 (EIN2-C), a key regulator of canonical ethylene signaling.
Passive endocytosis in model protocells
Authors: Zhang Stephanie J. , Lowe Lauren A. , Anees Palapuravan , Krishnan Yamuna , Fai Thomas G. , Szostak Jack W. , Wang Anna 
Published: January 2023

AbstractSemipermeable membranes are a key feature of all living organisms. While specialized membrane transporters in cells can import otherwise impermeable nutrients, the earliest cells would have lacked a mechanism to import nutrients rapidly under nutrient-rich circumstances. Using both experiments and simulations, we find that a process akin to passive endocytosis can be recreated in model primitive cells. Molecules that are too impermeable to be absorbed can be taken up in a matter of seconds in an endocytic vesicle. The internalized cargo can then be slowly released over hours, into the main lumen or putative cytoplasm. This work demonstrates a way by which primitive life could have broken the symmetry of passive permeation prior to the evolution of protein transporters.