bluuebunny/crossref_metadata_2025 huggingface dataset:
Incorporating Radiopacity into Implantable Polymeric Biomedical Devices for Clinical Radiological Monitoring
Authors: Pawelec Kendell M , Tu Ethan , Chakravarty Shatadru , Hix Jeremy ML , Buchanan Lane , Kenney Legend , Buchanan Foster , Chatterjee Nandini , Das Subhashri , Alessio Adam , Shapiro Erik M
Published: January 2023

Longitudinal radiological monitoring of biomedical devices is increasingly important, driven by risk of device failure following implantation. Polymeric devices are poorly visualized with clinical imaging, hampering efforts to use diagnostic imaging to predict failure and enable intervention. Introducing nanoparticle contrast agents into polymers is a potential method for creating radiopaque materials that can be monitored via computed tomography. However, properties of composites may be altered with nanoparticle addition, jeopardizing device functionality. This, we investigated material and biomechanical response of model nanoparticle-doped biomedical devices (phantoms), created from 0-40wt% TaOxnanoparticles in polycaprolactone, poly(lactide-co-glycolide) 85:15 and 50:50, representing non-, slow and fast degrading systems, respectively. Phantoms degraded over 20 weeks in vitro, in simulated physiological environments: healthy tissue (pH 7.4), inflammation (pH 6.5), and lysosomal conditions (pH 5.5), while radiopacity, structural stability, mechanical strength and mass loss were monitored. The polymer matrix determined overall degradation kinetics, which increased with lower pH and higher TaOxcontent. Importantly, all radiopaque phantoms could be monitored for a full 20-weeks. Phantoms implanted in vivo and serially imaged, demonstrated similar results. An optimal range of 5-20wt% TaOxnanoparticles balanced radiopacity requirements with implant properties, facilitating next-generation biomedical devices.
A biochemical analysis of Black Soldier fly (Hermetia illucens) larval frass plant growth promoting activity
Authors: Green Terrence
Published: January 2023

Black Soldier fly (Hermetia illucens) larval (BSFL) frass separated from BSFL processed catering waste, and that recovered directly from larvae, was examined for its nitrogen, phosphate and potassium (N:P205:K2O), phytohormone and biogenic amine content, its plant growth promoting activity, and screened to test the hypothesis that bacteria characteristic of the genusEnterococcus, present in the biome of decaying catering waste and the larval gut, pass freely through the gut and are excreted in viable form into their frass. Its plant growth promoting activity was measured by comparing the growth of winter wheat berry (Triticum aestivum) grown in frass treated soil relative to that measured in untreated (control) soil. Its N:P205:K2O, biogenic amine and phytohormone composition were determined by standard soil analysis, HPLC and HPLC/GC-MS methodologies, respectively, and found to be too low to account for its plant growth promoting activity which induced a 11% increase in arial mass and shoot length in treated plants over controls. Colonies ofEnterococcigrew out on streaking frass collected directly from larvae on standard bile-esculin azide agar culture plates, confirming the hypothesis that viableEnteroccociare excreted in their frass. SinceEnterococciare capable of colonizing the rhizosphere and boosting the growth of plants on amendment into soil, these findings lend further insight into the underlying mechanism(s) accounting for the increased growth of plants growing in frass treated soils.
High-parameter phenotypic characterization reveals a subset of human Th17 cells that preferentially produce IL17 againstM. tuberculosisantigen
Authors: Ogongo Paul , Tran Anthony , Marzan Florence , Gingrich David , Krone Melissa , Aweeka Francesca , Lindestam Arlehamn Cecilia S , Martin Jeffrey N. , Deeks Steven G. , Hunt Peter W. , Ernst Joel D.
Published: January 2023

Background

Interleukin 17 producing CD4 T cells contribute to the control ofMycobacterium tuberculosis (Mtb)infection in humans; whether infection with Human Immunodeficiency Virus (HIV) disproportionately affects distinct Th17 cell subsets that respond toMtbis incompletely defined.

Methods

We performed high-definition characterization of circulatingMtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by LC/MS on plasma and tested the hypothesis that tryptophan catabolism influences Th17 cell frequencies in this context.

Results

We identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2-CD161+CD26+and subset 2 defined as CD4+Vα7.2-CCR6+CXCR3-cells of which subset 1 was significantly reduced in LTBI with HIV-ART, yetMtb-responsive IL17-producing CD4 T cells were preserved; we found that IL17-producing CD4 T cells dominate the response toMtbantigen but not CMV antigen or staphylococcal enterotoxin B (SEB); and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17 cell frequencies.

Conclusions

We found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL17-producing CD4 T cells dominate responses toMtbbut not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.
Linking fluid-axons interactions to the macroscopic fluid transport properties of the brain
Authors: Yuan Tian , Zhan Wenbo , Dini Daniele
Published: January 2023

Many 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 significance

This 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

The 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

Malaria 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

Multispectral 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

Motivation

Kinase 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.

Results

In 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.

Availability

http://biohealth.snu.ac.kr/software/ensdti

Contact

sunkim.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

The 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.

Importance

Very 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

Ehrlichia 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 Summary

Ehrlichia 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

Background

The 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.

Objective

We 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.

Methods

We 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.

Results

Patterns 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.

Conclusions

Our findings highlight the heterogeneous impact of the COVID-19 pandemic within the Hispanic population.

Contributions

Our 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

The 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

Semipermeable 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.
INKILNis a novel long noncoding RNA promoting vascular smooth muscle inflammation via scaffolding MKL1 and USP10
Authors: Zhang Wei , Zhao Jinjing , Deng Lin , Ishimwe Nestor , Pauli Jessica , Wu Wen , Shan Shengshuai , Kempf Wolfgang , Ballantyne Margaret D , Kim David , Lyu Qing , Bennett Matthew , Rodor Julie , Turner Adam W. , Lu Yao Wei , Gao Ping , Choi Mihyun , Warthi Ganesh , Kim Ha Won , Barroso Margarida M , Bryant William B. , Miller Clint L. , Weintraub Neal L. , Maegdefessel Lars , Miano Joseph M. , Baker Andrew H , Long Xiaochun
Published: January 2023

Background

Activation of vascular smooth muscle cells (VSMCs) inflammation is vital to initiate vascular disease. However, the role of human-specific long noncoding RNAs (lncRNAs) in VSMC inflammation is poorly understood.

Methods

Bulk RNA-seq in differentiated human VSMCs revealed a novel human-specific lncRNA calledINflammatory MKL1InteractingLongNoncoding RNA (INKILN).INKILNexpression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation and human atherosclerosis and abdominal aortic aneurysm (AAA) samples. The transcriptional regulation ofINKILNwas determined through luciferase reporter system and chromatin immunoprecipitation assay. Both loss- and gain-of-function approaches and multiple RNA-protein and protein-protein interaction assays were utilized to uncover the role ofINKILNin VSMC proinflammatory gene program and underlying mechanisms. Bacterial Artificial Chromosome (BAC) transgenic (Tg) mice were utilized to studyINKLINexpression and function in ligation injury-induced neointimal formation.

Results

INKILNexpression is downregulated in contractile VSMCs and induced by human atherosclerosis and abdominal aortic aneurysm.INKILNis transcriptionally activated by the p65 pathway, partially through a predicted NF-κB site within its proximal promoter.INKILNactivates the proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. Mechanistically,INKILNphysically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-κB pathway.INKILNdepletion blocks ILIβ-induced nuclear localization of both p65 and MKL1. Knockdown ofINKILNabolishes the physical interaction between p65 and MKL1, and the luciferase activity of an NF-κB reporter. Further,INKILNknockdown enhances MKL1 ubiquitination, likely through the reduced physical interaction with the deubiquitinating enzyme, USP10.INKILNis induced in injured carotid arteries and exacerbates ligation injury-induced neointimal formation in BAC Tg mice.

Conclusions

These findings elucidate an important pathway of VSMC inflammation involving anINKILN/MKL1/USP10 regulatory axis. Human BAC Tg mice offer a novel and physiologically relevant approach for investigating human-specific lncRNAs under vascular disease conditions.
Genomic evidence for rapid speciation and gene flow between sympatric carnivorousNepenthespitcher plants
Authors: Scharmann M , Metali F , Grafe T U , Widmer A
Published: January 2023

Speciation can result from both neutral and adaptive processes, but their relative importance and the factors exerting selective pressures are incompletely understood. In theory, interspecific gene flow could suffice to reverse speciation, or else erode neutral divergence and expose traits and underlying genes whose divergence is due to selection. Hence, introgression can shed light on selection during the speciation process. Here we study mixed assemblages of carnivorousNepenthespitcher plants, which frequently produce natural hybrids yet maintain distinct phenotypes. Using ddRAD-seq markers, we characterize divergence and introgression for eightNepenthesspecies that grow sympatrically in communities of three to seven species at four locations in Southeast Asia, totalling 22 populations. The sympatric species fell into two discrete classes of high and low divergence. Five lineages with high divergence displayed little recent introgression in tests of location-dependent allele sharing (ABBA-BABA) despite the presence of some natural hybrids. However, all five lineages appear to have introgressed in the more distant past, as revealed by coalescent models with Approximate Bayesian Computation. In the same locations occur three further sympatric species with low genetic divergence. These incipient species also showed some natural hybrids, but in addition both ABBA-BABA tests and ABC suggested very recent or ongoing introgression, raising the question how divergence is maintained in these hybrid zones. One trait possibly involved in maintenance of divergence against gene flow might be the carnivorous pitcher traps, whose morphology showed greater divergence than expected under neutral evolution (Pst–Fst) in the introgressing species pairN. hemsleyanaandN. rafflesianat.f..
Endothelial SMAD1/5 signaling couples angiogenesis to osteogenesis during long bone growth
Authors: Lang Annemarie , Benn Andreas , Wolter Angelique , Balcaen Tim , Collins Joseph , Kerckhofs Greet , Zwijsen An , Boerckel Joel D.
Published: January 2023

Skeletal development depends on coordinated angiogenesis and osteogenesis. Bone morphogenetic proteins direct bone development by activating SMAD1/5 signaling in osteoblasts. However, the role of SMAD1/5 in skeletal endothelium is unknown. Here, we found that endothelial cell-conditional SMAD1/5 depletion in juvenile mice caused metaphyseal and diaphyseal hypervascularity, resulting in altered cancellous and cortical bone formation. SMAD1/5 depletion induced excessive sprouting, disrupting the columnar structure of the metaphyseal vessels and impaired anastomotic loop morphogenesis at the chondro-osseous junction. Endothelial SMAD1/5 depletion impaired growth plate resorption and, upon long term depletion, abrogated osteoprogenitor recruitment to the primary spongiosa. Finally, in the diaphysis, endothelial SMAD1/5 activity was necessary to maintain the sinusoidal phenotype, with SMAD1/5 depletion inducing formation of large vascular loops, featuring elevated endomucin expression, ectopic tip cell formation, and hyperpermeability. Together, endothelial SMAD1/5 activity sustains skeletal vascular morphogenesis and function and coordinates growth plate remodeling and osteoprogenitor recruitment dynamics during bone growth.
IraM Remodels the RssB Segmented Helical Linker to Stabilize σsagainst Degradation by ClpXP
Authors: Brugger C , Srirangam S , Deaconescu Alexandra M
Published: January 2023

Upon Mg2+starvation, a condition often associated with virulence, enterobacteria inhibit the ClpXP-dependent proteolysis of the master transcriptional regulator, σs, via IraM, a poorly understood anti-adaptor that prevents RssB-dependent loading of σsonto ClpXP. This inhibition results in σsaccumulation, and expression of stress resistance genes. Here we report on the structural analysis of RssB bound to IraM, which reveals that IraM induces two folding transitions within RssB, which are amplified via a segmental helical linker. This work highlights the remarkable structural plasticity of RssB and reveals how a stress-specific RssB antagonist modulates a core stress response pathway that could be leveraged to control biofilm formation, virulence, and the development of antibiotic resistance.
Development of Multiomicsin situPairwise Sequencing (MiP-Seq) for Single-cell Resolution Multidimensional Spatial Omics
Authors: Wu Xiaofeng , Xu Weize , Deng Lulu , Li Yue , Wang Zhongchao , Sun Leqiang , Gao Anran , Wang Haoqi , Yang Xiaodan , Wu Chengchao , Zou Yanyan , Yan Keji , Liu Zhixiang , Zhang Lingkai , Du Guohua , Yang Liyao , Lin Da , Wang Ping , Han Yunyun , Fu Zhenfang , Dai Jinxia , Cao Gang
Published: January 2023

Delineating the spatial multiomics landscape will pave the way to understanding the molecular basis of physiology and pathology. However, current spatial omics technology development is still in its infancy. Here, we developed a high-throughput multiomicsin situpairwise sequencing (MiP-Seq) strategy to efficiently decipher multiplexed DNAs, RNAs, proteins, and small biomolecules at subcellular resolution. We delineated dynamic spatial gene profiles in the hypothalamus using MiP-Seq. Moreover, MiP-Seq was unitized to detect tumor gene mutations and allele-specific expression of parental genes and to differentiate sites with and without the m6A RNA modification at specific sites. MiP-Seq was combined within vivoCa2+imaging and Raman imaging to obtain a spatial multiomics atlas correlated to neuronal activity and cellular biochemical fingerprints. Importantly, we proposed a “signal dilution strategy” to resolve the crowded signals that challenge the applicability ofin situsequencing. Together, our method improves spatial multiomics and precision diagnostics and facilitates analyses of cell function in connection with gene profiles.
DPHL v2: An updated and comprehensive DIA pan-human assay library for quantifying more than 14,000 proteins
Authors: Xue Zhangzhi , Zhu Tiansheng , Zhang Fangfei , Zhang Cheng , Xiang Nan , Qian Liujia , Yi Xiao , Sun Yaoting , Liu Wei , Cai Xue , Wang Linyan , Dai Xizhe , Yue Liang , Li Lu , Pham Thang V. , Piersma Sander R. , Xiao Qi , Luo Meng , Lu Cong , Zhu Jiang , Zhao Yongfu , Wang Guangzhi , Xiao Junhong , Liu Tong , Liu Zhiyu , He Yi , Wu Qijun , Gong Tingting , Zhu Jianqin , Zheng Zhiguo , Ye Juan , Li Yan , Jimenez Connie R. , Jun A , Guo Tiannan
Published: January 2023

A comprehensive pan-human spectral library is critical for biomarker discovery using mass spectrometry (MS)-based proteomics. DPHL v1, a previous pan-human library built from 1096 data-dependent acquisition (DDA) MS data of 16 human tissue types, allows quantifying 10,943 proteins. However, a major limitation of DPHL v1 is the lack of semi-tryptic peptides and protein isoforms, which are abundant in clinical specimens. Here, we generated DPHL v2 from 1608 DDA-MS data acquired using Orbitrap mass spectrometers. The data included 586 DDA-MS newly acquired from 17 tissue types, while 1022 files were derived from DPHL v1. DPHL v2 thus comprises data from 24 sample types, including several cancer types (lung, breast, kidney, and prostate cancer, among others). We generated four variants of DPHL v2 to include semi-tryptic peptides and protein isoforms. DPHL v2 was then applied to a publicly available colorectal cancer dataset with 286 DIA-MS files. The numbers of identified and significantly dysregulated proteins increased by at least 21.7% and 14.2%, respectively, compared with DPHL v1. Our findings show that the increased human proteome coverage of DPHL v2 provides larger pools of potential protein biomarkers.
Impact of urbanization on the taxonomic and functional diversity of spider assemblages in Guwahati City, Assam, India
Authors: Sharma Ankita , Deka Bitupan , Bishaya Puja , Kumar Raman , Sharma Narayan
Published: January 2023

The homogenous nature of the urban environment rapidly alters community dynamics of extant flora and fauna due to short-term spatial and temporal factors. However, such impacts of urbanization are mostly investigated in terms of taxonomic diversity, while its impact on functional diversity remains poorly understood. Whereas taxonomic information is limited to the identity of species, functional traits determine the relationship between species identity and ecosystem functioning. Studies investigating the role of urbanization in altering these ecological parameters have mostly focused on avian communities or plant species, while arthropods such as spiders which are integral components of urban households have largely been overlooked. This study aims to understand the impact of urbanization on both taxonomic diversity and functional diversity of spider assemblages across an urban–semi-urban–forest gradient in Guwahati, a rapidly growing city in northeast India. We surveyed spiders at 13 sites representing four habitat types (urban, urban parks, semi-urban, and forests) using belt transects, and also recorded functional traits relating to key life history processes. Spider species composition differed significantly between various habitats. The taxonomic diversity of spiders was highest in forests and lowest in urban parks. The turnover component was the major contributor to changing the β-diversity of spiders. Reduced diversity in urban regions was likely due to the dominance of a few synanthropic species. Generalised linear mixed-effects model analysis indicated that the habitat types significantly impacted spider abundance. Functional richness was maximum in forests (Fric= 23.43) and minimum in urban habitats (Fric= 12.98), while functional divergence was maximum in urban sites (Fdiv= 0.79). Our study demonstrates that urban land-use change can alter the structure and functioning of the spider community.
Mechanostat parameters estimated from time-lapsedin vivomicro-computed tomography data of mechanically driven bone adaptation are logarithmically dependent on loading frequency
Authors: Marques Francisco C. , Boaretti Daniele , Walle Matthias , Scheuren Ariane C. , Schulte Friederike A. , Müller Ralph
Published: January 2023

Mechanical loading is a key factor governing bone adaptation. Both preclinical and clinical studies have demonstrated its effects on bone tissue, which were also notably predicted in the mechanostat theory. Indeed, existing methods to quantify bone mechanoregulation have successfully associated the frequency of (re)modeling events with local mechanical signals, combining time-lapsedin vivomicro-computed tomography (micro-CT) imaging and micro-finite element (micro-FE) analysis. However, a correlation between the local surface velocity of (re)modeling events and mechanical signals has not been shown. As many degenerative bone diseases have also been linked to impaired bone (re)modeling, this relationship could provide an advantage in detecting the effects of such conditions and advance our understanding of the underlying mechanisms. Therefore, in this study, we introduce a novel method to estimate (re)modeling velocity curves from time-lapsedin vivomouse caudal vertebrae data under static and cyclic mechanical loading. These curves can be fitted with piecewise linear functions as proposed in the mechanostat theory. Accordingly, new (re)modeling parameters can be derived from such data, including formation saturation levels, resorption velocity modulus, and (re)modeling thresholds. Our results revealed that the norm of the gradient of strain energy density yielded the highest accuracy in quantifying mechanoregulation data using micro-FE analysis with homogeneous material properties, while effective strain was the best predictor for micro-FE analysis with heterogeneous material properties. Furthermore, (re)modeling velocity curves could be accurately described with piecewise linear and hyperbola functions (root mean square error below 0.2 µm/day for weekly analysis), and several (re)modeling parameters determined from these curves followed a logarithmic relationship with loading frequency. Crucially, (re)modeling velocity curves and derived parameters could detect differences in mechanically driven bone adaptation, which complemented previous results showing a logarithmic relationship between loading frequency and net change in bone volume fraction over four weeks. Together, we expect this data to support the calibration ofin silicomodels of bone adaptation and the characterization of the effects of mechanical loading and pharmaceutical treatment interventionsin vivo.
Growth responses ofCelosia argenteaL. in soils polluted with microplastics
Authors: Ikhajiagbe Beckley , Omoregie Gloria Omorowa , Adama Susan Ojonugwa , Esheya Kingsley Ume
Published: January 2023

This research was carried out to study the various toxic effects of microplastics on commercial leafy vegetableCelosia argenteaL. Plastics used in this experiment were obtained from heterogeneous sources from around different dumpsites in the University of Benin Ugbowo Campus. The plastics collected were grinded into three different bits and sizes, filtered and applied to the different plastic pots in the measurement of 5g, 10g and 20g respectively. The seeds ofCelosia argenteaL. was sown in the microplastic polluted soils and also the control Morphological characteristics were also observed and recorded and they include plant height, stem girth, leaf area amongst others. The plants were harvested after 52 days of observation and taken to the laboratory for heavy metal analysis. Results showed evidence of stunted growth, and chlorosis as compared to the control. Significant heavy metal accumulation was also recorded in the leaves and they include nickel, lead and cadmium.
The mechanosensitive ion channel Piezo1 contributes to ultrasound neuromodulation
Authors: Zhu Jiejun , Xian Quanxiang , Hou Xuandi , Wong Kin Fung , Zhu Tingting , Chen Zihao , He Dongming , Kala Shashwati , Jing Jianing , Wu Yong , Zhao Xinyi , Li Danni , Guo Jinghui , Qiu Zhihai , Sun Lei
Published: January 2023

Transcranial low-intensity ultrasound is a promising neuromodulation modality, with the advantages of non-invasiveness, deep penetration, and high spatiotemporal accuracy. However, the underlying biological mechanism of ultrasonic neuromodulation remains unclear, hindering the development of efficacious treatments. Here, the well-known Piezo1, was studied through a conditional knockout mouse model as a major molecule for ultrasound neuromodulationex vivoandin vivo. We showed that Piezo1 knockout in the right motor cortex of mice significantly reduced ultrasound-induced neuronal calcium responses, limb movement and muscle EMG responses. We also detected higher Piezo1 in the central amygdala (CEA) which were found more sensitive to ultrasound stimulation than that of cortex. Knocking out the Piezo1 in CEA neurons showed a significant reduction of response under ultrasound stimulation while knocking out astrocytic Piezo1 showed no obvious changes in neuronal responses. Additionally, we excluded an auditory confound by monitoring auditory cortical activation and using smooth waveform ultrasound with randomized parameters to stimulate P1KO ipsilateral and contralateral regions of the same brain and recording evoked movement in the corresponding limb. Thus, we demonstrate that Piezo1 is functionally expressed in different brain regions, and that it is an important mediator of ultrasound neuromodulation in the brain, laying the ground for further mechanistic studies of ultrasound.
All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomainsin situ
Authors: Koren Shon A. , Selim Nada A. , De La Rosa Lizbeth , Horn Jacob , Farooqi M. Arsalan , Wei Alicia Y. , Müller-Eigner Annika , Emerson Jacen , Johnson Gail V.W. , Wojtovich Andrew P.
Published: January 2023

Hydrogen peroxide (H2O2) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of ROS generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though our understanding of these processes remains limited. Here, we couple the H2O2biosensor, HyPer7, with optogenetic stimulation of the ROS-generating protein KillerRed targeted into multiple mitochondrial microdomains. Single mitochondrial photogeneration of H2O2demonstrates the spatiotemporal dynamics of ROS diffusion and transient hyperfusion of mitochondria due to ROS. Measurement of microdomain-specific H2O2diffusion kinetics reveals directionally selective diffusion through mitochondrial microdomains. All-optical generation and detection of physiologically-relevant concentrations of H2O2between mitochondrial compartments provide a map of mitochondrial H2O2diffusion dynamicsin situ. These kinetic details of spatiotemporal ROS dynamics and inter-mitochondrial spreading forms a framework to understand the role of ROS in health and disease.