bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood flow synchronization in renal microcirculation - a high-resolution imaging study
Authors: Postnov Dmitry D. , Marsh Donald J. , Cupples Will A. , Holstein-Rathlou Niels-Henrik , Sosnovtseva Olga 
Published: October 2021

ABSTRACTAimsInternephron signalling and interaction are fundamental for kidney function. Earlier studies have shown that nephrons signal to each other over short distances and adjust their activity accordingly. Micropuncture experiments revealed synchronous clusters of 2-3 nephrons formed from such interactions, while imaging and modelling results suggested the possibility of larger clusters. Such clusters are expected to play an important role in renal autoregulation, but their presence has not been confirmed and their size has not been estimated. In this study, we present methodology for high resolution renal blood flow imaging and apply it to estimate frequency and phase angle differences in kidney blood vessels under normal conditions and after administration of the vasoactive agents angiotensin II and acetylcholine.Methods and resultsTo resolve signals from separate arterioles in a sufficiently large field of view, we developed a method for renal laser speckle contrast imaging. Our setup provides imaging of blood flow in the kidney cortex with a limit of image resolution at 0.8μm per pixel and imaging frequency of 160Hz. We used the method to record from 1.5×1.5 mm2 sections of the renal surface in anaesthetised Sprague-Dawley rats in unstimulated conditions and during IV infusion of the vasoconstrictor angiotensin II or the vasodilator acetylcholine. In each section, we resolved and segmented 94.8±15.66 individual arterioles and venules, and analyzed blood flow using wavelet spectral analysis to identify clusters of synchronized blood vessels.ConclusionsWe observed spatial and temporal evolution of blood vessel clusters of various sizes, including the formation of large (>90 vessels) long-lived clusters (>10 periods) locked at the frequency of the tubular glomerular feedback (TGF) mechanism. The analysis showed that synchronization patterns and thus the co-operative dynamics of nephrons change significantly when either of the vasoactive agents is administered. On average, synchronization was stronger (larger clusters, longer duration) with angiotensin II administration than in the unstimulated state or with acetyl choline. While it weakens with distance, increased synchronization duration spanned the whole field of view, and likely, beyond it. Neighbouring vessels tend to demonstrate in-phase synchronization, especially in the vasoconstricted condition, which is expected to cause locally increased pressure variation. Our results confirm both the presence of the local synchronization in the renal microcirculatory blood flow and the fact that it changes depending on the condition of the vascular network and the blood pressure, which might have further implications for the role of such synchronization in pathologies development.
Amoeboid-like neuronal migration ensures correct horizontal cell layer formation in the developing vertebrate retina
Authors: Amini Rana , Schlüßler Raimund , Möllmert Stephanie , Bhatnagar Archit , Guck Jochen , Norden Caren 
Published: October 2021

ABSTRACTAs neurons are often born at positions different than where they ultimately function, neuronal migration is key to ensure successful nervous system development. Radial migration during which neurons featuring unipolar and bipolar morphology, employ pre-existing processes or underlying cells for directional guidance, is the most well explored neuronal migration mode. However, how neurons that display multipolar morphology, without such processes, move through highly crowded tissue environments towards their final positions remains elusive. To understand this, we here investigated multipolar migration of horizontal cells in the zebrafish retina. We found that horizontal cells tailor their movements to the environmental spatial constraints of the crowded retina, by featuring several characteristics of amoeboid migration. These include cell and nucleus shape changes, and persistent rearward polarization of stable F-actin, which enable horizontal cells to successfully move through the crowded retina. Interference with the organization of the developing retina by changing nuclear properties or overall tissue architecture, hampers efficient horizontal cell migration and layer formation. Thus, cell-tissue interplay is crucial for efficient migration of horizontal cells in the retina. In view of high proportion of multipolar neurons, the here uncovered ameboid-like neuronal migration mode might also be crucial in other areas of the developing brain.
Effects of dual deletion ofglnRandmtrAon expression of nitrogen metabolism genes inStreptomyces venezuelae
Authors: Zhu Yanping , Wang Jiao , Su Wenya , Lu Ting , Li Aiying , Pang Xiuhua 
Published: October 2021

SummaryGlnR activates nitrogen metabolism genes under nitrogen-limited conditions whereas MtrA represses these genes under nutrient-rich conditions inStreptomyces. In this study, we compared the transcription patterns of nitrogen metabolism genes in a double deletion mutant (ΔmtrA-glnR) lacking bothmtrAandglnRand in mutants lacking eithermtrA(ΔmtrA) orglnR(ΔglnR). The nitrogen metabolism genes were expressed similarly in ΔmtrA-glnRand ΔglnRunder both nitrogen-limited and nutrient-rich conditions, with patterns distinctly different from that of ΔmtrA, suggesting a decisive role for GlnR in the control of nitrogen metabolism genes and further suggesting that regulation of these genes by MtrA is GlnR-dependent. MtrA and GlnR utilize the same binding sites upstream of nitrogen metabolism genes, and we showed strongerin vivobinding of MtrA to these sites under nutrient-rich conditions and of GlnR under nitrogen-limited conditions, consistent with the higher levels of MtrA or GlnR under those respective conditions. In addition, we showed that bothmtrAandglnRare auto-regulatory. Our study provides new insights into the regulation of nitrogen metabolism genes inStreptomyces.
Airpart: Interpretable statistical models for analyzing allelic imbalance in single-cell datasets
Authors: Mu Wancen , Sarkar Hirak , Srivastava Avi , Choi Kwangbom , Patro Rob , Love Michael I. 
Published: October 2021

AbstractMotivationAllelic expression analysis aids in detection of cis-regulatory mechanisms of genetic variation which produce allelic imbalance (AI) in heterozygotes. Measuring AI in bulk data lacking time or spatial resolution has the limitation that cell-type-specific (CTS), spatial-, or time-dependent AI signals may be dampened or not detected.ResultsWe introduce a statistical method airpart for identifying differential CTS AI from single-cell RNA-sequencing (scRNA-seq) data, or other spatially- or time-resolved datasets. airpart outputs discrete partitions of data, pointing to groups of genes and cells under common mechanisms of cis-genetic regulation. In order to account for low counts in single-cell data, our method uses a Generalized Fused Lasso with Binomial likelihood for partitioning groups of cells by AI signal, and a hierarchical Bayesian model for AI statistical inference. In simulation, airpart accurately detected partitions of cell types by their AI and had lower RMSE of allelic ratio estimates than existing methods. In real data, airpart identified differential AI patterns across cell states and could be used to define trends of AI signal over spatial or time axes.AvailabilityThe airpart package is available as an R/Bioconductor package at https://bioconductor.org/packages/airpart.
Multiplexed ultrasound imaging using clustered gas vesicles and spectral imaging
Authors: Kim Sangnam , Zhang Siyuan , Yoon Sangpil 
Published: October 2021

AbstractCurrent advances in ultrasound imaging techniques including super-resolution ultrasound imaging allows us to visualize microvasculature in biological specimens using microbubbles. However, microbubbles diffuse in blood stream limiting imaging acquisition and frame subtraction scheme of super-resolution ultrasound imaging cannot improve spatial resolution without moving microbubbles. Fluorescent proteins revolutionized to understand molecular and cellular functions in biological systems. Here, we devised a panel of gas vesicles to realize multiplexed ultrasound imaging to uniquely visualize locations of different species of gas vesicles. Mid-band fit spectral imaging technique demonstrated that stationary gas vesicles were efficiently localized in gel phantom and murine liver specimens by visualizing three-dimensional vessel structures. Clustered and unclustered gas vesicles were phagocytosed by murine macrophages to serve as carriers and beacons for the proposed multiplexed and single cell level imaging technique. The spatial distribution of macrophages containing clustered and unclustered gas vesicles were reconstructed by mid-band fit spectral imaging with pseudo-coloring scheme.
Recurrent Independent Pseudogenization Events of the Sperm Fertilization Gene ZP3r in Apes and Monkeys
Authors: Carlisle J.A. , Gurbuz D.H. , Swanson W. J. 
Published: October 2021

AbstractIn mice, ZP3r/sp56 is a binding partner to the egg coat protein ZP3 and may mediate induction of the acrosome reaction. ZP3r, as a member of the RCA cluster, is surrounded by paralogs, some of which have been shown to be evolving under positive selection. Sequence divergence paired with paralogous relationships with neighboring genes, has complicated the accurate identification of the human ZP3r ortholog. Here, we phylogenetically and syntenically resolve that the human ortholog of ZP3r is the pseudogene C4BPAP1. We investigate the evolution of this gene within primates. We observe independent pseudogenization events of ZP3r in all Apes with the exception of Orangutans, and many monkey species. ZP3r in both primates that retain ZP3r and rodents contains positively selected sites. We hypothesize that redundant mechanisms mediate ZP3 recognition in mammals and ZP3r’s relative importance to ZP recognition varies across species.
Interactive 3D visualization and post-processing analysis of vertex-based unstructured polyhedral meshes with ParaView
Authors: Sanematsu Paula C. 
Published: October 2021

AbstractThe development of physics-based 3D models that investigate the behavior of biological tissues requires effective and efficient visualization tools. The open-source software ParaView has such capabilities, but often impose a steep learning curve due to the use of the Visualization Toolkit (VTK) data structures. To overcome this, I show how to setup the components of 3D vertex-like models, i.e., vertices, faces, and polyhedra, into the VTK data format and then output as ParaView unstructured grid files. I present a few relevant tools to visualize and analyze the files in ParaView. All sample codes are available in the Github repository vis3Dvertex.
Anti-TRAP/SSP2 monoclonal antibodies can inhibit sporozoite infection and enhance protection of anti-CSP monoclonal antibodies
Authors: Wilder Brandon K. , Vigdorovich Vladimir , Carbonetti Sara , Minkah Nana , Hertoghs Nina , Raappana Andrew , Cardamone Hayley , Oliver Brian G. , Trakhimets Olesya , Kumar Sudhir , Dambrauskas Nicholas , Arredondo Silvia A. , Camargo Nelly , Kappe Stefan H.I. , Sather D. Noah 
Published: October 2021

AbstractVaccine-induced sterilizing protection from infection by Plasmodium parasites, the pathogens that cause malaria, will be essential in the fight against malaria as it would prevent both malaria-related disease and transmission. Stopping the relatively small number of parasites injected by the mosquito before they can migrate from the skin to the liver is an attractive means to this goal. Antibody-eliciting vaccines have been used to pursue this objective by targeting the major parasite surface protein present during this stage, the circumsporozoite protein (CSP). While CSP-based vaccines have recently had encouraging success in disease reduction, this was only achieved with extremely high antibody titers and appeared less effective for a complete block of infection (i.e. sterile protection). While such disease reduction is important, these and other results indicate that strategies focusing on CSP alone may not achieve the high levels of sterile protection needed for malaria eradication. Here, we show that monoclonal antibodies (mAbs) recognizing another sporozoite protein, TRAP/SSP2, exhibit a range of inhibitory activity and that these mAbs can augment CSP-based protection despite conferring no sterile protection on their own. Therefore, pursuing a multivalent subunit vaccine immunization is a promising strategy for improving infection-blocking malaria vaccines.
Evolutionary epidemiology of a zoonosis
Authors: Corsi Giulia I. , Tichkule Swapnil , Sannella Anna Rosa , Vatta Paolo , Asnicar Francesco , Segata Nicola , Jex Aaron R. , Oosterhout Cock van , Cacciò Simone M. 
Published: October 2021

AbstractCryptosporidium parvum is a global zoonoses and a major cause of diarrhoea in humans and ruminants. The parasite’s life cycle comprises an obligatory sexual phase, during which genetic exchanges can occur between previously isolated lineages. Here, we compare 32 whole genome sequences from human- and ruminant-derived parasite isolates collected across Europe, Egypt and China. We identify three strongly supported clusters that comprise a mix of isolates from different host species, geographic origins, and subtypes. We show that: (1) recombination occurs between ruminant isolates into human isolates; (2) these recombinant regions can be passed on to other human subtypes through gene flow and population admixture; (3) there have been multiple genetic exchanges, and all are likely recent; (4) putative virulence genes are significantly enriched within these genetic exchanges, and (5) this results in an increase in their nucleotide diversity. We carefully dissect the phylogenetic sequence of two genetic exchanges, illustrating the long-term evolutionary consequences of these events. Our results suggest that increased globalisation and close human-animal contacts increase the opportunity for genetic exchanges between previously isolated parasite lineages, resulting in spillover and spillback events. We discuss how this can provide a novel substrate for natural selection at genes involved in host-parasite interactions, thereby potentially altering the dynamic coevolutionary equilibrium in the Red Queens arms race.Data SummaryAll raw and processed sequencing data generated and analysed during the current study have been submitted to the NCBI Sequence Read Archive (https://www.ncbi.nlm.nih.gov/bioproject/), under BioProjects PRJNA634014 and PRJNA633764.
Genomic insights into the population history and biological adaptation of Southwestern Chinese Hmong-Mien people
Authors: Liu Yan , Xie Jie , Wang Mengge , Liu Changhui , Zhu Jingrong , Zou Xing , Li Wenshan , Wang Lin , Leng Cuo , Xu Quyi , Yeh Hui-Yuan , Wang Chuan-Chao , Wen Xiaohong , Liu Chao , He Guanglin 
Published: October 2021

AbstractHmong-Mien-speaking (HM) populations, widely distributed in South China, North of Thailand, Laos and Vietnam, have experienced different settlement environments, dietary habits and pathogen exposure. However, their specific biological adaptation also remained largely uncharacterized, which is important in the population evolutionary genetics and Trans-Omics for regional Precision Medicine. Besides, the origin and genetic diversity of HM people and their phylogenetic relationship with surrounding modern and ancient populations are unknown. Here, we reported genome-wide SNPs in 52 representative Miao people and combined them with 144 HM people from 13 geographically representative populations to characterize the full genetic admixture and adaptive landscape of HM speakers. We found that obvious genetic substructures existed in geographically different HM populations and also identified one new ancestral lineage specifically exited in HM people, which spatially distributed from Sichuan and Guizhou in the North to Thailand in the South and temporally dated to at least 500 years. The sharing patterns of the newly-identified homogeneous ancestry component combined the estimated admixture times via the decay of Linkage Disequilibrium and haplotype sharing in GLOBETROTTER suggested that the modern HM-speaking populations originated from Southwest China and migrated southward recently, which is consistent with the reconstructed phenomena of linguistic and archeological documents. Additionally, we identified specific adaptive signatures associated with several important human nervous system biological functions. Our pilot work emphasized the importance of anthropologically-informed sampling and deeply genetic structure reconstruction via whole-genome sequencing in the next step in the deep Chinese population genomic diversity project (CPGDP), especially in the ethnolinguistic regions.
In vivo adenine base editing corrects newborn murine model of Hurler syndrome
Authors: Su Jing , Jin Xiu , She Kaiqin , Liu Yi , Zhong Xiaomei , Zhao Qinyu , Xiao Jianlu , Li Ruiting , Deng Hongxin , Yang Yang 
Published: October 2021

AbstractMucopolysaccharidosis type I (MPS I) is a severe disease caused by loss-of-function mutations variants in the α-L-iduronidase (IDUA) gene. In vivo genome editing represents a promising strategy to correct IDUA mutations, and has the potential to permanently restore IDUA function over the lifespan of the patients. Here, we used adenine base editing to directly convert A>G (TAG>TGG) in newborn murine model harboring Idua-W392X mutation, which recapitulates the human condition and is analogous to the highly prevalent human W402X mutation. We engineered a split-intein dual-adeno-associated virus (AAV) 9 in vivo adenine base editor to circumvent the package size limit of AAV vectors. Intravenous injection of AAV9-base editor system into MPS I newborn mice led to sustained enzyme expression sufficient for correction of metabolic disease (GAGs substrate accumulation) and prevention of neurobehavioral deficits. We observed a reversion of the W392X mutation in 22.46±6.74% of hepatocytes, 11.18±5.25% of heart and 0.34±0.12% of brain, along with decreased GAGs storage in peripheral organs (liver, spleen, lung and kidney). Collectively, these data showed the promise of a base editing approach to precisely correct a common genetic cause of MPS I in vivo and could be broadly applicable to the treatment of a wide array of monogenic diseases.
Amyloid-beta and tau pathologies are both necessary to induce novel stage-specific microglia subtypes during Alzheimer’s disease progression
Authors: Kim Dong Won , Tu Kevin , Wei Alice , Lau Ashley , Gonzalez-Gil Anabel , Cao Tianyu , Braunstein Kerstin , Ling Jonathan P. , Troncoso Juan C. , Wong Philip C. , Blackshaw Seth , Schnaar Ronald L. , Li Tong 
Published: October 2021

AbstractIt is unknown whether specific microglia are selectively induced by amyloid-β (Aβ), tau pathologies, or both in combination. To address this, we use single-cell RNA-sequencing to profile mice bearing both Aβ and tau pathologies during Alzheimer’s disease (AD) progression. We identify novel microglia subtypes induced in a disease stage-specific manner. We show that during early-stage disease, interferon signaling induces a subtype of microglia termed EADAM. During late-stage disease, a second microglia subtype termed LADAM is detected. While EADAM and LADAM-like microglia are observed in other neurodegenerative models, the magnitude and composition of subtype markers are distinct from microglia observed with AD-like pathology. The pattern of EADAM- and LADAM-associated gene expression is observed in microglia from human AD, during the early and late stages of disease, respectively. Furthermore, we observe that several siglec genes are selectively expressed in either EADAM or LADAM.Siglecgis expressed in white-matter-associated LADAM, and expression of the human orthologue ofSiglecgis progressively elevated in AD-stage-dependent manner but not shown in non-AD tauopathy. Our findings imply that both Aβ and tau pathologies are required for disease stage-specific induction of EADAM and LADAM.
Oxidative stress induces inflammation of lens cells and triggers immune surveillance of ocular tissues
Authors: Thompson Brian , Davidson Emily A. , Chen Ying , Orlicky David J. , Thompson David C. , Vasiliou Vasilis 
Published: October 2021

AbstractRecent reports have challenged the notion that the lens is immune-privileged. However, these studies have not fully identified the molecular mechanism(s) that promote immune surveillance of the lens. Using a mouse model of targeted glutathione (GSH) deficiency in ocular surface tissues, we have investigated the role of oxidative stress in upregulating cytokine expression and promoting immune surveillance of the eye. RNA-sequencing of lenses from postnatal day (P) 1- agedGclcf/f;Le-CreTg/−(KO) andGclcf/f;Le-Cre−/−control (CON) mice revealed upregulation of many cytokines (e.g., CCL4, GDF15, CSF1) and immune response genes in the lenses of KO mice. The eyes of KO mice had a greater number of cells in the aqueous and vitreous humors at P1, P20 and P50 than age-matched CON andGclcw/w;Le-CreTg/−(CRE) mice. Histological analyses revealed the presence of innate immune cells (i.e., macrophages, leukocytes) in ocular structures of the KO mice. At P20, the expression of cytokines and ROS content was higher in the lenses of KO mice than in those from age-matched CRE and CON mice, suggesting that oxidative stress may induce cytokine expression.In vitroadministration of the oxidant, hydrogen peroxide, and the depletion of GSH (using buthionine sulfoximine (BSO)) in 21EM15 lens epithelial cells induced cytokine expression, an effect that was prevented by co-treatment of the cells withN-acetyl-L-cysteine (NAC), a antioxidant. Thein vivoandex vivoinduction of cytokine expression by oxidative stress was associated with the expression of markers of epithelial-to-mesenchymal transition (EMT), α-SMA, in lens cells. Given that EMT of lens epithelial cells causes posterior capsule opacification (PCO), we propose that oxidative stress induces cytokine expression, EMT and the development of PCO in a positive feedback loop. Collectively these data indicate that oxidative stress induces inflammation of lens cells which promotes immune surveillance of ocular structures.HighlightsImmune surveillance of ocular structures occurs in mouse eyes deficient in glutathione.Oxidative stress upregulates the expression of pro-inflammatory cytokines (e.g., GDF15, CSF1) in lens cellsin vitroandin vivo.The upregulation of cytokines in lens cells is associated with markers of an epithelial-to-mesenchymal transition phenotype.Oxidative stress-induced inflammation and associated epithelial-to-mesenchymal transition may play a role in the development of posterior capsule opacification.