bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ensemble-specific deficit in neuronal intrinsic excitability in aged mice
Authors: Chen Lingxuan , Francisco Taylor R. , Baggetta Austin M. , Zaki Yosif , Ramirez Steve , Clem Roger L. , Shuman Tristan , Cai Denise J. 
Published: June 2022

AbstractWith the prevalence of age-related cognitive deficits on the rise, it is essential to identify cellular and circuit alterations that contribute to age-related memory impairment. Increased intrinsic neuronal excitability after learning is important for memory consolidation, and changes to this process could underlie memory impairment in old age. Some studies find age-related deficits in hippocampal neuronal excitability that correlate with memory impairment but others do not, possibly due to selective changes only in activated neural ensembles. Thus, we tagged CA1 neurons activated during learning and recorded their intrinsic excitability 5 hours or 7 days post-training. Adult mice exhibited increased neuronal excitability 5 hours after learning, specifically in ensemble (learning-activated) CA1 neurons. As expected, ensemble excitability returned to baseline 7 days post-training. In aged mice, there was no ensemble-specific excitability increase after learning, which was associated with impaired hippocampal memory performance. These results suggest that CA1 may be susceptible to age-related impairments in post-learning ensemble excitability and underscore the need to selectively measure ensemble-specific changes in the brain.
Optimization of a Translational Murine Model of Closed-head Traumatic Brain Injury
Authors: Mace Brian E. , Lassiter Eric , Arulraja Evangeline Kamalini , Chaparro Eduardo , Cantillana Viviana , Gupta Rupali , Faw Timothy D. , Laskowitz Daniel T. , Kolls Brad J 
Published: June 2022

AbstractTraumatic brain injury (TBI) from closed-head trauma is a leading cause of disability with limited effective interventions. Many TBI models impact brain parenchyma directly following craniotomy, and are limited by the fact that these forces do not recapitulate clinically relevant closed head injury. However, applying clinically relevant injury mechanics to an intact skull may lead to variability and as a result, modeling TBI remains a challenge. Moreover, current models often do not explore sex differences in TBI, which is critically important for translation to clinical practice. We systematically investigated sources of variability in a murine model of closed-head TBI and developed a framework to reduce variability across severity and sex. We manipulated pressure, dwell time, and displacement to determine effects on vestibulomotor performance, spatial learning, and neuronal damage in 10-week-old male and female mice. Increasing pressure beyond 70psi had a ceiling effect on cellular and behavioral outcomes, while manipulating dwell time only affected behavioral performance. Increasing displacement precisely graded injury severity in both sexes across all outcomes. Physical signs of trauma occurred more frequently at higher displacements. Females performed worse than males when injured at 2.7mm displacement, and had greater mortality at higher displacements. Stratifying severity based on day-1 rotarod performance retained cellular injury relationships and separated both sexes into injury severity cohorts with distinct behavioral recovery. Utilizing this stratification strategy, within-group rotarod variability over 6 days post-injury was reduced by 50%. These results have important implications for translational research in TBI and provide a framework for using this clinically relevant translational injury model in both male and female mice.
Lysosomal dysfunction in Down Syndrome and Alzheimer mouse models is caused by selective v-ATPase inhibition by Tyr682phosphorylated APP βCTF
Authors: Im Eunju , Jiang Ying , Stavrides Philip , Darji Sandipkumar , Erdjument-Bromage Hediye , Neubert Thomas A. , Choi Jun Yong , Wegiel Jerzy , Lee Ju-Hyun , Nixon Ralph A. 
Published: June 2022

AbstractLysosome dysfunction arises early and propels Alzheimer’s Disease (AD). Herein, we show that amyloid precursor protein (APP), linked to early-onset AD in Down Syndrome (DS), acts directly via its β-C-terminal fragment (βCTF) to disrupt lysosomal v-ATPase and acidification. In human DS fibroblasts, the phosphorylated682YENPTY internalization motif of APP-βCTF binds selectively within a pocket of the v-ATPase V0a1 subunit cytoplasmic domain and competitively inhibits association of the V1 subcomplex of v-ATPase, thereby reducing its activity. Lowering APP-βCTF Tyr682phosphorylation restores v-ATPase and lysosome function in DS fibroblasts andin vivoin brains of DS model mice. Notably, lowering APP-βCTF Tyr682phosphorylation below normal constitutive levels boosts v-ATPase assembly and activity, suggesting that v-ATPase may also be modulated tonically by phospho-APP-βCTF. Elevated APP-βCTF Tyr682phosphorylation in two mouse AD models similarly disrupts v-ATPase function. These findings offer new insight into the pathogenic mechanism underlying faulty lysosomes in all forms of AD.
Multiple particle tracking (MPT) using PEGylated nanoparticles reveals heterogeneity within murine lymph nodes and between lymph nodes at different locations
Authors: Ramirez Ann , Merwitz Brooke , Lee Hannah , Vaughan Erik , Maisel Katharina 
Published: June 2022

Lymph nodes (LNs) are highly structured lymphoid organs that compartmentalize B and T cells in the outer cortex and inner paracortex, respectively, and are supported by a collagen-rich reticular network. Tissue material properties like viscoelasticity and diffusion of materials within extracellular spaces and their implications on cellular behavior and therapeutic delivery have been a recent topic of investigation. Here, we developed a nanoparticle system to investigate the rheological properties, including pore size and viscoelasticity, through multiple particle tracking (MPT) combined with LN slice cultures. Dense coatings with polyethylene glycol (PEG) allow nanoparticles to diffuse within the LN extracellular spaces. Despite differences in function in B and T cell zones, we found that extracellular tissue properties and mesh spacing do not change significantly in the cortex and paracortex, though nanoparticle diffusion was slightly reduced in B cell zones. Interestingly, our data suggest that LN pore sizes are smaller than the previously predicted 10 – 20 μm, with pore sizes ranging from 500 nm - 1.5 μm. Our studies also confirm that LNs exhibit viscoelastic properties, with an initial solid-like response followed by stress-relaxation at higher frequencies. Finally, we found that nanoparticle diffusion is dependent on LN location, with nanoparticles in skin draining LNs exhibiting a higher diffusion coefficient and pore size compared to mesenteric LNs. Our data shed new light onto LN interstitial tissue properties, pore size, and define surface chemistry parameters required for nanoparticles to diffuse within LN interstitium. Our studies also provide both a tool for studying LN interstitium and developing design criteria for nanoparticles targeting LN interstitial spaces.AbbreviationsLNs, FBS, EDC, NHS, ECM, PEG
Engineered Wnt7a ligands rescue blood brain barrier and neurobehavioral deficits in a mouse model of COVID-19
Authors: Trevino Troy N. , Fogel Avital B. , Class Jacob , Sanborn Mark A. , Vanhollebeke Benoit , Rehman Jalees , Tai Leon M. , Richner Justin M. , Lutz Sarah E. 
Published: June 2022

AbstractRespiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating vascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we conduced unbiased transcriptional analysis to identify brain endothelial cell signaling pathways dysregulated by SARS-CoV-2in vivo. This analysis revealed significant suppression of Wnt/β-catenin signaling, a critical regulator of blood brain barrier integrity. We therefore hypothesized that enhancing cerebrovascular Wnt/β-catenin activity would offer protection against BBB permeability, neuroinflammation, and neurological signs in acute infection. Indeed, we found that delivery of cerebrovascular-targeted, engineered Wnt7a ligands protected blood brain barrier integrity, reduced T cell infiltration of the brain, and reduced microglial activation in SARS-CoV-2 infection. Importantly, this therapeutic strategy also mitigated SARS-CoV-2 induced deficits in the novel object recognition assay for learning and memory and the pole descent task for bradykinesia. These observations suggest that enhancement of Wnt/β-catenin signaling or its downstream effectors could be potential interventional strategies for restoring cognitive health following acute viral infections.
Parallel analysis of RNA ends reveals global microRNA-mediated target RNA cleavage in maize
Authors: He Juan , Xu Chi , You Chenjiang , Mo Beixin , Chen Xuemei , Gao Lei , Liu Lin 
Published: June 2022

ABSTRACTMicroRNAs (miRNAs) are endogenous 20-to 24-nucleotide (nt) noncoding RNAs that play important regulatory roles in many biological processes in eukaryotes. miRNAs modulate the expression of target genes at the post-transcriptional level by transcript cleavage or translational inhibition. Identification of miRNA target genes have been extensively investigated in Arabidopsis and rice, but an in-depth global analysis of miRNA-mediated target regulation is still lacking in maize. Here, we report a transcriptome-wide identification of miRNA targets by analyzing Parallel Analysis of RNA Ends (PARE) datasets derived from nine different tissues at five developmental stages of the maize (Zea mays L.) B73 cultivar. 246 targets corresponding to 60 miRNAs from 25 families were identified, including transcription factors and other genes. In addition, PARE analysis revealed that miRNAs guide specific target transcript cleavage in a tissue-preferential manner. Interestingly, primary transcripts of MIR159c and MIR169e were found to be cleaved by mature miR159 and miR169, respectively, indicating a positive-feedback regulatory mechanism in miRNA biogenesis. Moreover, several new miRNA-target gene pairs involved in seed germination were identified and experimentally validated. Our PARE analyses generated a wide and detailed miRNA-target interaction atlas, which provides a valuable resource for investigating the roles of miRNAs and their targets in maize.
Natural strongyle infection reduces relative abundance of inflammation-inducingPrevotellain wild primates
Authors: Cizauskas Carrie A. , Washburne Alex D. , Knelman Joseph E. , Hansen Christina B. , Nderitu Antony Mwangi , Esinyon Peter Lokwamo , Dobson Andrew P. , Graham Andrea L. 
Published: June 2022

AbstractMicrobes living within the mammalian gastrointestinal tract affect the metabolization and extraction of dietary nutrients, immune function, colonization by pathogens, and risk of autoimmune disease. While most microbiome studies focus on sequences of the 16S gene shared by Bacteria and Archaea, these are not the only regular inhabitants of mammalian guts. Macroparasites such as helminths are nearly ubiquitous in wildlife, and a quarter of the world’s human population harbors helminths; these worms affect host physiology as they compete with microbiota over host resources while also affecting host immunity, and changing the host microbiome. Little is understood about how helminths interact with microbiomes to affect host disease states, and few studies have examined these interactions in natural systems in genetically diverse hosts experiencing coinfections and other stressors.We surveyed the microbiomes and helminth parasites of wild primates and found strong associations between helminths and microbes in the bacterial microbiome. Notably, we find that the presence of a strongyle we hypothesize to be hookworm is correlated strongly with decreased relative abundance ofPrevotellaspecies, a lineage associated with inflammatory bowel disease humans. This observed decline inPrevotellarelative abundance, a genus implicated in several host autoimmune and inflammatory disorders, motivates future research on whether the mixed results of helminthic therapy (i.e., “infecting” patients with gastrointestinal nematodes to treat various diseases) stem from the mixed causes of inflammation, and whether inflammation specifically correlated withPrevotella-driven dysbiosis can be mediated through mechanisms mimicking how hookworms and other nematodes behave in the gastrointestinal ecosystem of their hosts. Our findings lend ground-truthed support to previous lab-based studies and limited/restricted human trials showing potential benefits, via microbial modulation, of nematode therapy in treating inflammatory bowel disease. Our study adds statistical weight to a link between helminths and a specific lineage of microbes associated with inflammation.
Structure-based prediction and characterization of photo-crosslinking in native protein-RNA complexes
Authors: Feng Huijuan , Lu Xiang-Jun , Liu Linxi , Ustianenko Dmytro , Zhang Chaolin 
Published: June 2022

AbstractUV-crosslinking of protein and RNA in direct contacts has been widely used to study protein-RNA complexes despite our poor understanding on the mechanisms of photo-crosslinking. This knowledge gap is due to the challenge to precisely map the crosslink sites in protein and RNA simultaneously in their native sequence and structural contexts. Here we developed PxR3D-map, a computational method to analyze protein-RNA interactions and photo-crosslinking by bridging crosslinked nucleotides and amino acids mapped using different assays with protein-RNA complex structures. PxR3D-map reliably predicts crosslink sites using structural information characterizing protein-RNA interaction interfaces. We found that photo-crosslinking is facilitated by base stacking with not only aromatic residues, but also dipeptide bonds that involve glycine, and distinct mechanisms are utilized by different types of RNA-binding domains. Our work suggests protein-RNA photocrosslinking is highly selective in the cellular environment, which can guide interpretation of data generated by UV-crosslinking-based assays and further technology development.
An integrated approach to evaluate the functional effects of disease-associated NMDA receptor variants
Authors: Moody Gabrielle , Musco Angela , Bennett Joseph , Wollmuth Lonnie P. 
Published: June 2022

ABSTRACTThe NMDA receptor (NMDAR) is a ubiquitously expressed glutamate-gated ion channel that plays key roles in brain development and function. Not surprisingly, a variety of disease-associated variants have been identified in genes encoding NMDAR subunits. A critical first step to assess whether these variants contribute to their associated disorder is to characterize their effect on receptor function. However, the complexity of NMDAR function makes this challenging, with most variants typically altering multiple functional properties. At synapses, NMDARs encode presynaptic activity to carry a charge transfer that alters membrane excitability and a Ca2+ influx that has both short- and long-term signaling actions. Here, we characterized epilepsy-associated variants in GluN1 and GluN2A subunits with various phenotypic severity. To capture the dynamics of NMDAR encoding, we applied 10 glutamate pulses at 10 Hz to derive a charge integral. This encoding assay is advantageous since it incorporates multiple gating parameters – activation, deactivation, and desensitization – into a single value. We then integrated this encoding with Mg2+ block and Ca2+ influx using fractional Ca2+ currents to generate indices of charge transfer and Ca2+ transfer over wide voltage ranges. This approach yields consolidated parameters that can be used as a reference to normalize allosteric modulation and has the potential to speed up future bench to bedside methods of investigating variants to determine patient treatment.
Divergent Evolutionary Pathways of Myxoma Virus in Australia: Virulence Phenotypes in Susceptible and Partially Resistant Rabbits Indicate Possible Selection for Transmissibility
Authors: Kerr Peter J , Cattadori Isabella M , Sim Derek , Liu June , Holmes Edward C. , Read Andrew F. 
Published: June 2022

ABSTRACTTo characterize the ongoing evolution of myxoma virus in Australian rabbits we used experimental infections of laboratory rabbits to determine the virulence and disease phenotypes of recent virus isolates. The viruses, collected between 2012-2015, fell into three lineages, one of which, lineage c, experienced a punctuated increase in evolutionary rate. All viruses were capable of causing acute death with aspects of neutropenic septicaemia, characterized by minimal signs of myxomatosis, the occurrence of pulmonary oedema and bacteria invasions throughout internal organs, but with no inflammatory response. For the viruses of highest virulence all rabbits usually died at this point. In more attenuated viruses some rabbits died acutely while others developed an amyxomatous phenotype. Rabbits that survived for longer periods developed greatly swollen cutaneous tissues with very high virus titres. This was particularly true of lineage c viruses. Unexpectedly, we identified a line of laboratory rabbits with some innate resistance to myxomatosis and used these in direct comparisons with the fully susceptible rabbit line. Importantly, the same disease phenotype occurred in both susceptible and resistant rabbits, although virulence was shifted towards more attenuated grades in resistant animals. We propose that selection against inflammation at cutaneous sites prolongs virus replication and enhances transmission, leading to the amyxomatous phenotype. In some virus backgrounds this creates an immunosuppressive state that predisposes to high virulence and acute death. The alterations in disease pathogenesis, particularly the overwhelming bacterial invasions that characterize the modern viruses, suggest that their virulence grades are not directly comparable with earlier studies.IMPORTANCEThe evolution of the myxoma virus (MYXV) following its release as a biological control for European rabbits in Australia is the textbook example of the co-evolution of virus virulence and host resistance. However, most of our knowledge of MYXV evolution only covers the first few decades of its spread in Australia and often with little direct connection between how changes in virus phenotype relate to those in the underlying virus genotype. By conducting detailed experimental infections of recent isolates of MYXV in different lines of laboratory rabbits we examined the ongoing evolution of MYXV disease phenotypes. Our results reveal a wide range of phenotypes, including an amyxomatous type as well as the impact of invasive bacteria, that in part depended on the level of rabbit host resistance. These results provide a unique insight into the complex virus and host factors that combine to shape disease phenotype and viral evolution.
EFFECT OF ORGANIC AND CHEMICAL FERTILIZERS ON THE NUTRITIONAL COMPOSITION OF Amaranthus spinosus
Authors: Raman Deepa , Joshi Namita , Rana Pawan Singh 
Published: June 2022

AbstractOrganic and chemical fertilizers are used in agriculture as they improve the fertility of soil and the growth of plants. So, the present investigation was designed to determine the effect of different fertilizers on the nutritional value of Amaranthus spinosus plant. The quantity of different fertilizers was used as 500 kg h-1. Some selected parameters of soil such as temperature (29.50 C), moisture (3.5 %), Water holding capacity (74%), pH (8.17), organic carbon % (1.90) and organic matter % (3.28) were measured and analysed. There was no significant variation in these parameters under different fertilizers treatment. The phytochemicals of Organic fertilizers treated plant sample had higher concentration of Alkaloid (1.06), flavonoid (0.89), tannin (1.48) and saponin (1.67), ash (7.75), moisture (87.6) and protein (9.1), Fe (0.054), Zn (0.008), Cu (0.001), Na (0.0080), Ca (113) and Mg (93) when compared to the other fertilizer treatments. Inorganic fertilizer did not show any significant effect on plant growth, while the combination of organic and chemical fertilizers was found to have a significant effect. The results reveal that organic fertilizers or their combination with chemical fertilizer are better for the crops than chemical fertilizers.
Temperature sensitivity of the interspecific interaction strength of coastal marine fish communities
Authors: Ushio Masayuki , Sado Tetsuya , Fukuchi Takehiko , Sasano Sachia , Masuda Reiji , Osada Yutaka , Miya Masaki 
Published: June 2022

AbstractThe effects of temperature on interaction strengths are important for understanding and forecasting how global climate change impacts marine ecosystems; however, tracking and quantifying interactions of marine fish species is practically difficult especially under field conditions, and thus, how temperature influences their interaction strengths under field conditions remains poorly understood. We herein performed quantitative fish environmental DNA (eDNA) metabarcoding on 550 seawater samples that were collected twice a month from 11 coastal sites for two years in the Boso Peninsula, Japan, and analyzed eDNA monitoring data using nonlinear time-series analytical tools. We detected fish-fish interactions as information flow between eDNA time series, reconstructed interaction networks for the top 50 frequently detected species, and quantified pairwise, fluctuating interaction strengths. Although there was a large variation, water temperature influenced fish-fish interaction strengths. The impact of water temperature on interspecific interaction strengths varied among fish species, suggesting that fish species identity influences the temperature effects on interactions. For example, interaction strengths thatHalichoeres tenuispinisandMicrocanthus stringatusreceived strongly increased with water temperature, while those ofEngraulis japonicusandGirella punctatadecreased with water temperature. An increase in water temperature induced by global climate change may change fish interactions in a complex way, which consequently influences marine community dynamics and stability. Our research demonstrates a practical research framework to study the effects of environmental variables on interaction strengths of marine communities in nature, which would contribute to understanding and predicting natural marine ecosystem dynamics.