bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Rer1 causes proteotoxic stress that drives cell competition and inhibits Myc-driven overgrowth
Authors: Paul Pranab Kumar , S Rishana Farin , Annaert Wim , Chaudhary Varun 
Published: August 2022

AbstractCell competition is a developmental phenomenon that allows the selection of healthier cells in a developing tissue. In this process, cells with reduced fitness, conceivably due to harmful mutations, acquire the ‘loser’ status and are eliminated by the fitter (winner) neighboring cells via juxtacrine cell-cell interactions. How various mutations trigger cell competition is an extensively studied question. However, the mechanism of cell competition remains largely elusive. In this study, we reveal previously unknown functions of an ER and Golgi localized protein Rer1 in the regulation of cell competition in the developing Drosophila wing epithelium. Our data show that loss of Rer1 leads to the proteotoxic stress marked by the increased phosphorylation of eIF2α. The increased proteotoxic stress in the rer1 mutant cells led to their elimination via cell competition. Interestingly, we find that Rer1 levels are upregulated upon Myc overexpression, which generates super-competitive cells that overgrow at the expense of the normal neighboring cells. Loss of Rer1 also restricts the growth of Myc-induced super-competitive cells. Moreover, consistent with its known function as a negative regulator of the Notch pathway, our results show that the increased levels of Rer1 in Myc-overexpression led to the downregulation of Notch activity. In summary, these observations provide the first characterization of Rer1 in Drosophila and reveal its role in triggering cell competition via the regulation of proteotoxic stress.
Design, fabrication, and preclinical testing of a miniaturized, multispectral, chip-on-tip, imaging probe for intraluminal fluorescence imaging of the gastrointestinal tract
Authors: Slomka Bridget , Duan Suzann , Sontz Ricky , Merchant Juanita L. , Sawyer Travis W. 
Published: August 2022

AbstractGastrointestinal cancers continue to account for a disproportionately large percentage of annual cancer deaths in the US. Advancements in miniature imaging technology combined with a need for precise and thorough tumor detection in gastrointestinal cancer screenings fuel the demand for new, small-scale, and low-cost methods of localization and margin identification with improved accuracy. Here, we report the development of a miniaturized, chip-on-tip, multispectral, fluorescence imaging probe designed to port through a gastroscope working channel with the aim of detecting cancerous lesions in point-of-care endoscopy of the gastrointestinal lumen. Preclinical testing has confirmed fluorescence sensitivity and supports that this miniature probe can locate structures of interest via detection of fluorescence emission from exogenous contrast agents. This work demonstrates the design and preliminary performance evaluation of a miniaturized, single-use, chip-on-tip fluorescence imaging system, capable of detecting multiple fluorochromes, and devised for deployment via the accessory channel of a standard gastroscope.
MMP14 cleaves PTH1R in the chondrocyte derived osteoblast lineage, curbing signaling intensity for proper bone anabolism
Authors: Chu Tsz Long , Chen Peikai , Yu Anna Xiaodan , Kong Mingpeng , Tan Zhijia , Tsang Kwok Yeung , Zhou Zhongjun , Cheah Kathryn S.E. 
Published: August 2022

AbstractBone homeostasis is regulated by hormones such as parathyroid hormone (PTH). While PTH can stimulate osteo-progenitor expansion and bone synthesis, how PTH-signaling intensity in progenitors is controlled is unclear. Endochondral bone osteoblasts arise from perichondrium-derived osteoprogenitors and hypertrophic chondrocytes (HC). We found, via single-cell transcriptomics, HC descendent cells activate membrane-type 1 metalloproteinase 14 (MMP14) and the PTH pathway as they transition to osteoblasts in neonatal and adult mice. Unlike Mmp14 global knockouts, HC lineage-specific Mmp14 null mutants (Mmp14ΔHC) produce more bone. Mechanistically, MMP14 cleaves the extracellular domain of PTH1R, dampening PTH signaling and PTH signaling is enhanced in Mmp14ΔHC mutants. We found HC-derived osteoblasts contribute ∼50% of osteogenesis promoted by treatment with PTH 1-34 and this response was amplified in Mmp14ΔHC. MMP14 control of PTH signaling likely applies also to both HC- and non- HC-derived osteoblasts because their transcriptomes are highly similar. Our study identifies a novel paradigm of MMP14 activity-mediated titration of PTH signaling in the osteoblast lineage, contributing new insights into bone metabolism with therapeutic significance for bone-wasting diseases.
AICAR prevents doxorubicin-induced heart failure in rats by ameliorating cardiac atrophy and improving fatty acid oxidation
Authors: Choksey Anurag , Thackray Benjamin D. , Ball Vicky , Ha Lea Hong Tuan , Sharma Eshita , Kennedy Brett W. C. , Carter Ryan D. , Broxholme John , Murphy Michael P , Heather Lisa C , Tyler Damian J , Timm Kerstin N 
Published: August 2022

AbstractDoxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to functional cardiac decline and ultimately, congestive heart failure (HF). Impaired mitochondrial function and energetics are thought to be key factors driving progression into HF. We have previously shown in a rat model of chronic intravenous DOX-administration that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and oxidative metabolism, including fatty acid oxidation. We hypothesized that AMPK activation could restore mitochondrial number and function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. We therefore set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this clinically relevant rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. We show that this could be due to normalisation of substrate supply to the heart, as AICAR prevented DOX-induced dyslipidaemia. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, despite no increase in mitochondrial number. In addition, we found that AICAR prevented excessive myocardial atrophy, and RNAseq analysis showed that this may be due to normalisation of protein synthesis pathways, which are impaired in DOX-treated rat hearts. Taken together, these results show promise for use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac mass and improve cardiac function.
CRISPR interference for Sequence-Specific Regulation of Fibroblast Growth Factor Receptor A in Schistosoma mansoni
Authors: Du Xiaofeng , McManus Donald P. , French Juliet D. , Collinson Natasha , Sivakumaran Haran , MacGregor Skye R. , Fogarty Conor E. , Jones Malcolm K. , You Hong 
Published: August 2022

AbstractEmploying the flatworm parasite Schistosoma mansoni as a model, we report the first application of CRISPR interference (CRISPRi) in parasitic helminths for loss-of-function targeting the SmfgfrA gene which encodes the stem cell marker, fibroblast growth factor receptor A. SmFGFRA is essential for maintaining schistosome stem cells and critical in the schistosome-host interplay. The SmfgfrA gene was targeted in S. mansoni adult worms, eggs and schistosomula using a catalytically dead Cas9 (dCas9) fused to a transcriptional repressor KRAB. We showed that SmfgfrA repression resulted in considerable phenotypic differences in the modulated parasites compared with controls, including reduced levels of SmfgfrA transcription and decreased protein expression of SmFGFRA, a decline in EdU (thymidine analog 5-ethynyl-2’-deoxyuridine, which specifically stains schistosome stem cells) signal, and an increase in cell apoptosis. Notably, reduced SmfgfrA transcription was evident in miracidia hatched from SmfgfrA-repressed eggs, and resulted in a significant change in miracidial behavior, indicative of a durable repression effect caused by CRISPRi. Intravenous injection of mice with SmfgfrA-repressed eggs resulted in granulomas that were markedly reduced in size and a decline in the level of serum IgE, emphasizing the importance of SmFGFRA in regulating the host immune response induced during schistosome infection. Our findings show the feasibility of applying CRISPRi for effective, targeted transcriptional repression in schistosomes, and provide the basis for employing CRISPRi to selectively perturb gene expression in parasitic helminths on a genome-wide scale.
Uncovering brain tissue architecture across scales with super-resolution light microscopy
Authors: Michalska Julia M. , Lyudchik Julia , Velicky Philipp , Korinkova Hana , Watson Jake F. , Cenameri Alban , Sommer Christoph , Venturino Alessandro , Roessler Karl , Czech Thomas , Siegert Sandra , Novarino Gaia , Jonas Peter , Danzl Johann G. 
Published: August 2022

AbstractMapping the complex and dense arrangement of cells and their connectivity in brain tissue demands nanoscale spatial resolution imaging. Super-resolution optical microscopy excels at visualizing specific molecules and individual cells but fails to provide tissue context. Here we developed Comprehensive Analysis of Tissues across Scales (CATS), a technology to densely map brain tissue architecture from millimeter regional to nanoscopic synaptic scales in diverse chemically fixed brain preparations, including rodent and human. CATS leverages fixation-compatible extracellular labeling and advanced optical readout, in particular stimulated-emission depletion and expansion microscopy, to comprehensively delineate cellular structures. It enables 3D-reconstructing single synapses and mapping synaptic connectivity by identification and tailored analysis of putative synaptic cleft regions. Applying CATS to the hippocampal mossy fiber circuitry, we demonstrate its power to reveal the system’s molecularly informed ultrastructure across spatial scales and assess local connectivity by reconstructing and quantifying the synaptic input and output structure of identified neurons.
Comparison of progressive hold and progressive response schedules of reinforcement
Authors: Alvarez-Sekely Celeste Sofia , Toscano-Zapien Ana Laura , Salles-Ize Paloma , Lopez-Guzman Maria Almudena , Velázquez-Martinez David N. 
Published: August 2022

AbstractProgressive ratio (PR) schedules had been widely used to study motivation to work for a reinforcer. After a post-reinforcer pause, subjects engage pressing a lever until a reinforcer is obtained. However, the discrete nature of lever presses allows alternative behaviors during inter-response time and had lead to the suggestion of several behavioral categories to explain pauses and work time. A progressive hold-down (PH) is incompatible with alternative responses and may allow a precise estimation of work time. Performance of rats trained in both PR and PH that received sucrose or intracranial self-stimulation (ICSS) as reinforcer were compared. We observed that rats mastered the PR and PH schedules. Post-reinforcer pauses, work time and inter-reinforcer time increased as a function of the response or hold requirement. However, rat’s performance suggest that the PH progression may be experienced by the rats as easier that the PR progression. Elimination of consummatory behavior with ICSS reduced PSRP and in accordance with predictions of explanatory models of fixed and variable schedules of reinforcement. In the case of PH performance, intermediate requirements leveled off pauses but inceased rapidly on later requirements; since rats controlled pause length and work time was close to hold requirement, time allocation between PR and PH schedules diverged. Finally, the Mathematical Principles of Reinforcement model of Bradshaw and Killeen (Psychopharmacology 2012, 222: 549) rendered a good description of the performance in both PR and PH schedules.
Distinct effects of intracellular vs. extracellular acidic pH on the cardiac metabolome during ischemia and reperfusion
Authors: Milliken Alexander S. , Ciesla Jessica H. , Nadtochiy Sergiy M. , Brookes Paul S. 
Published: August 2022

ABSTRACTTissue ischemia results in intracellular pH (pHIN) acidification, and while accumulation of metabolites such as lactate is a known driver of acidic pHIN, less is known about how acidic pHIN regulates metabolism. Furthermore, acidic extracellular (pHEX) during early reperfusion confers cardioprotection, but how this impacts metabolism is unclear. Herein we employed LCMS based targeted metabolomics to analyze perfused mouse hearts exposed to: (i) control perfusion, (ii) hypoxia, (iii) ischemia, (iv) enforced acidic pHIN, (v) control reperfusion, and (vi) acidic pHEX (6.8) reperfusion. Surprisingly little overlap was seen between metabolic changes induced by hypoxia, ischemia, and acidic pHIN. Acidic pHIN elevated metabolites in the top half of glycolysis, and enhanced glutathione redox state. Acidic pHEX reperfusion induced substantial metabolic changes in addition to those seen in control reperfusion. This included elevated metabolites in the top half of glycolysis, prevention of purine nucleotide loss, and an enhancement in glutathione redox state. These data led to parallel hypotheses regarding potential roles for methylglyoxal inhibiting the mitochondrial permeability transition pore, and for acidic inhibition of ecto-5’-nucleotidase, as potential mediators of cardioprotection by acidic pHEX reperfusion. However, neither hypothesis was supported by subsequent experiments. In contrast, analysis of cardiac effluents revealed complex effects of pHEX on metabolite transport, suggesting that mildly acidic pHEX may protect in part by enhancing succinate release during reperfusion. Overall, each intervention had distinct and overlapping metabolic effects, suggesting acidic pH is an independent metabolic regulator regardless which side of the cell membrane it is imposed.HIGHLIGHTSHypoxia, ischemia and acidic pHIN each induce unique cardiac metabolic profiles.Acidic pHEX at reperfusion prevents purine loss and enhances succinate release.
Genetic and ecological drivers of molt in a migratory bird
Authors: Contina Andrea , Bossu Christen M. , Allen Daniel , Wunder Michael B. , Ruegg Kristen C. 
Published: August 2022

ABSTRACTThe ability of animals to sync the timing and location of molting (the replacement of hair, skin, exoskeletons or feathers) with peaks in resource availability has important implications for their ecology and evolution. In migratory birds, the timing and location of pre-migratory feather molting, a period when feathers are shed and replaced with newer, more aerodynamic feathers, can vary within and between species. While hypotheses to explain the evolution of intraspecific variation in the timing and location of molt have been proposed, little is known about the genetic basis of this trait or the specific environmental drivers that may result in natural selection for distinct molting phenotypes. Here we take advantage of intraspecific variation in the timing and location of molt in the iconic songbird, the Painted Bunting (Passerina ciris) to investigate the genetic and ecological drivers of distinct molting phenotypes. Specifically, we use genome-wide genetic sequencing in combination with stable isotope analysis to determine population genetic structure and molting phenotype across thirteen breeding sites. We then use genome-wide association analysis (GWAS) to identify a suite of genes associated with molting and pair this with gene-environment association analysis (GEA) to investigate potential environmental drivers of genetic variation in this trait. Associations between genetic variation in molt-linked genes and the environment are further tested via targeted SNP genotyping in 25 additional breeding populations across the range. Together, our integrative analysis suggests that molting is in part regulated by genes linked to feather development and structure (GLI2 and CSPG4) and that genetic variation in these genes is associated with seasonal variation in precipitation and aridity. Overall, this work provides important insights into the genetic basis and potential selective forces behind phenotypic variation in what is arguably one of the most important fitness-linked traits in a migratory bird.
A PATHWAY FOR T3 SIGNALING IN THE BRAIN TO IMPROVE THE VARIABLE EFFECTIVENESS OF THERAPY WITH L-T4
Authors: Salas-Lucia Federico , Fekete Csaba , Sinkó Richárd , Egri Péter , Rada Kristóf , Ruska Yvette , Bocco Barbara , Fonseca Tatiana , Gereben Balázs , Bianco Antonio C. 
Published: August 2022

AbstractThe effectiveness of therapy for hypothyroidism with levothyroxine (L-T4) depends on patients’ ability to activate T4 to T3 —altered in carriers of a common deiodinase polymorphism (Thr92Ala-DIO2). Some patients that exhibit impaired mood and cognition improve with liothyronine (L-T3), but the underlying mechanisms remain unknown. Here we show that the T3-indicator mouse carrying the Thr92Ala-DIO2 polymorphism exhibits a hippocampal-specific reduction in T3 activation and signaling that limits the effectiveness of L-T4 therapy. To understand the L-T3 effect, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering relatively large amounts of T3 to the cell nucleus, doubling the expression of the T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and the type 3 deiodinase (Dio3), which transports and inactivates T3, respectively. Notwithstanding, T3 gets away from degradation because D3 active center is in the cytosol. These findings provide (i) a basis for the variable effectiveness of L-T4 therapy, (ii) a pathway for L-T3 to reach neurons, and (iii) resolve the paradox of T3 signaling in the brain amid high D3 activity.
Timing of Transcranial Direct Current Stimulation at M1 Does Not Affect Motor Sequence Learning
Authors: Kim Hakjoo , King Bradley R. , Verwey Willem B. , Buchanan John J. , Wright David L. 
Published: August 2022

AbstractAdministering anodal tDCS at the primary motor cortex (M1) at various temporal loci relative to motor training is reported to affect subsequent performance gains. Stimulation administered in conjunction with motor training appears to offer the most robust benefit that emerges during offline epochs. This conclusion is made, however, based on between-experiment comparisons that involved varied methodologies. The present experiment addressed this shortcoming by administering the same 15-minute dose of anodal tDCS at M1 before, during, or after practice of a serial reaction time task (SRTT). It was anticipated that exogenous stimulation during practice with a novel SRTT would facilitate offline gains. Ninety participants were randomly assigned to one of four groups: tDCS before practice, tDCS during practice, tDCS after practice, or no tDCS. Each participant was exposed to 15 minutes of 2 mA of tDCS and motor training of an eight-element SRTT. The anode was placed at right M1 with the cathode at left M1, and the left hand was used to execute the SRTT. Test blocks were administered 1 and 24 hours after practice concluded. The results revealed significant offline gain for all conditions at the 1-hour and 24-hour test blocks. Importantly, exposure to anodal tDCS at M1 at any point before, during, or after motor training failed to change the trajectory of skill development as compared to the no stimulation control condition. These data add to the growing body of evidence questioning the efficacy of exogenous stimulation as an adjunct to motor training for fostering skill learning.HighlightsTime-dependent consolidation of a novel motor skill occurred within 1 hour after the first practice blockFurther consolidation of this memory still occurred 24 hours after practicetDCS at M1 before, during, or after the initial bout of practice did not modify online or offline performance gains
A microbiota-derived metabolite instructs peripheral efferocytosis
Authors: Saavedra Pedro H. V. , Trzeciak Alissa , Wang Zhaoquan , Saitz Rojas Waleska , Zago Giulia , Docampo Melissa D. , Verter Jacob G. , van den Brink Marcel R. M. , Lucas Christopher D. , Anderson Christopher J. , Rudensky Alexander Y. , Perry Justin S. A. 
Published: August 2022

AbstractThe phagocytic clearance of dying cells, termed efferocytosis, is essential for both tissue homeostasis and tissue health during cell death-inducing treatments. Failure to efficiently clear dying cells augments the risk of pathological inflammation and has been linked to a myriad of autoimmune and inflammatory diseases. Although past studies have elucidated local molecular signals that regulate efferocytosis in a tissue, whether signals arising distally also regulate efferocytosis remains elusive. Interestingly, clinical evidence suggests that prolonged use of antibiotics is associated with an increased risk of autoimmune or inflammatory disease development. We therefore hypothesized that intestinal microbes produce molecular signals that regulate efferocytotic ability in peripheral tissue phagocytes. Here, we find that macrophages, the body’s professional phagocyte, display impaired efferocytosis in peripheral tissues in both antibiotic-treated and germ-free mice in vivo, which could be rescued by fecal microbiota transplantation. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosted efferocytosis efficiency and capacity in mouse and human macrophages, with both intestinal and local delivery of butyrate capable of rescuing antibiotic-induced peripheral efferocytosis defects. Bulk mRNA sequencing of primary macrophages treated with butyrate in vitro and single cell mRNA sequencing of macrophages isolated from antibiotic-treated and butyrate-rescued mice revealed specific regulation of phagocytosis-associated transcriptional programs, in particular the induction of programs involved in or supportive of efferocytosis. Surprisingly, the effect of butyrate on efferocytosis was not mediated through G protein-coupled receptor signaling, but instead acted by inhibition of histone deacetylase 3. Strikingly, peripheral efferocytosis was impaired well-beyond withdrawal of antibiotics and, importantly, antibiotic-treated mice exhibited a poorer response to a sterile efferocytosis-dependent inflammation model. Collectively, our results demonstrate that a process essential for tissue homeostasis, efferocytosis, relies on distal molecular signals, and suggest that a defect in peripheral efferocytosis may contribute to the clinically-observed link between broad-spectrum antibiotics use and inflammatory disease.