Radiation Induces Metabolic Dysregulation in Pulmonary Fibroblasts

Rationale: Exposure of the lung to ionizing radiation, such as during radiotherapy, can result in pulmonary fibrosis (PF), which has few treatment options. PF is characterized by an accumulation of extracellular matrix proteins that form scar tissue, resulting in dyspnea, disruption of gas exchange, and even death. We and others have shown that metabolic reprogramming is a hallmark of idiopathic pulmonary fibrosis (IPF). IPF lung tissue, and lung fibroblasts treated with TGF-β, exhibit increased aerobic glycolysis with increased expression of lactate dehydrogenase A (LDHA) and excess production of lactate, leading to reduced extracellular pH that activates latent TGF-β. Here, we hypothesized that ionizing radiation would cause aerobic glycolytic metabolic dysregulation in primary human lung fibroblasts. Results: Primary non-fibrotic HLFs exposed to irradiation exhibited significant upregulation of Pyruvate Dehydrogenase Kinase (PDK1 (0.5 – 3-fold, p\u3c0.05) and LDHA (1.4-fold, p\u3c0.05). Cell viability was unaffected by increased radiation dose. Conclusions: Radiation increased fibroblast expression of genes involved in fibrotic phenotypes (αSMA) and aerobic glycolysis (PDK1 and LDHA), in a similar pattern to that seen in IPF fibroblasts. The metabolic changes are closely associated with creating a profibrotic extracellular environment in IPF by promoting an acidic environment. Our evidence suggests this phenomenon can be driven by radiation in lung fibroblasts and affirm that glycolytic reprogramming may also be a hallmark of radiation-induced fibrosis. Further understanding of the common mechanisms that create this metabolic shift could provide novel therapeutics for fibrosis treatment.https://scholarscompass.vcu.edu/gradposters/1158/thumbnail.jp

Pervasive and dynamic protein binding sites of the mRNA transcriptome in Saccharomyces cerevisiae

Abstract Background Protein-RNA interactions are integral components of nearly every aspect of biology, including regulation of gene expression, assembly of cellular architectures, and pathogenesis of human diseases. However, studies in the past few decades have only uncovered a small fraction of the vast landscape of the protein-RNA interactome in any organism, and even less is known about the dynamics of protein-RNA interactions under changing developmental and environmental conditions. Results Here, we describe the gPAR-CLIP (global photoactivatable-ribonucleoside-enhanced crosslinking and immunopurification) approach for capturing regions of the untranslated, polyadenylated transcriptome bound by RNA-binding proteins (RBPs) in budding yeast. We report over 13,000 RBP crosslinking sites in untranslated regions (UTRs) covering 72% of protein-coding transcripts encoded in the genome, confirming 3' UTRs as major sites for RBP interaction. Comparative genomic analyses reveal that RBP crosslinking sites are highly conserved, and RNA folding predictions indicate that secondary structural elements are constrained by protein binding and may serve as generalizable modes of RNA recognition. Finally, 38% of 3' UTR crosslinking sites show changes in RBP occupancy upon glucose or nitrogen deprivation, with major impacts on metabolic pathways as well as mitochondrial and ribosomal gene expression. Conclusions Our study offers an unprecedented view of the pervasiveness and dynamics of protein-RNA interactions in vivo.http://deepblue.lib.umich.edu/bitstream/2027.42/112318/1/13059_2012_Article_3050.pd

Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD

Campbell's Monkeys Use Affixation to Alter Call Meaning

Human language has evolved on a biological substrate with phylogenetic roots deep in the primate lineage. Here, we describe a functional analogy to a common morphological process in human speech, affixation, in the alarm calls of free-ranging adult Campbell's monkeys (Cercopithecus campbelli campbelli). We found that male alarm calls are composed of an acoustically variable stem, which can be followed by an acoustically invariable suffix. Using long-term observations and predator simulation experiments, we show that suffixation in this species functions to broaden the calls' meaning by transforming a highly specific eagle alarm to a general arboreal disturbance call or by transforming a highly specific leopard alarm call to a general alert call. We concluded that, when referring to specific external events, non-human primates can generate meaningful acoustic variation during call production that is functionally equivalent to suffixation in human language

Combinatoriality in the vocal systems of nonhuman animals

A key challenge in the field of human language evolution is the identification of the selective conditions that gave rise to language's generative nature. Comparative data on nonhuman animals provides a powerful tool to investigate similarities and differences among nonhuman and human communication systems and to reveal convergent evolutionary mechanisms. In this article, we provide an overview of the current evidence for combinatorial structures found in the vocal system of diverse species. We show that considerable structural diversity exits across and within species in the forms of combinatorial structures used. Based on this we suggest that a fine‐grained classification and differentiation of combinatoriality is a useful approach permitting systematic comparisons across animals. Specifically, this will help to identify factors that might promote the emergence of combinatoriality and, crucially, whether differences in combinatorial mechanisms might be driven by variations in social and ecological conditions or cognitive capacities

On the Matter of Time

Drawing on several disciplinary areas, this article considers diverse cultural concepts of time, space, and materiality. It explores historical shifts in ideas about time, observing that these have gone full circle, from visions in which time and space were conflated, through increasingly divergent linear understandings of the relationship between them, to their reunion in contemporary notions of space-time. Making use of long-term ethnographic research and explorations of the topic of Time at Durham University’s Institute of Advanced Study (2012–13), the article considers Aboriginal Australian ideas about relationality and the movement of matter through space and time. It asks why these earliest explanations of the cosmos, though couched in a wholly different idiom, seem to have more in common with the theories proposed by contemporary physicists than with the ideas that dominated the period between the Holocene and the Anthropocene. The analysis suggests that such unexpected resonance between these oldest and newest ideas about time and space may spring from the fact that they share an intense observational focus on material events. Comparing these vastly different but intriguingly compatible worldviews meets interdisciplinary aims in providing a fresh perspective on both of them

The specificity and the development of social-emotional competence in a multi-ethnic-classroom

<p>Abstract</p> <p>Background</p> <p>Ethnic diversity in schools increases due to globalization. Thus, the children's social-emotional competence development must be considered in the context of a multi-ethnic classroom.</p> <p>Methods</p> <p>In this study, the social-emotional competence of 65 Asian-American and Latin-American children was observed at the beginning and the end of their kindergarten year.</p> <p>Results</p> <p>Initially, significant differences existed among these ethnic groups in respect to moral reasoning. Furthermore, the male children showed more dysregulated aggression but the female children implemented more moral reasoning than their male counterparts. These ethnic specificities did not disappear over the course of the year. In addition, a significant change in avoidance strategies as well as expressed emotions in the narrative took place over the course of one year.</p> <p>Conclusion</p> <p>Ethnic specificity in social-emotional competence does exist independent of gender at the beginning as well as at the end of the kindergarten year in a multi-ethnic kindergarten classroom.</p

Linking social complexity and vocal complexity: a parid perspective

The Paridae family (chickadees, tits and titmice) is an interesting avian group in that species vary in important aspects of their social structure and many species have large and complex vocal repertoires. For this reason, parids represent an important set of species for testing the social complexity hypothesis for vocal communication—the notion that as groups increase in social complexity, there is a need for increased vocal complexity. Here, we describe the hypothesis and some of the early evidence that supported the hypothesis. Next, we review literature on social complexity and on vocal complexity in parids, and describe some of the studies that have made explicit tests of the social complexity hypothesis in one parid—Carolina chickadees, Poecile carolinensis. We conclude with a discussion, primarily from a parid perspective, of the benefits and costs of grouping and of physiological factors that might mediate the relationship between social complexity and changes in signalling behaviour

Ready for O4 II: GRANDMA Observations of Swift GRBs during eight-weeks of Spring 2022

We present a campaign designed to train the GRANDMA network and its infrastructure to follow up on transient alerts and detect their early afterglows. In preparation for O4 II campaign, we focused on GRB alerts as they are expected to be an electromagnetic counterpart of gravitational-wave events. Our goal was to improve our response to the alerts and start prompt observations as soon as possible to better prepare the GRANDMA network for the fourth observational run of LIGO-Virgo-Kagra (which started at the end of May 2023), and future missions such as SM. To receive, manage and send out observational plans to our partner telescopes we set up dedicated infrastructure and a rota of follow-up adcates were organized to guarantee round-the-clock assistance to our telescope teams. To ensure a great number of observations, we focused on Swift GRBs whose localization errors were generally smaller than the GRANDMA telescopes' field of view. This allowed us to bypass the transient identification process and focus on the reaction time and efficiency of the network. During 'Ready for O4 II', 11 Swift/INTEGRAL GRB triggers were selected, nine fields had been observed, and three afterglows were detected (GRB 220403B, GRB 220427A, GRB 220514A), with 17 GRANDMA telescopes and 17 amateur astronomers from the citizen science project Kilonova-Catcher. Here we highlight the GRB 220427A analysis where our long-term follow-up of the host galaxy allowed us to obtain a photometric redshift of $z=0.82\pm0.09$, its lightcurve elution, fit the decay slope of the afterglows, and study the properties of the host galaxy

Time-Efficient Inspiratory Muscle Strength Training Lowers Blood Pressure and Improves Endothelial Function, NO Bioavailability, and Oxidative Stress in Midlife/Older Adults With Above-Normal Blood Pressure

Background High‐resistance inspiratory muscle strength training (IMST) is a novel, time‐efficient physical training modality. &nbsp; Methods and Results We performed a double‐blind, randomized, sham‐controlled trial to investigate whether 6&nbsp;weeks of IMST (30&nbsp;breaths/day, 6&nbsp;days/week) improves blood pressure, endothelial function, and arterial stiffness in midlife/older adults (aged 50&ndash;79&nbsp;years) with systolic blood pressure &ge;120&nbsp;mm&nbsp;Hg, while also investigating potential mechanisms and long‐lasting effects. Thirty‐six participants completed high‐resistance IMST (75% maximal inspiratory pressure, n=18) or low‐resistance sham training (15% maximal inspiratory pressure, n=18). IMST was safe, well tolerated, and had excellent adherence (&asymp;95% of training sessions completed). Casual systolic blood pressure decreased from 135&plusmn;2&nbsp;mm&nbsp;Hg to 126&plusmn;3&nbsp;mm&nbsp;Hg (P&lt;0.01) with IMST, which was &asymp;75% sustained 6&nbsp;weeks after IMST (P&lt;0.01), whereas IMST modestly decreased casual diastolic blood pressure (79&plusmn;2&nbsp;mm&nbsp;Hg to 77&plusmn;2&nbsp;mm&nbsp;Hg, P=0.03); blood pressure was unaffected by sham training (all P&gt;0.05). Twenty‐four hour systolic blood pressure was lower after IMST versus sham training (P=0.01). Brachial artery flow‐mediated dilation improved &asymp;45% with IMST (P&lt;0.01) but was unchanged with sham training (P=0.73). Human umbilical vein endothelial cells cultured with subject serum sampled after versus before IMST exhibited increased NO bioavailability, greater endothelial NO synthase activation, and lower reactive oxygen species bioactivity (P&lt;0.05). IMST decreased C‐reactive protein (P=0.05) and altered select circulating metabolites (targeted plasma metabolomics) associated with cardiovascular function. Neither IMST nor sham training influenced arterial stiffness (P&gt;0.05). &nbsp; Conclusions High‐resistance IMST is a safe, highly adherable lifestyle intervention for improving blood pressure and endothelial function in midlife/older adults with above‐normal initial systolic blood pressure. &nbsp; Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03266510. &nbsp;</p