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| Open AccessPhox2b-expressing neurons contribute to breathing problems in Kcnq2 loss- and gain-of-function encephalopathy models
Kcnq2 disfunction can cause developmental and epileptic encephalopathy (DEE). Here, authors show loss or gain of Kcnq2 function in Phox2b-expressing neurons disrupts breathing, thus identifying these cells as a likely basis for DEE breathing problems.
- J. Soto-Perez
- , C. M. Cleary
- & D. K. Mulkey
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Article
| Open AccessStructure of a membrane-bound menaquinol:organohalide oxidoreductase
The structure of a bacterial membrane protein complex involved in the bioremediation of tetrachloroethene, a major chlorinated organic pollutant, was determined. It elucidates the path of electrons from menaquinol to the active site of the enzyme.
- Lorenzo Cimmino
- , Américo G. Duarte
- & Julien Maillard
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Article
| Open AccessSRC and TKS5 mediated podosome formation in fibroblasts promotes extracellular matrix invasion and pulmonary fibrosis
The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components is a pathogenic hallmark of idiopathic pulmonary fibrosis. Here, the authors show that the formation of podosomes in lung fibroblasts stimulates extracellular matrix invasion in a mouse model of the disease, suggesting that pharmacological targeting of podosome formation or organization might be a therapeutic option.
- Ilianna Barbayianni
- , Paraskevi Kanellopoulou
- & Vassilis Aidinis
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Article
| Open AccessPurinergic signaling mediates neuroglial interactions to modulate sighs
Sighs are augmented breaths necessary to maintain normal breathing. Here, the authors show that sighs are generated within the preBötzinger complex by emergent network properties that involve neuroglial interactions mediated by purinergic signaling as well as intrinsic and extrinsic modulatory inputs.
- Liza J. Severs
- , Nicholas E. Bush
- & Jan-Marino Ramirez
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Article
| Open AccessModulatory dynamics of periodic and aperiodic activity in respiration-brain coupling
Respiration modulates neural oscillations, but its link to aperiodic brain activity is not known. With a multi-centre human MEG and EEG study, here the authors show that fluctuations of aperiodic brain activity are phase-locked to the respiratory cycle.
- Daniel S. Kluger
- , Carina Forster
- & Joachim Gross
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Article
| Open AccessHippocampal ensemble dynamics and memory performance are modulated by respiration during encoding
Breathing might be crucial for cognition during both offline and online brain states. Here, the authors show that temporal apnea induced by activating the PreBötzinger complex during memory formation resulted in memory impairments.
- Nozomu H. Nakamura
- , Hidemasa Furue
- & Yoshitaka Oku
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Matters Arising
| Open AccessPotential contribution of PEP carboxykinase-dependent malate dismutation to the hypoxia response in C. elegans
- Rosina Comas-Ghierra
- , Laura Romanelli-Cedrez
- & Gustavo Salinas
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Matters Arising
| Open AccessReply to: Potential contribution of PEP carboxykinase-dependent malate dismutation to the hypoxia response in C. elegans
- Mehul Vora
- , Stephanie M. Pyonteck
- & Christopher Rongo
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Article
| Open AccessUpregulation of breathing rate during running exercise by central locomotor circuits in mice
The neuronal basis for respiratory augmentation during running is poorly understood. Here, the authors identify two neuronal pathways by which the central locomotor network can upregulate respiratory rate in running mice.
- Coralie Hérent
- , Séverine Diem
- & Julien Bouvier
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Article
| Open AccessInsights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis
Osteoclasts are derived from circulating myeloid cells to mediate bone repair, maintenance and remodeling. Here, the authors show that the lung also recruits and reprograms monocytes and alveolar macrophages into osteoclast-like cells to clear pathogenic particles from the airspace.
- Yasuaki Uehara
- , Yusuke Tanaka
- & Francis X. McCormack
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Article
| Open AccessTransgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice
Activation of breathing during hypoxia is abolished in mice lacking mitochondrial complex I in carotid body chemoreceptors, however the specific contribution of mitochondrial complex I to this process is unclear. Here, the authors show that recovery of NADH dehydrogenase activity, but not proton pumping, by transgenic expression of a yeast enzyme rescues cellular and systemic sensitivity to changes in O2 tension.
- Blanca Jiménez-Gómez
- , Patricia Ortega-Sáenz
- & José López-Barneo
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Article
| Open AccessRetinoids stored locally in the lung are required to attenuate the severity of acute lung injury in male mice
Retinoids can act as transcriptional regulators to regulate cell proliferation, differentiation, and other processes. Here, the authors show that uncompromised vitamin A (retinoid) metabolism and signaling in alveolar lipofibroblasts, endothelial and epithelial cells are required to lessen the severity of an acute inflammatory challenge in adult mouse lungs.
- Igor O. Shmarakov
- , Galina A. Gusarova
- & William S. Blaner
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Article
| Open AccessAn engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration
Mitochondrial fatty acid synthesis (mtFAS) generates the precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. Here, the authors generated an engineered variant of human 2E-enoyl-ACP reductase (MECR) of mtFAS to study the role of long chain fatty acids.
- M. Tanvir Rahman
- , M. Kristian Koski
- & Kaija J. Autio
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Article
| Open AccessAntagonizing cholecystokinin A receptor in the lung attenuates obesity-induced airway hyperresponsiveness
The underlying mechanisms of how obesity increases asthma prevalence and severity are not well understood. Here, the authors show that antagonizing cholecystokinin and its receptor, CCKAR, in the lung attenuates obesity-associated airway hyperresponsiveness in mice.
- Ronald Allan M. Panganiban
- , Zhiping Yang
- & Quan Lu
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Article
| Open AccessThe endocannabinoid anandamide is an airway relaxant in health and disease
Obstructive lung diseases are a frequent cause of morbidity worldwide. Here, the authors identify the endocannabinoid anandamide (AEA) as an airway relaxant under physiological and pathophysiological conditions that can be locally applied to the lung as an aerosol in mice.
- Annika Simon
- , Thomas von Einem
- & Daniela Wenzel
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Article
| Open AccessThe hypoxia response pathway promotes PEP carboxykinase and gluconeogenesis in C. elegans
The hypoxia response pathway can counter pathological damage caused by low oxygen availability. Here the authors employ a multiomics approach to show how the pathway reprograms metabolism towards gluconeogenesis to combat oxidative stress.
- Mehul Vora
- , Stephanie M. Pyonteck
- & Christopher Rongo
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Article
| Open AccessThe mitochondrial calcium uniporter of pulmonary type 2 cells determines severity of acute lung injury
Acute lung injury caused by inhalation of pathogens leads to mortality, but the mechanisms are unclear. Here, the authors show in mice that that loss of the mitochondrial calcium uniporter (MCU) of alveolar type 2 cells (AT2) impaired mitochondrial Ca2+ buffering and surfactant secretion, and increased mortality, in response to LPS instillation, suggesting the MCU as a potential therapeutic target in ALI.
- Mohammad Naimul Islam
- , Galina A. Gusarova
- & Jahar Bhattacharya
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Article
| Open AccessMafa-dependent GABAergic activity promotes mouse neonatal apneas
Apneas are associated with many pathological conditions. Here, the authors show in a mouse model that stabilization of the transcription factor Mafa in brainstem GABAergic neurons may contribute to apnea, by decreasing motor drive to muscles controlling the airways.
- Laure Lecoin
- , Bowen Dempsey
- & Jean Champagnat
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Article
| Open AccessLung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice
Excess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.
- Barbara Spix
- , Elisabeth S. Butz
- & Christian Grimm
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Article
| Open AccessDisordered breathing in a Pitt-Hopkins syndrome model involves Phox2b-expressing parafacial neurons and aberrant Nav1.8 expression
Disordered breathing is a hallmark of Pitt-Hopkins syndrome (PTHS), yet little is known regarding how loss of Tcf4 (gene associated with PTHS) affects development and function of respiratory neurons. Here, the authors show that parafacial respiratory neurons are selectively disrupted in a mouse model of PTHS, and central Nav1.8 channels can be targeted to improve PTHS-associated behavior abnormalities.
- C. M. Cleary
- , S. James
- & D. K. Mulkey
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Article
| Open AccessCryo-EM structures of engineered active bc1-cbb3 type CIII2CIV super-complexes and electronic communication between the complexes
Respiratory chains generate the proton motive force used for ATP synthesis. Cryo-EM structures of functional respiratory CIII2CIV supercomplex and native CIII2 from Rhodobacter capsulatus provide insight into CIII2CIV assembly and respiratory electron transport pathways in Gram-negative bacteria.
- Stefan Steimle
- , Trevor van Eeuwen
- & Fevzi Daldal
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Article
| Open AccessPrevalent and sex-biased breathing patterns modify functional connectivity MRI in young adults
Functional connectivity measured from fMRI data is widely used in neuroscience. Here the authors report an association between two types of breathing signature and obtained BOLD data, and associated sex differences.
- Charles J. Lynch
- , Benjamin M. Silver
- & Jonathan D. Power
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Article
| Open AccessModeling lung perfusion abnormalities to explain early COVID-19 hypoxemia
Early stages of the novel coronavirus disease (COVID-19) have been associated with silent hypoxia and poor oxygenation despite relatively small fractions of afflicted lung. Here, the authors present a mathematical model which reproduces the vascular pulmonary mechanisms observed in patients with early COVID-19.
- Jacob Herrmann
- , Vitor Mori
- & Béla Suki
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Article
| Open AccessAlveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis
Injury repair is characterized by the generation of transient cell states important for tissue recovery. Here, the authors present a single cell RNA-seq map of recovery from bleomycin lung injury in mice and uncover a Krt8+ transitional stem cell state that precedes the regeneration of AT1 cells and persists in human lung fibrosis.
- Maximilian Strunz
- , Lukas M. Simon
- & Herbert B. Schiller
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Article
| Open AccessCerebral oxygenation during locomotion is modulated by respiration
Understanding mechanisms of cerebral oxygen regulation is critical for healthy brain function. Here the authors show that respiration is a key modulator of cerebral oxygenation, which will be helpful in better resolving neurally-generated functional brain imaging signals, such as BOLD fMRI.
- Qingguang Zhang
- , Morgane Roche
- & Patrick J. Drew
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Article
| Open AccessThe nasal methylome as a biomarker of asthma and airway inflammation in children
Epigenetic differences in nasal epithelium have been proposed as a biomarker for lower airway disease and asthma. Here, in epigenome-wide association studies for asthma and other airway traits using nasal swabs, the authors identify differentially methylated CpGs that highlight genes involved in TH2 response.
- Andres Cardenas
- , Joanne E. Sordillo
- & Diane R. Gold
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Article
| Open AccessRapid and robust restoration of breathing long after spinal cord injury
Respiratory failure is one of the leading causes of death following spinal cord injury and it is unclear if normal respiratory motor activity can be recovered after chronic injury-induced paralysis. Here, authors show that treatment with chondroitinase ABC induces robust rescue of breathing up to 1.5 years following complete hemidiaphragm paralysis.
- Philippa M. Warren
- , Stephanie C. Steiger
- & Jerry Silver
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Article
| Open AccessThe interdependence of excitation and inhibition for the control of dynamic breathing rhythms
Excitatory neurons in the preBötzinger Complex generate bursting activity responsible for breathing, but these alone cannot generate physiological breathing frequencies. Here the authors show how inhibition regulates refractory properties of excitatory neurons to allow dynamic breathing rhythms.
- Nathan Andrew Baertsch
- , Hans Christopher Baertsch
- & Jan Marino Ramirez
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Article
| Open AccessAstrocytes modulate brainstem respiratory rhythm-generating circuits and determine exercise capacity
Circuits of the preBötzinger complex generate rhythms needed for breathing. Here, the authors provide evidence, using a combination of chemogenetic approaches and approaches to inhibit vesicular release, that astrocytes play a role in regulating respiratory rate.
- Shahriar Sheikhbahaei
- , Egor A. Turovsky
- & Alexander V. Gourine
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Article
| Open AccessMetabolic rate evolves rapidly and in parallel with the pace of life history
The ‘pace of life’ depends on both metabolic rate and life history traits; however, whether these evolve similarly in response to the environment is not clear. Here, Auer et al. show parallel evolution of metabolic rate and a suite of life history traits in response to predator environment in Trinidadian guppies.
- Sonya K. Auer
- , Cynthia A. Dick
- & David N. Reznick
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Article
| Open AccessAirway surface liquid pH is not acidic in children with cystic fibrosis
Modulation of airway surface liquid pH has been proposed as a therapy for cystic fibrosis, but whether pH is indeed altered in cystic fibrosis is controversial. Here, the authors develop a novel fibre-optic based pH measurement technology, and show that pH is not altered in children with cystic fibrosis.
- André Schultz
- , Ramaa Puvvadi
- & Stephen M. Stick
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Article
| Open AccessTRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells
LPS is a major component of gram-negative bacterial cell walls, and triggers immune responses in airway epithelium by activating TLR4. Here the authors show that LPS also activates TRPV4, thereby inducing fast defense responses such as nitric oxide production and increased ciliary beating in mice.
- Yeranddy A. Alpizar
- , Brett Boonen
- & Karel Talavera
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Article
| Open AccessD-serine released by astrocytes in brainstem regulates breathing response to CO2 levels
Astrocytes are involved in chemoreception in brainstem areas that regulate breathing rhythm, and astrocytes are known to release d-serine. Here the authors show that astrocyte release of d-serine contributes to CO2 sensing and breathing in brainstem slices, and in vivo in awake unrestrained mice.
- S. Beltrán-Castillo
- , M. J. Olivares
- & J. L. Eugenín
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Article
| Open AccessCellular senescence mediates fibrotic pulmonary disease
Removal of senescent cells rejuvenates lungs of aged mice. Here the authors show that elimination of senescent cells using either genetic or pharmacological means improves lung function and physical health in a mouse model of idiopathic pulmonary fibrosis (IPF), suggesting potential therapy for treatment of human IPF.
- Marissa J. Schafer
- , Thomas A. White
- & Nathan K. LeBrasseur
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Article
| Open AccessIdentification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor
Asthma is characterized by abnormal airway hyperresponsiveness. Here the authors identify BPIFA1 as a factor secreted by airway epithelial cells, and show that it regulates contractility of airway smooth muscle cells by binding to and regulating the Orai1 Ca2+channel.
- Tongde Wu
- , Julianne Huang
- & Robert Tarran
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Article
| Open AccessThe aryl hydrocarbon receptor controls cyclin O to promote epithelial multiciliogenesis
Epithelia are barriers against environmental insults and express the transcription factor aryl hydrocarbon receptor (AhR). Here the authors show that AhR regulates multiciliogenesis via cyclin O and Multicilin in a Notch-dependent manner and that this is blocked by toxic ligands.
- Matteo Villa
- , Stefania Crotta
- & Andreas Wack
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Article
| Open AccessFish optimize sensing and respiration during undulatory swimming
Head movements of swimming fishes are thought to exist only because of recoil of the oscillating tail. Here, Akanyeti et al. show that by controlling the timing of head movements, fish can improve their swimming efficiency while simultaneously optimizing sensing and respiration.
- O. Akanyeti
- , P. J. M. Thornycroft
- & J. C. Liao
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Article
| Open AccessInhibition of stationary phase respiration impairs persister formation in E. coli
A few bacterial cells within a genetically homogeneous population can become ‘persisters’, or temporarily tolerant to antibiotics. Here Orman and Brynildsen show that development of persisters among growth-arrested E. colicells can be prevented by inhibiting bacterial respiration.
- Mehmet A. Orman
- & Mark P. Brynildsen
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Article
| Open AccessBoth respiration and photosynthesis determine the scaling of plankton metabolism in the oligotrophic ocean
Whether the oligotrophic ocean is net heterotrophic or net autotrophic has been a matter of debate for many years. Here Serret et al. show that, rather than being one or the other, the oligotrophic ocean is functionally diverse, with different metabolic states in different gyres.
- Pablo Serret
- , Carol Robinson
- & Rob Thomas
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Article
| Open AccessWhisker barrel cortex delta oscillations and gamma power in the awake mouse are linked to respiration
Oscillatory neuronal activity in the mammalian neocortex is implicated in cognitive processes but its generation is poorly understood. In this study, the authors show that delta band oscillatory activity in mice phase-locks with respiratory activity and that this is mediated by activity in the olfactory bulb.
- J. Ito
- , S. Roy
- & D.H. Heck