scholarly journals Absent phasing of respiratory and locomotor rhythms in running mice

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Coralie Hérent ◽  
Séverine Diem ◽  
Gilles Fortin ◽  
Julien Bouvier
Keyword(s):  
Mouse Model ◽  
Respiratory Rate ◽  
Breathing Frequency ◽  
Limb Movements ◽  
Temporal Coordination ◽  
Running Exercise ◽  
Exercise Hyperpnoea ◽  
Wide Range ◽  
Locomotor Rhythms

Examining whether and how the rhythms of limb and breathing movements interact is highly informative about the mechanistic origin of hyperpnoea during running exercise. However, studies have failed to reveal regularities. In particular, whether breathing frequency is inherently proportional to limb velocity and imposed by a synchronization of breaths to strides is still unclear. Here, we examined respiratory changes during running in the resourceful mouse model. We show that, for a wide range of trotting speeds on a treadmill, respiratory rate increases to a fixed and stable value irrespective of trotting velocities. Respiratory rate was yet further increased during escape-like running and most particularly at gallop. However, we found no temporal coordination of breaths to strides at any speed, intensity, or gait. Our work thus highlights that exercise hyperpnoea can operate, at least in mice and in the presently examined running regimes, without phasic constraints from limb movements.

scholarly journals Independent respiratory and locomotor rhythms in running mice

2020 ◽  
Author(s):  
Coralie Hérent ◽  
Séverine Diem ◽  
Gilles Fortin ◽  
Julien Bouvier
Keyword(s):  
Respiratory Rate ◽  
Respiratory Frequency ◽  
Breathing Frequency ◽  
Limb Movements ◽  
Temporal Coordination ◽  
Locomotor Rhythms

ABSTRACTExamining whether and how the rhythms of limb and breathing movements interact is highly informative about the mechanistic origin of hyperpnoea to exercise. However, studies have failed to reveal regularities. In particular, whether breathing frequency is inherently proportional to limb velocity and/or imposed by a synchronization of breaths to strides is still unclear. Here, we examined the specifications of respiratory changes during running in mice, the premier model for investigating, in a standardized manner, complex integrative tasks including adaptive breathing. We show that respiratory rate increases during running to a fixed and stable value, irrespective of trotting velocities and of inclination. Yet, respiratory rate was further enhanced during gallop. We also demonstrate the absence of temporal coordination of breaths to strides at any speed, intensity or gait. Our work thus highlights a hardwired mechanism that sets respiratory frequency independently of limb movements but in relation with the engaged locomotor program.

scholarly journals Deficits in memory-guided limb movements impair obstacle avoidance locomotion in Alzheimer's disease mouse model

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
Susumu Setogawa ◽  
Hiroshi Yamaura ◽  
Tomoko Arasaki ◽  
Shogo Endo ◽  
Dai Yanagihara
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Obstacle Avoidance ◽  
Limb Movements

scholarly journals An optimized live bacterial delivery platform for the production and delivery of therapeutic nucleic acids and proteins

2021 ◽  
Author(s):  
Darcy S.O. Mora ◽  
Madeline Cox ◽  
Forgivemore Magunda ◽  
Ashley B. Williams ◽  
Lyndsey Linke
Keyword(s):  
Epithelial Cells ◽  
Mouse Model ◽  
Nucleic Acids ◽  
Endosomal Escape ◽  
Therapeutic Window ◽  
Target Cells ◽  
Full Potential ◽  
Wide Range ◽  
Delivery Platform

There is an unmet need for delivery platforms that realize the full potential of next-generation therapeutic and vaccine technologies, especially those that require intracellular delivery of nucleic acids. The in vivo usefulness of the current state-of-the-art delivery systems is limited by numerous intrinsic weaknesses, including lack of targeting specificity, inefficient entry and endosomal escape into target cells, undesirable immune activation, off-target effects, a small therapeutic window, limited genetic encoding and cargo capacity, and manufacturing challenges. Here we present our characterization of a delivery platform based on the use of engineered live, tissue-targeting, non-pathogenic bacteria (Escherichia coli strain SVC1) for intracellular cargo delivery. The SVC1 bacteria are engineered to specifically bind to epithelial cells via a surface-expressed targeting ligand, to escape the endosome upon intracellularization, and to have minimal immunogenicity. Here we report findings on key features of this system. First, we demonstrated that bacterial delivery of a short hairpin RNA (shRNA) can target and silence a gene in an in vitro mammalian respiratory cell model. Next, we used an in vivo mouse model to demonstrate that SVC1 bacteria are invasive to epithelial cells of various tissues and organs (eye, nose, mouth, stomach, vagina, skeletal muscle, and lungs) via local administration. We also showed that repeat dosing of SVC1 bacteria to the lungs is minimally immunogenic and that it does not have adverse effects on tissue homeostasis. Finally, to validate the potential of SVC1 bacteria in therapeutic applications, we demonstrated that bacterial delivery of influenza- targeting shRNAs to the respiratory tissues can mitigate viral replication in a mouse model of influenza infection. Our ongoing work is focused on further refining this platform for efficient delivery of nucleic acids, gene editing machinery, and therapeutic proteins, and we expect that this platform technology will enable a wide range of advanced therapeutic approaches.

scholarly journals Robot Modeling for Physical Rehabilitation

Robotics ◽  
2013 ◽  
pp. 1212-1232 ◽  
Author(s):  
Rogério Sales Gonçalves ◽  
João Carlos Mendes Carvalho
Keyword(s):  
Mathematical Models ◽  
Three Dimensional ◽  
Mechanical Systems ◽  
Industrial Robots ◽  
Limb Movements ◽  
Rehabilitation Robots ◽  
Wide Range ◽  
Movable Platform ◽  
Human Limb ◽  
Robot Modeling

The science of rehabilitation shows that repeated movements of human limbs can help the patient regain function in the injured limb. There are three types of mechanical systems used for movement rehabilitation: robots, cable-based manipulators, and exoskeletons. Industrial robots can be used because they provide a three-dimensional workspace with a wide range of flexibility to execute different trajectories, which are useful for motion rehabilitation. The cable-based manipulators consist of a movable platform and a base, which are connected by multiple cables that can extend or retract. The exoskeleton is fixed around the patient's limb to provide the physiotherapy movements. This chapter presents a summary of the principal human limb movements, a review of several mechanical systems used for rehabilitation, as well as common mathematical models of such systems.

scholarly journals Diverse tumour susceptibility in Collaborative Cross mice: identification of a new mouse model for human gastric tumourigenesis

Gut ◽  
2019 ◽  
Vol 68 (11) ◽  
pp. 1942-1952 ◽  
Author(s):  
Pin Wang ◽  
Yunshan Wang ◽  
Sasha A Langley ◽  
Yan-Xia Zhou ◽  
Kuang-Yu Jen ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Mouse Model ◽  
Rna Sequencing ◽  
Genetic Association ◽  
Association Analysis ◽  
Collaborative Cross ◽  
Sequencing Analysis ◽  
Genetic Association Analysis ◽  
Mouse Population ◽  
Wide Range

ObjectiveThe Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum.DesignWe monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis.ResultsCC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40% of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκb1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS.ConclusionsCC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.

scholarly journals Non-contact vital-sign monitoring of patients undergoing haemodialysis treatment

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mauricio Villarroel ◽  
João Jorge ◽  
David Meredith ◽  
Sheera Sutherland ◽  
Chris Pugh ◽  
...  
Keyword(s):  
Heart Rate ◽  
Respiratory Rate ◽  
Reference Values ◽  
Mean Absolute Error ◽  
Absolute Error ◽  
Recording Time ◽  
Wide Range ◽  
Auto Regressive ◽  
The Mean ◽  
Haemodialysis Treatment

Abstract A clinical study was designed to record a wide range of physiological values from patients undergoing haemodialysis treatment in the Renal Unit of the Churchill Hospital in Oxford. Video was recorded for a total of 84 dialysis sessions from 40 patients during the course of 1 year, comprising an overall video recording time of approximately 304.1 h. Reference values were provided by two devices in regular clinical use. The mean absolute error between the heart rate estimates from the camera and the average from two reference pulse oximeters (positioned at the finger and earlobe) was 2.8 beats/min for over 65% of the time the patient was stable. The mean absolute error between the respiratory rate estimates from the camera and the reference values (computed from the Electrocardiogram and a thoracic expansion sensor—chest belt) was 2.1 breaths/min for over 69% of the time for which the reference signals were valid. To increase the robustness of the algorithms, novel methods were devised for cancelling out aliased frequency components caused by the artificial light sources in the hospital, using auto-regressive modelling and pole cancellation. Maps of the spatial distribution of heart rate and respiratory rate information were developed from the coefficients of the auto-regressive models. Most of the periods for which the camera could not produce a reliable heart rate estimate lasted under 3 min, thus opening the possibility to monitor heart rate continuously in a clinical environment.

scholarly journals Interferon-Induced Protein 44 and Interferon-Induced Protein 44-Like Restrict Replication of Respiratory Syncytial Virus

2020 ◽  
Vol 94 (18) ◽  
Author(s):  
D. C. Busse ◽  
D. Habgood-Coote ◽  
S. Clare ◽  
C. Brandt ◽  
I. Bassano ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Mouse Model ◽  
Severe Disease ◽  
Early Time ◽  
Airway Epithelial Cells ◽  
Knockout Mouse Model ◽  
Antiviral Genes ◽  
Wide Range ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT Cellular intrinsic immunity, mediated by the expression of an array of interferon-stimulated antiviral genes, is a vital part of host defense. We have previously used a bioinformatic screen to identify two interferon-stimulated genes (ISG) with poorly characterized function, interferon-induced protein 44 (IFI44) and interferon-induced protein 44-like (IFI44L), as potentially being important in respiratory syncytial virus (RSV) infection. Using overexpression systems, CRISPR-Cas9-mediated knockout, and a knockout mouse model, we investigated the antiviral capability of these genes in the control of RSV replication. Overexpression of IFI44 or IFI44L was sufficient to restrict RSV infection at an early time postinfection. Knocking out these genes in mammalian airway epithelial cells increased levels of infection. Both genes express antiproliferative factors that have no effect on RSV attachment but reduce RSV replication in a minigenome assay. The loss of Ifi44 was associated with a more severe infection phenotype in a mouse model of infection. These studies demonstrate a function for IFI44 and IFI44L in controlling RSV infection. IMPORTANCE RSV infects all children under 2 years of age, but only a subset of children get severe disease. We hypothesize that susceptibility to severe RSV necessitating hospitalization in children without predefined risk factors is, in part, mediated at the antiviral gene level. However, there is a large array of antiviral genes, particularly in the ISG family, the mechanism of which is poorly understood. Having previously identified IFI44 and IFI44L as possible genes of interest in a bioinformatic screen, we dissected the function of these two genes in the control of RSV. Through a range of overexpression and knockout studies, we show that the genes are antiviral and antiproliferative. This study is important because IFI44 and IFI44L are upregulated after a wide range of viral infections, and IFI44L can serve as a diagnostic biomarker of viral infection.

Interactive effects of CO2 and upper airway negative pressure on breathing pattern

1987 ◽  
Vol 63 (1) ◽  
pp. 229-237 ◽  
Author(s):  
E. van Lunteren
Keyword(s):  
Tidal Volume ◽  
Respiratory Rate ◽  
Negative Pressure ◽  
Upper Airway ◽  
Interactive Effects ◽  
Inspiratory Time ◽  
Diaphragm Electrical Activity ◽  
Wide Range ◽  
Inspiratory Activity ◽  
The Relationship

The interactive effects of upper airway negative pressure and hypercapnia on the pattern of breathing were assessed in pentobarbital-anesthetized cats. At any given level of pressure in the upper airway, hypercapnia increased respiratory rate, reduced inspiratory time, and augmented tidal volume, inspiratory airflow, and the peak and rate of rise of diaphragm electrical activity. Conversely, at any given level of CO2, upper airway negative pressure decreased respiratory rate, prolonged inspiratory time, and depressed inspiratory airflow and diaphragm electromyogram (EMG) rate of rise. Application of negative pressure to the upper airway shifted the relationship between tidal volume and inspiratory time upward and rightward. The relationship between inspiratory and expiratory times, however, was linearly correlated over a wide range of chemical drives and levels of upper airway pressure. These results suggest that in the anesthetized cat upper airway negative pressure afferent inputs 1) interact in an additive fashion with hypercapnia to alter the pattern of breathing, 2) interact multiplicatively with CO2 to influence mean inspiratory airflow and diaphragm EMG rate of rise, 3) depress the generation of central inspiratory activity, 4) increase the time-dependent volume threshold for inspiratory termination, and 5) affect the ratio between inspiratory and expiratory times in a similar manner as alterations in PCO2.

Targeting TMPRSS6 Using Antisense Technology for the Treatment of Beta-Thalassemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 753-753 ◽  
Author(s):  
Shuling Guo ◽  
Mariam Aghajan ◽  
Carla Casu ◽  
Sara Gardenghi ◽  
Sheri Booten ◽  
...  
Keyword(s):  
Mouse Model ◽  
Targeted Delivery ◽  
Serum Iron ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Beta Thalassemia ◽  
Control Group ◽  
Mrna Levels ◽  
Antisense Technology ◽  
Wide Range

Abstract Antisense technology is a powerful drug discovery approach for identifying oligonucleotide analogs that can specifically modify RNA expression through multiple mechanisms including RNase H-mediated degradation of RNA and modulation of RNA splicing. We have successfully applied this technology towards targeting a number of transcripts in a wide-range of therapeutic areas. Beta-thalassemia, one of the most common genetic disorders worldwide, is characterized by reductions in beta-globin and ineffective erythropoiesis. This in turn leads to suppression of hepcidin, a peptide hormone that serves as the master regulator of iron homeostasis. Inappropriately low levels of hepcidin trigger increased dietary iron absorption resulting in iron overload, which is the major cause of morbidity and mortality in beta-thalassemia patients. TMPRSS6 is a transmembrane serine protease mainly produced by hepatocytes that negatively regulates hepcidin expression. Previous mouse and human genetic data from multiple groups suggest that lowering TMPRSS6 expression could up-regulate hepcidin and ameliorate many of the disease symptoms associated with β-thalassemia. We identified potent antisense oligonucleotides (ASOs) against mouse TMPRSS6. Downregulation of TMPRSS6 with ASO treatment resulted in dose-dependent hepcidin upregulation and reduction in serum iron and transferrin saturation in normal mice. In a mouse model of beta-thalassemia (th3/+ mice), which effectively recapitulates beta-thalassemia intermedia in humans, TMPRSS6 reduction resulted in induction of hepcidin and dramatic reductions of serum transferrin saturation (from 55-63% in control group down to 20-26% in treatment group). Liver iron concentration (LIC) was also greatly reduced (40-50%). Moreover, anemia endpoints were significantly improved with ASO treatment, including increases in red blood cells (~30-40%), hemoglobin (~2 g/dl), and hematocrit (~20%); reduction of splenomegaly; decreases in serum erythropoietin levels; improved erythroid maturation as indicated by a strong reduction in reticulocyte number and a normalized proportion between the pool of erythroblasts and enucleated erythroid cells. Encouraged by the strong pharmacology of TMPRSS6 suppression in animal models, we initiated an effort to identify a human TMPRSS6 clinical candidate with a liver-targeted delivery strategy. Over 2000 ASOs were screened in cell lines and the most active compounds were evaluated in rodent tolerability studies. A human TMPRSS6 transgenic mouse model was established enabling evaluation of ASO activity toward human TMPRSS6 transcript in vivo. Furthermore, lead compounds were tested in a 3-month study in normal monkeys. With repeated dosing, TMPRSS6 mRNA levels in monkey liver were reduced by >90%, accompanied by time-dependent reductions of serum iron (from ~100-120ug/dl to <40ug/dl), transferrin saturation (from ~30-35% to <10%), and hemoglobin. These compounds were well tolerated in rodents and in monkeys. Collectively, our data demonstrate that TMPRSS6 ASO could be an effective therapeutic for patients with beta-thalassemia and related disorders. A Phase 1 clinical trial is planned to initiate in 2016. Disclosures Guo: Isis Pharmaceuticals: Employment, Other: Shareholder. Aghajan:Isis Pharmaceuticals: Employment, Other: Shareholder. Booten:Isis Pharmaceuticals: Employment, Other: Shareholder. Monia:Isis Pharmaceuticals: Employment, Other: Shareholder.

scholarly journals Altered canonical hedgehog-gli signalling axis in pesticide-induced bone marrow aplasia mouse model

2012 ◽  
Vol 63 (3) ◽  
pp. 271-282 ◽  
Author(s):  
Malay Chaklader ◽  
Prosun Das ◽  
Jacintha Archana Pereira ◽  
Samaresh Chaudhuri ◽  
Sujata Law
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Pesticide Exposure ◽  
Receptor Expression ◽  
Human Beings ◽  
Bone Marrow Aplasia ◽  
Hedgehog Signalling ◽  
Pesticide Treatment ◽  
Wide Range

The mechanistic interplay between pesticide exposure and development of marrow aplasia is not yet well established but there are indices that chronic pesticide exposure in some instances causes marrow aplasia like haematopoietic degenerative condition in human beings. Canonical Hedgehog (Hh) signalling has multiple roles in a wide range of developmental processes, including haematopoiesis. The present study was designed to explore the status of four important components of the canonical Hedgehog signalling cascade, the Sonic Hedgehog (Shh), Ptch1, Smo, and Gli1, in a mouse model of chronic pesticide-induced bone marrow aplasia. We used 5 % aqueous mixture of pesticides (chlorpyriphos, prophenophos, cypermethrin, alpha-methrin, and hexaconazole) for inhalation and dermal exposure of 6 hours per day and 5 days a week up to 90 days. Murine bone marrow aplasia related to chronic pesticide treatment was confi rmed primarily by haemogram, bone marrow cellularity, short term bone marrow explant culture for cellular kinetics, bone marrow smear, and fl ow cytometric Lin-Sca-1+C-kit+ extracellular receptor expression pattern. Later, components of hedgehog signalling were analysed in the bone marrow of both control and pesticide-treated aplastic groups of animals. The results depicted pancytopenic feature of peripheral blood, developmental anomaly of neutrophils, depression of primitive stem and progenitor population along with Shh, Ptch1, Smo and Gli1 expression in aplasia group. This investigation suggests that pesticide-induced downregulation of two critically important proteins - Ptch1 and Gli1 - inside the haematopoietic stem and progenitor cell population impairs haematopoietic homeostasis and regeneration mechanism in vivo concurrent with bone marrow aplasia.

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