Functional organisation of anterior thoracic stretch receptors in the deep-sea isopod Bathynomus doederleini: Behavioural, morphological and physiological studies

The relationship between segmental mobility and the organisation of thoracic stretch receptors was examined in the deep-sea isopod Bathynomus doederleini, which shows a developed adaptive behaviour during digging. The movements of segments during digging were analysed from video recordings, which showed that a large excursion occurred in the anterior thoracic segments. Dyefills of axons revealed four types of thoracic stretch receptor (TSR): an N-cell type (TSR-1), a differentiated Ncell type (TSR-2), a muscle receptor organ (MRO)-type with a long, single receptor muscle (TSR-3) and an MROtype with a short, single receptor muscle (TSR-4 to TSR-7). Physiologically, TSR-1 and TSR-2 are tonic-type stretch receptors. TSR-3 to TSR-7 show two kinds of stretchactivated responses, a tonic response and a phasico-tonic response in which responses are maintained as long as the stretch stimulus is delivered. Both TSR-2, with a long muscle strand, and TSR-3, with a single, long receptor muscle, have a wide dynamic range in their stretchactivated response. In addition, TSR-2 is controlled by an intersegmental inhibitory reflex from TSR-3. These results suggest that, although TSR-1 has no receptor muscle and TSR-2 has a less-differentiated receptor-like muscle, they are fully functional position detectors of segmental movements, as are the MRO-type receptors TSR-3 to TSR-7.</p

Peripheral targets of centrally located putative accessory neurons of MRO in the isopod Ligia exotica

The three centrally located putative accessory neurons of the muscle receptor organ (MRO) of the isopod Ligia exotica were identified to the third segmental nerve (N3) of the thoracic ganglion by backfilling with Lucifer Yellow. These neurons were then studied intracellularly and extracellularly to determine whether they suppressed the stretch-activated responses of thoracic stretch receptors. Intracellular injection of depolarizing currents into these three putative accessory neurons revealed that only neuron #3 had an inhibitory effect, suggesting that it is an inhibitory accessory neuron related to thoracic stretch receptors. We searched for the peripheral targets of neurons #1 and #2 by intracellular filling with Lucifer Yellow or by recording of junctional potentials in extensor muscles, and show that they are motor neurons that innervate the deep extensor and superficial extensor muscles, respectively.</p

Circadian Rhythms of Atrioventricular Conduction Properties in Chronic Atrial Fibrillation With and Without Heart Failure

AbstractObjectives. We examined the circadian variations in atrioventricular (AV) conduction properties during atrial fibrillation (AF) by a technique based on the Lorenz plot of successive ventricular response (VR) intervals and analyzed their relations with clinical features.Background. The VR interval in chronic AF shows circadian variation, which is attenuated in patients with an increased risk of death. Although the VR interval is determined by the dynamic processes in the AV node randomly stimulated by rapid atrial activity, the circadian variations of the AV conduction properties related to this mechanism are unknown.Methods. In 48 patients with chronic AF, Lorenz plots were generated on overlapping sequential segments of 512 VR intervals in 24-h ambulatory electrocardiograms. For each scatter plot, the 1.0-s intercept of the lower envelope (LE1.0) of the plot and the degree of scatter above the envelope (root mean square difference from the envelope [scattering index]) were measured for estimating AV node refractoriness and concealed AV conduction, respectively.Results. In all patients, a significant circadian rhythm was observed for the average VR interval, LE1.0and scattering index, with an acrophase occurring at night. The mesor, amplitude and acrophase of LE1.0and the scattering index closely and independently correlated with the corresponding rhythm variables of the average VR interval (partial r20.98, 0.86 and 0.68 for LE1.0and 0.98, 0.92 and 0.92 for scattering index). The amplitudes of these measures were lower in patients with congestive heart failure (CHF) even after adjustment for the effects of age, duration of AF, medications, left atrial diameter and blood pressure (p < 0.01 for all).Conclusions. These results suggest that 1) both AV node refractoriness and the degree of concealed AV conduction during AF may show a circadian rhythm; 2) the circadian rhythms of these properties may independently contribute to the circadian variation of the VR interval; and 3) these circadian rhythms may be attenuated in patients with CHF

Minimum oxygen cost of human walking with geometrically similar leg movements

The mechanism by which the expenditure of oxygen to walk per unit distance at an intermediate speed is minimized, by definition optimal walking, was investigated to characterize optimal walking in humans with variations in individual walking speeds. Oxygen uptake and step rate（SR）were measured among 7 young male subjects walking at an increasing speed from 16.7 to 131.7 m min−1 with 5 m min−1 increments every 1 min on a level treadmill. Measurements of leg length（L）were also made and step length（SL）was calculated by dividing walking speed by SR. The hip joint angle（θ）was calculated as a function of both L and SL such that θ＝2sin−［1 SL（／ 2L）］ deduced from a mathematical geometrically similar model of pendulum−like legs. The minimum oxygen cost to walk per unit distance for each subject was observed over a wide range of speeds from 60 to 100 m min−1.However, the oxygen cost of walking for all the subjects was minimized during a step cycle through a hip−joint angle of about 46 deg in the astride position, regardless of L. The stifflegged model demonstrated that the pathway of the trunk during optimal walking with a swing leg angle of 46 deg was approximately maintained at an even level by the counteracting effects of the leg decline and the heel rise. These results suggest that the minimum oxygen cost of transport during optimal walking was achieved by the mechanism underlying the maximum interchange between the gravitational−potential and kinetic energy for the body with an even level of the trunk that reduces extra muscular work needed against internal and external resistance, as well as against gravit

Essential Role of the \u3ci\u3eCrk\u3c/i\u3e Family-Dosage in DiGeorge-Like Anomaly and Metabolic Homeostasis

CRK and CRKL (CRK-like) encode adapter proteins with similar biochemical properties. Here, we show that a 50% reduction of the family-combined dosage generates developmental defects, including aspects of DiGeorge/del22q11 syndrome in mice. Like the mouse homologs of two 22q11.21 genes CRKL and TBX1, Crk and Tbx1 also genetically interact, thus suggesting that pathways shared by the three genes participate in organogenesis affected in the syndrome. We also show that Crk and Crkl are required during mesoderm development, and Crk/Crkl deficiency results in small cell size and abnormal mesenchyme behavior in primary embryonic fibroblasts. Our systems-wide analyses reveal impaired glycolysis, associated with low Hif1a protein levels as well as reduced histone H3K27 acetylation in several key glycolysis genes. Furthermore, Crk/Crkl deficiency sensitizes MEFs to 2deoxy-D-glucose, a competitive inhibitor of glycolysis, to induce cell blebbing. Activated Rapgef1, a Crk/Crkl-downstream effector, rescues several aspects of the cell phenotype, including proliferation, cell size, focal adhesions, and phosphorylation of p70 S6k1 and ribosomal protein S6. Our investigations demonstrate that Crk/Crkl-shared pathways orchestrate metabolic homeostasis and cell behavior through widespread epigenetic controls

Nanogel-Based PspA Intranasal Vaccine Prevents Invasive Disease and Nasal Colonization by Streptococcus pneumoniae

ABSTRACT To establish a safer and more effective vaccine against pneumococcal respiratory infections, current knowledge regarding the antigens common among pneumococcal strains and improvements to the system for delivering these antigens across the mucosal barrier must be integrated. We developed a pneumococcal vaccine that combines the advantages of pneumococcal surface protein A (PspA) with a nontoxic intranasal vaccine delivery system based on a nanometer-sized hydrogel (nanogel) consisting of a cationic cholesteryl group-bearing pullulan (cCHP). The efficacy of the nanogel-based PspA nasal vaccine (cCHP-PspA) was tested in murine pneumococcal airway infection models. Intranasal vaccination with cCHP-PspA provided protective immunity against lethal challenge with Streptococcus pneumoniae Xen10, reduced colonization and invasion by bacteria in the upper and lower respiratory tracts, and induced systemic and nasal mucosal Th17 responses, high levels of PspA-specific serum immunoglobulin G (IgG), and nasal and bronchial IgA antibody responses. Moreover, there was no sign of PspA delivery by nanogel to either the olfactory bulbs or the central nervous system after intranasal administration. These results demonstrate the effectiveness and safety of the nanogel-based PspA nasal vaccine system as a universal mucosal vaccine against pneumococcal respiratory infection

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout

Peptide Array X-Linking (PAX): A New Peptide-Protein Identification Approach

Many protein interaction domains bind short peptides based on canonical sequence consensus motifs. Here we report the development of a peptide array-based proteomics tool to identify proteins directly interacting with ligand peptides from cell lysates. Array-formatted bait peptides containing an amino acid-derived cross-linker are photo-induced to crosslink with interacting proteins from lysates of interest. Indirect associations are removed by high stringency washes under denaturing conditions. Covalently trapped proteins are subsequently identified by LC-MS/MS and screened by cluster analysis and domain scanning. We apply this methodology to peptides with different proline-containing consensus sequences and show successful identifications from brain lysates of known and novel proteins containing polyproline motif-binding domains such as EH, EVH1, SH3, WW domains. These results suggest the capacity of arrayed peptide ligands to capture and subsequently identify proteins by mass spectrometry is relatively broad and robust. Additionally, the approach is rapid and applicable to cell or tissue fractions from any source, making the approach a flexible tool for initial protein-protein interaction discovery.National Institutes of Health (U.S.) (Grant R21-CA-140030-01