Left-right Pattern Research Articles

Ccdc141 is required for left-right axis development by regulating cilia formation in the Kupffer's vesicle of zebrafish

Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development. Defects in the process can result in severe organ mispositioning. Coiled-coil domain containing 141 (CCDC141) has been previously known as a centrosome-related gene, but its role in left-right (LR) asymmetry has not been characterized. In this study, we utilize the zebrafish model and human exome analysis to elucidate the function of ccdc141 in laterality defects. The knockdown of ccdc141 in zebrafish disrupts early LR signaling pathways, cilia function, and Kupffer's vesicle formation. Unlike ccdc141-knockdown embryos exhibiting aberrant LR patterns, ccdc141-null mutants show no apparent abnormality, suggesting a genetic compensation response effect. In parallel, we observe a marked reduction in α-tubulin acetylation levels in the ccdc141 crispants. The treatment with histone deacetylase (HDAC) inhibitors, particularly the HDAC6 inhibitor, rescues the ccdc141 crispant phenotypes. Furthermore, exome analysis of 70 patients with laterality defects reveals an increased burden of CCDC141 mutations, with in-vivo studies verifying the pathogenicity of the patient mutation CCDC141-R123G. Our findings highlight the critical role of ccdc141 in ciliogenesis and demonstrate that CCDC141 mutations lead to abnormal LR patterns, identifying it as a candidate gene for laterality defects.

A spatiotemporal barrier formed by Follistatin is required for left–right patterning

How left-right (LR) asymmetry emerges in a patterning field along the anterior-posterior axis remains an unresolved problem in developmental biology. Left-biased Nodal emanating from the LR organizer propagates from posterior to anterior (PA) and establishes the LR pattern of the whole embryo. However, little is known about the regulatory mechanism of the PA spread of Nodal and its asymmetric activation in the forebrain. Here, we identify bilaterally expressed Follistatin (Fst) as a regulator blocking the propagation of the zebrafish Nodal ortholog Southpaw (Spaw) in the right lateral plate mesoderm (LPM), and restricting Spaw transmission in the left LPM to facilitate the establishment of a robust LR asymmetric Nodal patterning. In addition, Fst inhibits the Activin-Nodal signaling pathway in the forebrain thus preventing Nodal activation prior to the arrival, at a later time, of Spaw emanating from the left LPM. This contributes to the orderly propagation of asymmetric Nodal activation along the PA axis. The LR regulation function of Fst is further confirmed in chick and frog embryos. Overall, our results suggest that a robust LR patterning emerges by counteracting a Fst barrier formed along the PA axis.

Adaptation of bilateral coordination of gait during split belt walking as reflected by the phase coordination index.

The Split belt treadmill (SBTM) has recently been used in research and rehabilitation to study and utilize gait adaptations. The Phase coordination index (PCI) is useful in assessing bilateral coordination of gait by quantifying the consistency and accuracy in generating the anti-phased left-right stepping pattern. Recently we proposed that 23 strides are sufficient to reliably characterize PCI values from regular over ground and treadmill walking RESEARCH QUESTION: Can we detect the effect of SBTM on PCI using only 23 gait cycles also from SBTM walking? Young healthy participants (n = 13) with right side motor dominance performed SBTM walking trials. Experiment protocol began by walking in tied belt (TB) mode, followed by an incremental speed increase of one of the belts by 50 % - split belt (SB) mode. This was performed for each side. Two 1-minute segments were analyzed per participant, TB and SB. PCI analysis was carried out upon fewer strides (n = 23) and compared to PCI that was obtained based on all available strides (n = 56 ± 5). Clear SBTM walking effects on PCI were seen in both experiments, for example, PCI increased from 4.46 ± 1.5 % (TB) to 10.07 ± 3.6 % (SB) for left belt speed increase. Twenty three strides from each trail were sufficient to demonstrate the effect. PCI can be a useful metric to characterize changes in bilateral coordination of gait during SBTM gait adaptations. The fact that 23 strides are sufficient for its reliable estimation, contribute to the continued monitoring through the adaptation process (i.e., by using time windows).

Wall shear stress angle determines aortic growth in patients with bicuspid aortic valves

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The Dutch Heart Foundation Background Patients with bicuspid aortic valve (BAV) have altered flow velocity patterns with different wall shear stress (WSS) distributions in the ascending aorta compared to patients with tricuspid aortic valves. These WSS distributions are associated with aortic dilatation in cross sectional studies, however, longitudinal data demonstrating a potential causative role is missing. Purpose The aim of this study was to assess the differences in WSS distributions between BAV patients and healthy subjects and to determine the predictive value of WSS for aortic growth in patients with a BAV. Methods Forty patients with a BAV and 32 healthy matched subjects were prospectively studied by 4D-flow cardiovascular magnetic resonance (CMR). Peak velocity, pulse wave velocity, aortic distensibility, peak systolic WSS (magnitude), the different WSS components (axial and circumferential), and WSS angle were assessed in the proximal ascending aorta. WSS angle was defined as the angle between the WSSmagnitude and WSSaxial component. In the BAV patients, aortic volumetric growth over three years was determined in the proximal ascending aorta (first 5cm) based on CT angiography. Multivariate linear regression analysis was used to identify independent predictors of aortic volumetric growth. Results Of the BAV patients, 21 (53%) had a left-right fusion pattern and eight patients had Turner syndrome. WSSaxial was significantly lower in BAV patients compared to healthy subjects (p = 0.008) and WSScircumferential and WSS angle were significantly higher (both p < 0.001, see Figure). WSSmagnitude, pulse wave velocity, and aorta distensibility were not statistically significant different. WSSmagnitude (0.69 N/m² [0.51-0.81] vs 1.08 N/m² [0.89-1.24], p = 0.005), WSSaxial (0.50 N/m² [0.39-0.61] vs 0.72 N/m² [0.54-0.94], p = 0.015) and WSScircumferential (0.34 N/m² [0.32-0.46] vs 0.64 N/m² [0.47-0.81], p = 0.008) were significantly lower in BAV Turner patients compared to BAV non-Turner patients, while WSS angle (40° [34-41] vs 40° [32-48], p = 0.607) was not statistically significant different. During a follow-up of three years, there was a significant growth of the proximal ascending aorta in the BAV patients (1.2 cm3 [-0.2-2.5], p = 0.001). In multivariate analysis corrected for baseline aortic volume and diastolic blood pressure, WSS angle was the only independent predictor for proximal aortic volume growth (β=0.108, p = 0.030). Conclusions Increased WSScircumferential and especially WSS angle are present in patients with BAV. WSS angle was the only independent predictor of aortic growth. These findings highlight the potential role of WSS measurements in patients with BAV to stratify patients at risk for aortic dilation.

CFD study of hull wakes in oblique flow at model and full scales

The characteristic of hull wake for a ship operating in oblique flow significantly affects the ship performance at off-design conditions. This paper presents a numerical study on the hull wakes under oblique flow conditions and analyzes the scale effect. RANS method combined with SST k-ω turbulence model is adopted and an international benchmark ship, Japan Bulk Carrier (JBC), is computed. Drift angles ranging from 0° to 20° with an interval of 5° are considered. Results show that the oblique flow considerably changes the hull wake field. Unlike a left-right symmetric pattern at zero drift angle, the nominal wake in oblique flow conditions shows a strong asymmetry since the flow at the windward side is close to the incoming flow whereas the flow at the leeward side is featured by the vortices detached from the hull. It is also revealed that the mean wake fraction decreases as the drift angle increases. Both model and full scales are simulated and the comparison between them shows significant differences in the wake pattern on the leeward side and the magnitude of the mean wake fraction. Compared with the model scale, the full scale has a stronger aft-body vortex and a smaller mean wake fraction.

Does the Leaflet Fusion Subtype Affect Pattern and Rate of Growth in BAV Aortopathy?: A Study of 102 BAV Aortopathy Cases With A Literature Review

Bicuspid aortic valves (BAV) and related aortopathy remain an intriguing topic. Not all BAVs get diseased and around 40% would develop aortic dilatation in their lifetime. If haemodynamic theory is to be believed, then leaflet fusion pattern should have an impact. This study sought to compare the association of aortic morphologies and rate of growth in a set of 102 BAV acropathies operated at a single centre, based on the fusion patterns. Data on aortic valve replacements over a 10-year period was analysed from a prospectively maintained database. Of the 198 BAV undergoing surgery, 102 had aortic dilatation above 40 mm on echocardiogram. These underwent computed tomography (CT) aortograms and were followed up as a part of a database. The impact of leaflet fusion patterns on aortic dilatation pattern and rate was analysed. Of the 102, two patients had type 0 pathology and one had left-noncoronary (LN) leaflet fusion. Seventy-four (74) had type 1A or left-right (RL) fusion and 25 had type 1B right-noncoronary (RN) fusion. RL fusion had more males, were taller, bigger and had more proportion of aortic stenosis (AS). Aortic diameters, angles and growth rates at root, ascending/descending aorta and arch were not different. Regression analyses for size or growth did not show any significant impact of fusion pattern. Left-right fusion pattern comprised three-quarters of BAV in this cohort and these patients were bigger, taller and had a greater proportion of males with increased rate of aortic stenosis. Despite these differences, there was no significant impact of fusion pattern on aortic size or rate of growth.

Alteration in the Global and Regional Left Ventricular and Right Ventricular Myocardial Strain Patterns in Patients with Inferior ST-Elevation Myocardial Infarction Early and Late after Percutaneous Coronary Intervention

Background: Precise evaluation of regional or global heart contractility is very important for the diagnosis, decision of treatment options, and prognosis of clinical outcomes in the Myocardial Ischemia (MI) and infarction. Aims: Evaluation of the regional or global distortion of Left Ventricle (LV) and Right Ventricle (RV) in cases with Inferior Wall Myocardial Ischemia (IWMI) early and late afterward percutaneous coronary treatment. Materials and Methods: This prospective study was conducted at Monofia University Hospital during the period from November 2017 till December 2019. The study included patients who presented to the cardiology department with inferior ST Segment Elevation MI (STEMI). Only 40 patients fulfilled the criteria of inclusion and were classified to 2 groups; Group I: include cases suffering from inferior STEMI. Group II (control): 20 healthy volunteer subjects. Results: This study showed that LV global strain were reduced with highly significant value in cases suffering from IWMI prior to Percutaneous Coronary Intervention (PCI) than in controls (-11.10±1.75 vs -19.84±1.37) P value <0.001 respectively While LV global strain was significantly improved in cases with post-PCI than pre-PCI (-15.86±1.50 vs -11.10 ±1.75) P value < 0.001 respectively. Conclusion: Reperfusion by PCI outcomes in significant recovery of LV and RV global strains, which are at most exist in the infarct and adjacent myocardium of apical and middle segments.

A temporal analysis of bilateral gait coordination in people with multiple sclerosis

Background: Gait performance often dictates an individual's ability to navigate the dynamic environments of everyday living. With each stride, the lower extremities move through phases of stance, swing, and double support. Coordinating these motions with high accuracy and consistency is imperative to constraining the center of mass within the base of support, thereby maintaining balance. Gait abnormalities accompany neurodegeneration, impeding stride to stride cohesion and increasing the likelihood of a fall. This study sought to identify the temporal actions underlying bilateral coordination in people with multiple sclerosis (PwMS) and furthermore, how bilateral coordination is affected by gait speed augmentation in these individuals. Methods: The Phase Coordination Index (PCI), a temporal analysis of left-right step pattern generations throughout the gait cycle was used to quantify bilateral coordination in twenty-nine neurotypical (21 females and 8 males) and twenty-seven PwMS (20 females and 7 males). PCI was acquired with inertial monitoring units while performing two-minute over ground gait trials while walking at a self-selected pace and at a fast pace. Results: PwMS displayed significantly worse bilateral coordination compared to neurotypical adults regardless of gait speed. The poorer left-right stepping patterns generated by PwMS were derived from significant decreases in both phase (step) generation accuracy and consistency. In addition to demonstrating poorer bilateral coordination, PwMS walked more slowly than their neurotypical peers during each walking condition. Conclusion: PwMS exhibited poorer left-right coordinated stepping patterns during gait compared to neurotypical peers across walking conditions. Beyond the novelty of this examination, this assessment highlights PCI as a potential target for future rehabilitative interventions for PwMS and individualized rehabilitation strategies aimed at improving the health span and overall quality of life for PwMS.

Left-right pigmentation pattern of Japanese flounder corresponds to expression levels of melanocortin receptors (MC1R and MC5R), but not to agouti signaling protein 1 (ASIP1) expression

Body coloration in flatfish is one of the most distinctive asymmetries in the animal kingdom, although the fundamental molecular mechanism of the pigmentation is unclear. In the dorso-ventral coloration (countershading) of other teleost fishes, ventral-specific expression of agouti signaling protein 1 (ASIP1), an endogenous antagonist of melanocortin 1 receptor (MC1R), has been reported to play a pivotal role. Contribution of ASIP1 is also suggested in the asymmetrical pigmentation of flatfish. In order to confirm the contribution of ASIP1 and further examine receptor function in the body coloration of Japanese flounder, expression levels of asip1, mc1r, melanocortin 5 receptor (mc5r), and melanin-concentrating hormone receptor 2 (mchr2) were measured in the normally pigmented area of the left side, the normally non-pigmented area of the right side, and the abnormally pigmented (exhibiting hypermelanosis) area of the right side. Measurement was also carried out under conditions of hypermelanosis stimulated by cortisol and during the transition from non-pigmentation to pigmentation in areas of hypermelanosis. Contrary to our expectations, no difference was detected in asip1 expression between pigmented and non-pigmented areas. There was also no difference between normal and hormonally stimulated pigmented conditions in areas of hypermelanosis or during the transition process. Instead, the expression levels of mc1r, mc5r, and mchr2 were consistently higher in pigmented areas, and were especially increased under hormonally stimulated conditions. In addition, expressions of these receptor genes increased prior to pigmentation in areas of future hypermelanosis. Our results suggest that MC1Rand MC5R, but not necessarily ASIP1, contribute to pigmentation and hypermelanosis in Japanese flounder. We propose a yet unknown molecular mechanism for asymmetrical pigmentation in flatfish that is distinct from that of countershading in other vertebrates.

How many strides are required for a reliable estimation of temporal gait parameters? Implementation of a new algorithm on the phase coordination index.

BackgroundThe Phase coordination index (PCI), a temporal gait measure that quantifies consistency and accuracy in generating the anti-phased left-right stepping pattern, assesses bilateral coordination of gait in various cohorts (e.g., Parkinson's disease, post stroke). As PCI is based on mean values calculated across a series of gait cycles, individuals are required to perform lengthy walking trials, prolonging gait assessments which cause discomfort to some of them. This study introduces an algorithm to identify the required number of strides to obtain a reliable, characteristic PCI value.MethodsSimulated data sets, as well as physiological data (obtained from healthy elderly and young persons, from over ground and treadmill trials) were used in this research. A series of N-1 PCI values was calculated for i = 2,3,4…N gait cycles for each participant. There is a value i = k, representing certain number of cycles, for which no significant change in PCI occurs as additional cycles are added, termed point of stabilization (POS). The algorithm presented here uses a 2-stage iterative process to determine POS. Stage 1 searches for the gross location of the interval of PCI values containing the POS. In stage 2, the algorithm performs a high-resolution recursive, iterative process within this interval to find the exact point. The criterion for defining stability within a window of PCI values is a coefficient of variation (CV) of ≤ 5%.ResultsOur recursive, iterative algorithm indicates that ~23 strides on average should be captured to attain a characteristic PCI.ConclusionsGait trials with at least 23 strides on average should suffice to obtain a reliable estimation of PCI in healthy young adults. While this methodology may be considered generic, future studies should obtain POS values based on additional cohorts (e.g., disabled participants, fixed walking speeds).

A unique pattern of cortical connectivity characterizes patients with attention deficit disorders: a large electroencephalographic coherence study

BackgroundAttentional disorders (ADD) feature decreased attention span, impulsivity, and over-activity interfering with successful lives. Childhood onset ADD frequently persists to adulthood. Etiology may be hereditary or disease associated. Prevalence is 5% but recognition may be ‘overshadowed’ by comorbidities (brain injury, mood disorder) thereby escaping formal recognition. Blinded diagnosis by MRI has failed. ADD may not itself manifest a single anatomical pattern of brain abnormality but may reflect multiple, unique responses to numerous and diverse etiologies. Alternatively, a stable ADD-specific brain pattern may be better detected by brain physiology. EEG coherence, measuring cortical connectivity, is used to explore this possibility.MethodsParticipants: Ages 2 to 22 years; 347 ADD and 619 neurotypical controls (CON). Following artifact reduction, principal components analysis (PCA) identifies coherence factors with unique loading patterns. Discriminant function analysis (DFA) determines discrimination success differentiating ADD from CON. Split-half and jackknife analyses estimate prospective diagnostic success. Coherence factor loading constitutes an ADD-specific pattern or ‘connectome’. ResultsPCA identified 40 factors explaining 50% of total variance. DFA on CON versus ADD groups utilizing all factors was highly significant (p≤0.0001). ADD subjects were separated into medication and comorbidity subgroups. DFA (stepping allowed) based on CON versus ADD without comorbidities or medication treatment successfully classified the correspondingly held out ADD subjects in every instance. Ten randomly generated split-half replications of the entire population demonstrated high-average classification success for each of the left out test-sets (overall: CON, 83.65%; ADD, 90.07%). Higher success was obtained with more restricted age sub-samples using jackknifing: 2-8 year olds (CON, 90.0%; ADD, 90.6%); 8-14 year olds (CON, 96.8%; ADD 95.9%); and 14-20 year-olds (CON, 100.0%; ADD, 97.1%). The connectome manifested decreased and increased coherence. Patterns were complex and bi-hemispheric; typically reported front-back and left-right loading patterns were not observed. Subtemporal electrodes (seldom utilized) were prominently involved. ConclusionsResults demonstrate a stable coherence connectome differentiating ADD from CON subjects including subgroups with and without comorbidities and/or medications. This functional ‘connectome’, constitutes a diagnostic ADD phenotype. Split-half replications support potential for EEG-based ADD diagnosis, with increased accuracy using limited age ranges. Repeated studies could assist recognition of physiological change from interventions (pharmacological, behavioral).

Transcriptome-wide analysis reveals candidate genes responsible for the asymmetric pigment pattern in scallop Patinopecten yessoensis

Yesso scallop Patinopecten yessoensis is an economically important marine bivalve species in aquaculture and fishery in Asian countries. The colors of the left and right shells are obviously distinct, typically having reddish-brown for the left and white for the right. This left-right asymmetric pigment pattern is a very unique phenomenon among invertebrates, whereas the molecular mechanisms that control regional differences in pigmentation are not clear. To better understand the left-right asymmetric pigment pattern, we apply Illumina digital gene expression (DGE) to characterize the gene expression profiles in left and right mantle tissues, and identify five differentially expressed genes, including Cytochrome P450 and other four unknown genes. Among the five genes, one gene shows significantly higher expression in the right mantle, while other four exhibit significantly higher expression in the left mantle. We further validate the DGE results by using quantitative real-time PCR for P450, resulting in approximately 32-fold higher expression in the left mantle than that in the right mantle. These findings will not only help assist our understanding of the sophisticated processes of shell pigmentation in scallops, but also provide new insights into the adaptive evolution of phenotypes to maximize survival that underlie the left-right asymmetric pigment pattern in molluscs.

Both ciliary and non-ciliary functions of Foxj1a confer Wnt/β-catenin signaling in zebrafish left-right patterning.

ABSTRACTThe Wnt/β-catenin pathway is implicated in left-right (LR) axis determination; however, the underlying mechanism remains elusive. Prompted by our recent discovery that Wnt signaling regulates ciliogenesis in the zebrafish Kupffer's vesicle (KV) via Foxj1a, a ciliogenic transcription factor, we decided to elucidate functions of Foxj1a in Wnt-regulated LR pattern formation. We showed that targeted injection of wnt8a mRNA into a single cell at the 128-cell stage is sufficient to induce ectopic foxj1a expression and ectopic cilia. By interrogating the transcription circuit of foxj1a regulation, we found that both Lef1 and Tcf7 bind to a consensus element in the foxj1a promoter region. Depletion of Lef1 and Tcf7 inhibits foxj1a transcription in the dorsal forerunner cells, downregulates cilia length and number in KV, and randomizes LR asymmetry. Targeted overexpression of a constitutively active form of Lef1 also induced an ectopic protrusion that contains ectopic transcripts for sox17, foxj1a, and charon, and ectopic monocilia. Further genetic studies using this ectopic expression platform revealed two distinct functions of Foxj1a; mediating Wnt-governed monocilia length elongation as well as charon transcription. The novel Foxj1a-charon regulation is conserved in KV, and importantly, it is independent of the canonical role of Foxj1a in the biosynthesis of motile cilia. Together with the known function of motile cilia movement in generating asymmetric expression of charon, our data put forward a hypothesis that Foxj1a confers both ciliary and non-ciliary functions of Wnt signaling, which converge on charon to regulate LR pattern formation.

Organization of left-right coordination of neuronal activity in the mammalian spinal cord: Insights from computational modelling.

Coordination of neuronal activity between left and right sides of the mammalian spinal cord is provided by several sets of commissural interneurons (CINs) whose axons cross the midline. Genetically identified inhibitory V0D and excitatory V0V CINs and ipsilaterally projecting excitatory V2a interneurons were shown to secure left-right alternation at different locomotor speeds. We have developed computational models of neuronal circuits in the spinal cord that include left and right rhythm-generating centres interacting bilaterally via three parallel pathways mediated by V0D , V2a-V0V and V3 neuron populations. The models reproduce the experimentally observed speed-dependent left-right coordination in normal mice and the changes in coordination seen in mutants lacking specific neuron classes. The models propose an explanation for several experimental results and provide insights into the organization of the spinal locomotor network and parallel CIN pathways involved in gait control at different locomotor speeds. Different locomotor gaits in mammals, such as walking or galloping, are produced by coordinated activity in neuronal circuits in the spinal cord. Coordination of neuronal activity between left and right sides of the cord is provided by commissural interneurons (CINs), whose axons cross the midline. In this study, we construct and analyse two computational models of spinal locomotor circuits consisting of left and right rhythm generators interacting bilaterally via several neuronal pathways mediated by different CINs. The CIN populations incorporated in the models include the genetically identified inhibitory (V0D ) and excitatory (V0V ) subtypes of V0 CINs and excitatory V3 CINs. The model also includes the ipsilaterally projecting excitatory V2a interneurons mediating excitatory drive to the V0V CINs. The proposed network architectures and CIN connectivity allow the models to closely reproduce and suggest mechanistic explanations for several experimental observations. These phenomena include: different speed-dependent contributions of V0D and V0V CINs and V2a interneurons to left-right alternation of neural activity, switching gaits between the left-right alternating walking-like activity and the left-right synchronous hopping-like pattern in mutants lacking specific neuron classes, and speed-dependent asymmetric changes of flexor and extensor phase durations. The models provide insights into the architecture of spinal network and the organization of parallel inhibitory and excitatory CIN pathways and suggest explanations for how these pathways maintain alternating and synchronous gaits at different locomotor speeds. The models propose testable predictions about the neural organization and operation of mammalian locomotor circuits.

Evaluation the immediate effects of bracing on kinetic parameters in adolescent idiopathic scoliosis patients

Background Idiopathic scoliosis induces change in coordination between body segments, spinal anatomy, left-right trunk symmetry and gait pattern. Various treatment methods have being used for scoliosis which includes: physical therapy, occupational therapy, osteopathic therapy, casting, bracing and surgery. However, using brace is a commonly used method in this regard. Although, the influence of brace to reduce the scoliosis curve has been investigated in lots of research studies, there is not enough research regarding the influence of brace on performance of scoliotic subjects while walking and standing. Therefore, the purpose of this study was to evaluate the immediate effect of brace on stability performance of scoliotic subjects and the symmetry of the ground reaction force applied on the right and left feet while walking. Method Then girls aged between 8 and 12 years were recruited in this study. The gait analysis was assessed using a three-dimensional motion analysis and a force plate (Kistler) in two conditions, with and without Boston brace. Moreover their stability was evaluated by use of force plate. The difference of kinetic and stability parameters between two conditions(with and without Boston brace)was checked by use of paired T-test. Results

Mathematical modeling and analysis of spinal circuits involved in locomotor pattern generation and frequency-dependent left-right coordination

Coordination between left and right neural activities in the spinal cord during locomotion is controlled by commissural interneurons (CINs). Several CIN types have been genetically identified, including the excitatory V3 and excitatory and inhibitory V0 types. Talpalar et al. [1] recently reported that genetic elimination of the V0 CINs caused switching from a normal left-right alternating pattern of motor activity to a left-right synchronized “hopping” pattern. Furthermore, ablation of only the inhibitory V0 neurons (V0D subtype) resulted in a lack of left-right alternation at low locomotor frequencies and maintaining this alternation at high frequencies, whereas selective ablation of the excitatory V0 neurons (V0V subtype) maintained the left–right alternation at low locomotor frequencies and switched the motor output to a left-right synchronized (hopping) pattern at high frequencies. To analyze and explain the above findings, we developed a simplified mathematical model of neural circuits consisted of four pacemaker neurons representing left (LF) and right (RF) flexor and left (LE) and right (RE) extensor half-centers interacting via commissural pathways representing V3, V0D, and V0V CINs (Fig. ​(Fig.1).1). The “locomotor” frequency in the model was controlled by a parameter defining the excitability of neurons (via the leak reversal potentials) and commissural pathways, whose changes represented the corresponding changes induced by changing the concentration of N-methyl-D-aspartate (NMDA) applied to control the locomotor frequency in the isolated rodent spinal cord preparations [1]. Figure 1 Model schematic. The model demonstrated: (1) a typical left-right alternating pattern under control conditions; (2) switching to a synchronized hopping activity at any frequency after removing commissural connections representing both V0 (V0D and V0V) neurons; (3) a synchronized left-right pattern at low frequencies and left-right alternation of activity at high frequencies after removing the commissural connections representing V0D neurons; (4) an alternating left-right pattern at low frequencies with synchronized hopping at high frequencies after removing the commissural connections representing V0V neurons. We used the bifurcation and fast–slow decomposition methods to analyze the behavior of this network in the four above states/regimes and transitions between them. The model was able to reproduce and provide explanation to several important experimental phenomena and generated predictions that can be tested experimentally.

Two interconnected kernels of reciprocally inhibitory interneurons underlie alternating left-right swim motor pattern generation in the mollusk Melibe leonina

The central pattern generator (CPG) underlying the rhythmic swimming behavior of the nudibranch Melibe leonina (Mollusca, Gastropoda, Heterobranchia) has been described as a simple half-center oscillator consisting of two reciprocally inhibitory pairs of interneurons called swim interneuron 1 (Si1) and swim interneuron 2 (Si2). In this study, we identified two additional pairs of interneurons that are part of the swim CPG: swim interneuron 3 (Si3) and swim interneuron 4 (Si4). The somata of Si3 and Si4 were both located in the pedal ganglion, near that of Si2, and both had axons that projected through the pedal commissure to the contralateral pedal ganglion. These neurons fulfilled the criteria for inclusion as members of the swim CPG: 1) they fired at a fixed phase in relation to Si1 and Si2, 2) brief changes in their activity reset the motor pattern, 3) prolonged changes in their activity altered the periodicity of the motor pattern, 4) they had monosynaptic connections with each other and with Si1 and Si2, and 5) their synaptic actions helped explain the phasing of the motor pattern. The results of this study show that the motor pattern has more complex internal dynamics than a simple left/right alternation of firing; the CPG circuit appears to be composed of two kernels of reciprocally inhibitory neurons, one consisting of Si1, Si2, and the contralateral Si4 and the other consisting of Si3. These two kernels interact with each other to produce a stable rhythmic motor pattern.

Flight Attitudes and Spray Patterns of a Roll-Balanced Agricultural Unmanned Helicopter

<abstract><title><italic>Abstract. </italic></title> Unmanned agricultural helicopters have certainly made precise and timely aerial spraying possible in Korean farming. A rotorcraft system depends on various dynamic factors for a roll-balanced maneuver. Even with the aid of an autopilot system, conventional agricultural helicopters cannot maintain a lateral balance due to issues with physical dynamics. Most agricultural helicopters exhibit biased downwash, resulting in an uneven spray pattern. To address this problem, a roll-balanced agricultural helicopter with an elevated-pylon tail rotor system was developed (Koo et al., 2010). In this study, we evaluated the effectiveness of a roll balanced helicopter during hovering and cruising spray maneuvers by analyzing flight attitudes and spray patterns. The hovering spray was performed at a height of 3.5 m, and the pattern was determined by a string deposition analysis system. The practical cruise spray maneuver was performed at a 50-m long cultivating field, and the pattern was acquired using water sensitive strips. Spray deposits from the left and right sides of the fuselage were compared and evaluated. For the hovering and cruise spray maneuvers, fluctuations in the roll and pitch angles were found for both the manual pilot and autopilot operations. However, the average values of roll angle were maintained at 0°, supporting the lateral balance. The spray patterns and roll attitudes under conditions of hovering and cruising were steadily balanced. The uniformity of the spray patterns with the roll-balanced helicopter was satisfactory in both manual pilot and autopilot operations. Consequently, the balancing behavior of the developed helicopter resulted in left-right balanced spray patterns with coverage rates of 20% to 25% during aerial applications.

Dual-mode operation of neuronal networks involved in left–right alternation

All forms of locomotion are repetitive motor activities that require coordinated bilateral activation of muscles. The executive elements of locomotor control are networks of spinal neurons that determine gait pattern through the sequential activation of motor-neuron pools on either side of the body axis. However, little is known about the constraints that link left-right coordination to locomotor speed. Recent advances have indicated that both excitatory and inhibitory commissural neurons may be involved in left-right coordination. But the neural underpinnings of this, and a possible causal link between these different groups of commissural neurons and left-right alternation, are lacking. Here we show, using intersectional mouse genetics, that ablation of a group of transcriptionally defined commissural neurons--the V0 population--leads to a quadrupedal hopping at all frequencies of locomotion. The selective ablation of inhibitory V0 neurons leads to a lack of left-right pattern at low frequencies, mixed coordination at medium frequencies, and alternation at high locomotor frequencies. When ablation is targeted to excitatory V0 neurons, left-right alternation is present at low frequencies, and hopping is restricted to medium and high locomotor frequencies. Therefore, the intrinsic logic of the central control of locomotion incorporates a modular organization, with two subgroups of V0 neurons required for the existence of left-right alternating modes at different speeds of locomotion. The two molecularly distinct sets of commissural neurons may constrain species-related naturally occurring frequency-dependent coordination and be involved in the evolution of different gaits.

Impaired Cerebellar and Limbic Responses to the Valsalva Maneuver in Heart Failure

Heart failure (HF) patients show an inability to regulate autonomic functions, a characteristic which is associated with increased mortality. These autonomic deficits may stem from earlier demonstrated injury to central autonomic regulatory areas, providing a structural basis for the autonomic abnormalities. However, knowledge of structural injury provides insufficient insights into timing and magnitude of signal patterns within affected areas which lead to impaired autonomic outflow. Among damaged brain areas, cerebellar sites are key for timely coordination of sympathetic and parasympathetic attributes, and for dampening extremes of hypotension and hypertension induced by other injured sites, including hypothalamic and limbic areas. We collected functional magnetic resonance imaging (fMRI) signals in cerebellar and limbic areas to characterize amplitude and timing patterns of neural responses to the Valsalva maneuver, an autonomic challenge that elicits sequential sympathetic and parasympathetic responses, in 16 HF patients and 33 control subjects. HF patients showed distorted fMRI signal patterns during the challenge period in the cerebellar vermis, left cerebellar crus II, and left insula, whereas the right crus II and insula, and bilateral amygdalae showed normal patterns. However, all structures, except the left crus II, showed altered responses in HF during the recovery period. Crus II patterns reflected a failure of HF subjects to demonstrate the normal lateralized responses, while in the insula, HF subjects exhibited abnormal left-right patterns, relative to controls. The abnormal timing and response patterns in these injured areas critical for autonomic regulation likely contribute to the enhanced sympathetic outflow and autonomic dysfunction characteristic of HF.