Electromechanical coupling and anatomy of the in vivo gastroduodenal junction.

Few biomarkers support the diagnosis and treatment of disorders of gut-brain interaction (DGBI), although gastroduodenal junction (GDJ) electromechanical coupling is a target for novel interventions. Rhythmic "slow waves," generated by interstitial cells of Cajal (ICC), and myogenic "spikes" are bioelectrical mechanisms underpinning motility. In this study, simultaneous in vivo high-resolution electrophysiological and impedance planimetry measurements were paired with immunohistochemistry to elucidate GDJ electromechanical coupling. Following ethical approval, the GDJ of anaesthetized pigs (n = 12) was exposed. Anatomically specific, high-resolution electrode arrays (256 electrodes) were applied to the serosa. EndoFLIP catheters (16 electrodes; Medtronic, MN) were positioned luminally to estimate diameter. Postmortem tissue samples were stained with Masson's trichrome and Ano1 to quantify musculature and ICC. Electrical mapping captured slow waves (n = 512) and spikes (n = 1,071). Contractions paralleled electrical patterns. Localized slow waves and spikes preceded rhythmic contractions of the antrum and nonrhythmic contractions of the duodenum. Slow-wave and spike amplitudes were correlated in the antrum (r = 0.74, P < 0.001) and duodenum (r = 0.42, P < 0.001). Slow-wave and contractile amplitudes were correlated in the antrum (r = 0.48, P < 0.001) and duodenum (r = 0.35, P < 0.001). Distinct longitudinal and circular muscle layers of the antrum and duodenum had a total thickness of (2.8 ± 0.9) mm and (0.4 ± 0.1) mm, respectively. At the pylorus, muscle layers merged and thickened to (3.5 ± 1.6) mm. Pyloric myenteric ICC covered less area (1.5 ± 1.1%) compared with the antrum (4.2 ± 3.0%) and duodenum (5.3 ± 2.8%). Further characterization of electromechanical coupling and ICC biopsies may generate DGBI biomarkers.NEW & NOTEWORTHY This study applies electrical mapping, impedance planimetry, and histological techniques to the gastroduodenal junction to elucidate electromechanical coupling in vivo. Contractions of the terminal antrum and pyloric sphincter were associated with gastric slow waves. In the duodenum, bursts of spike activity triggered oscillating contractions. The relative sparsity of myenteric interstitial cells of Cajal in the pylorus, compared with the adjacent antrum and duodenum, is hypothesized to prevent coupling between antral and duodenal slow waves.

Pulsed-field ablation: an alternative ablative method for gastric electrophysiological intervention.

Pulsed-field ablation (PFA) is an emerging ablative technology that has been used successfully to eliminate cardiac arrhythmias. As a nonthermal technique, it has significant benefits over traditional radiofrequency ablation with improved target tissue specificity and reduced risk of adverse events during cardiac applications. We investigated whether PFA is safe for use in the stomach and whether it could modulate gastric slow waves. Female weaner pigs were fasted overnight before anesthesia was induced using tiletamine hydrochloride (50 mg·mL-1) and zolazepam hydrochloride (50 mg·mL-1) and maintained with propofol (Diprivan 2%, 0.2-0.4 mg·kg-1·min-1). Pulsed-field ablation was performed on their gastric serosa in vivo. Adjacent point lesions (n = 2-4) were used to create a linear injury using bipolar pulsed-field ablation consisting of 40 pulses (10 Hz frequency, 0.1 ms pulse width, 1,000 V amplitude). High-resolution electrical mapping defined baseline and postablation gastric slow-wave patterns. A validated five-point scale was used to evaluate tissue damage in hematoxylin and eosin-stained images. Results indicated that PFA successfully induced complete conduction blocks in all cases, with lesions through the entire thickness of the gastric muscle layers. Consistent postablation slow-wave patterns emerged immediately following ablation and persisted over the study period. Pulsed-field ablation induces rapid conduction blocks as a tool to modulate slow-wave patterns, indicating it may be suitable as an alternative to radiofrequency ablation.NEW & NOTEWORTHY Results show that pulsed-field ablation can serve as a gastric slow-wave intervention by preventing slow-wave propagation across the lesion site. Stable conduction blocks were established immediately following energy delivery, faster than previous examples of radiofrequency gastric ablation. Pulsed-field ablation may be an alternative for gastric slow-wave intervention, and further functional and posthealing studies are now warranted.

Spatial response of jejunal pacing defined by a novel high-resolution multielectrode array.

Gastric pacing has shown preclinical success in modulating bioelectrical slow-wave activity and has potential as a novel therapy for functional motility disorders. However, the translation of pacing techniques to the small intestine remains preliminary. This paper presents the first high-resolution framework for simultaneous pacing and response mapping of the small intestine. A novel surface-contact electrode array, capable of simultaneous pacing and high-resolution mapping of the pacing response, was developed and applied in vivo on the proximal jejunum of pigs. Pacing parameters including the input energy and pacing electrode orientation were systematically evaluated, and the efficacy of pacing was determined by analyzing spatiotemporal characteristics of entrained slow waves. Histological analysis was conducted to determine if the pacing resulted in tissue damage. A total of 54 studies were conducted on 11 pigs, and pacemaker propagation patterns were successfully achieved at both low (2 mA, 50 ms) and high (4 mA, 100 ms) energy levels with the pacing electrodes oriented in the antegrade, retrograde, and circumferential directions. The high energy level performed significantly better (P = 0.014) in achieving spatial entrainment. Comparable success (greater than 70%) was achieved when pacing in the circumferential and antegrade pacing directions, and no tissue damage was observed at the pacing sites. This study defined the spatial response of small intestine pacing in vivo revealing effective pacing parameters for slow-wave entrainment in the jejunum. Intestinal pacing now awaits translation to restore disordered slow-wave activity associated with motility disorders.NEW & NOTEWORTHY A novel surface-contact electrode array customized for the small intestine anatomy enabled simultaneous pacing and high-resolution response mapping. The spatial response of small intestine bioelectrical activity to pacing was mapped for the first time in vivo. Antegrade and circumferential pacing achieved spatial entrainment over 70% of the time and their induced pattern was held for 4-6 cycles postpacing at high energy (4 mA, 100 ms, at ∼2.7 s which corresponds to 1.1 × intrinsic frequency).

Power-Controlled, Irrigated Radio-Frequency Ablation of Gastric Tissue: A Biophysical Analysis of Lesion Formation.

BACKGROUND: Radio-frequency ablation of gastric tissue is in its infancy compared to its extensive history and use in the cardiac field. AIMS: We employed power-controlled, irrigated radio-frequency ablation to create lesions on the serosal surface of the stomach to examine the impact of ablation power, irrigation, temperature, and impedance on lesion formation and tissue damage. METHODS: A total of 160 lesions were created in vivo in female weaner pigs (n = 5) using a combination of four power levels (10, 15, 20, 30 W) at two irrigation rates (2, 5 mL min-1) and with one temperature-controlled (65 °C) reference setting previously validated for electrophysiological intervention in the stomach. RESULTS: Power and irrigation rate combinations above 15 W resulted in lesions with significantly higher surface area and depth than the temperature-controlled setting. Irrigation resulted in significantly lower temperature (p < 0.001) and impedance (p < 0.001) compared to the temperature-controlled setting. No instances of perforation or tissue pop were recorded for any ablation sequence. CONCLUSION: Power-controlled, irrigated radio-frequency ablation of gastric tissue is effective in creating larger and deeper lesions at reduced temperatures than previously investigated temperature-controlled radio-frequency ablation, highlighting a substantial improvement. These data define the biophysical impact of ablation parameters in gastric tissue, and they will guide future translation toward clinical application and in silico gastric ablation modeling. Combination of ablation settings (10-30 W power, 2-5 mL min-1 irrigation) were used to create serosal spot lesions. Histological analysis of lesions quantified localized tissue damage.

The bioelectrical conduction system around the ileocecal junction defined through in vivo high-resolution mapping in rabbits.

Coordinated contractions across the small and large intestines via the ileocecal junction (ICJ) are critical to healthy gastrointestinal function and are in part governed by myoelectrical activity. In this study, the spatiotemporal characteristics of the bioelectrical conduction across the ICJ and its adjacent regions were quantified in anesthetized rabbits. High-resolution mapping was applied from the terminal ileum (TI) to the sacculus rotundus (SR), across the ICJ and into the beginning of the large intestine at the cecum ampulla coli (AC). Orally propagating slow wave patterns in the SR did not entrain the TI. However, aborally propagating patterns from the TI were able to entrain the SR. Bioelectrical activity was recorded within the ICJ and AC, revealing complex interactions of slow waves, spike bursts, and bioelectrical quiescence. This suggests the involvement of myogenic coordination when regulating motility between the small and large intestines. Mean slow wave frequency between regions did not vary significantly (13.74-17.16 cycles/min). Slow waves in the SR propagated with significantly faster speeds (18.51 ± 1.57 mm/s) compared with the TI (14.05 ± 2.53 mm/s, P = 0.0113) and AC (9.56 ± 1.56 mm/s, P = 0.0001). Significantly higher amplitudes were observed in both the TI (0.28 ± 0.13 mV, P = 0.0167) and SR (0.24 ± 0.08 mV, P = 0.0159) within the small intestine compared with the large intestine AC (0.03 ± 0.01 mV). We hypothesize that orally propagating slow waves facilitate a motor-brake pattern in the SR to limit outflow into the ICJ, similar to those previously observed in other gastrointestinal regions.NEW & NOTEWORTHY Competing slow wave pacemakers were observed in the terminal ileum and sacculus rotundus. Prevalent oral propagation in the sacculus rotundus toward the terminal ileum potentially acts as a brake mechanism limiting outflow. Slow waves and periods of quiescence at the ileocecal junction suggest that activation may depend on the coregulatory flow and distention pathways. Slow waves and spike bursts in the cecum impart a role in the coordination of motility.

Targeted ablation of gastric pacemaker sites to modulate patterns of bioelectrical slow wave activation and propagation in an anesthetized pig model.

Gastric motility is coordinated by underlying bioelectrical slow waves. Gastric dysrhythmias occur in gastrointestinal (GI) motility disorders, but there are no validated methods for eliminating dysrhythmias. We hypothesized that targeted ablation could eliminate pacemaker sites in the stomach, including dysrhythmic ectopic pacemaker sites. In vivo high-resolution serosal electrical mapping (16 × 16 electrodes; 6 × 6 cm) was applied to localize normal and ectopic gastric pacemaker sites in 13 anesthetized pigs. Radiofrequency ablation was performed in a square formation surrounding the pacemaker site. Postablation high-resolution mapping revealed that ablation successfully induced localized conduction blocks after 18 min (SD 5). Normal gastric pacemaker sites were eliminated by ablation (n = 6), resulting in the emergence of a new pacemaker site immediately distal to the original site in all cases. Ectopic pacemaker sites were similarly eliminated by ablation in all cases (n = 7), and the surrounding mapped area was then entrained by normal antegrade activity in five of those cases. Histological analysis showed that ablation lesions extended through the entire depth of the muscle layer. Immunohistochemical staining confirmed localized interruption of the interstitial cell of Cajal (ICC) network through the ablation lesions. This study demonstrates that targeted gastric ablation can effectively modulate gastric electrical activation, including eliminating ectopic sites of slow wave activation underlying gastric dysrhythmias, without disrupting surrounding conduction capability or tissue structure. Gastric ablation presents a powerful new research tool for modulating gastric electrical activation and may likely hold therapeutic potential for disorders of gastric function.NEW & NOTEWORTHY This study presents gastric ablation as a novel tool for modulating gastric bioelectrical activation, including eliminating the normal gastric pacemaker site as well as abnormal ectopic pacemaker sites underlying gastric dysrhythmias. Targeted application of radiofrequency ablation was able to eliminate these pacemaker sites without disrupting surrounding conduction capability or tissue structure. Gastric ablation presents a powerful new research tool for modulating gastric electrical activation and may likely hold therapeutic potential for disorders of gastric function.

Localized bioelectrical conduction block from radiofrequency gastric ablation persists after healing: safety and feasibility in a recovery model.

Gastric ablation has demonstrated potential to induce conduction blocks and correct abnormal electrical activity (i.e., ectopic slow-wave propagation) in acute, intraoperative in vivo studies. This study aimed to evaluate the safety and feasibility of gastric ablation to modulate slow-wave conduction after 2 wk of healing. Chronic in vivo experiments were performed in weaner pigs (n = 6). Animals were randomly divided into two groups: sham-ablation (n = 3, control group; no power delivery, room temperature, 5 s/point) and radiofrequency (RF) ablation (n = 3; temperature-control mode, 65°C, 5 s/point). In the initial surgery, high-resolution serosal electrical mapping (16 × 16 electrodes; 6 × 6 cm) was performed to define the baseline slow-wave activation profile. Ablation (sham/RF) was then performed in the mid-corpus, in a line around the circumferential axis of the stomach, followed by acute postablation mapping. All animals recovered from the procedure, with no sign of perforation or other complications. Two weeks later, intraoperative high-resolution mapping was repeated. High-resolution mapping showed that ablation successfully induced sustained conduction blocks in all cases in the RF-ablation group at both the acute and 2 wk time points, whereas all sham-controls had no conduction block. Histological and immunohistochemical evaluation showed that after 2 wk of healing, the lesions were in the inflammation and early proliferation phase, and interstitial cells of Cajal (ICC) were depleted and/or deformed within the ablation lesions. This safety and feasibility study demonstrates that gastric ablation can safely and effectively induce a sustained localized conduction block in the stomach without disrupting the surrounding slow-wave conduction capability.NEW & NOTEWORTHY Ablation has recently emerged as a tool for modulating gastric electrical activation and may hold interventional potential for disorders of gastric function. However, previous studies have been limited to the acute intraoperative setting. This study now presents the safety of gastric ablation after postsurgical recovery and healing. Localized electrical conduction blocks created by ablation remained after 2 wk of healing, and no perforation or other complications were observed over the postsurgical period.

In vivo experimental validation of detection of gastric slow waves using a flexible multichannel electrogastrography sensor linear array.

BACKGROUND: Cutaneous electrogastrography (EGG) is a non-invasive technique that detects gastric bioelectrical slow waves, which in part govern the motility of the stomach. Changes in gastric slow waves have been associated with a number of functional gastric disorders, but to date accurate detection from the body-surface has been limited due to the low signal-to-noise ratio. The main aim of this study was to develop a flexible active-electrode EGG array. METHODS: Two Texas Instruments CMOS operational amplifiers: OPA2325 and TLC272BID, were benchtop tested and embedded in a flexible linear array of EGG electrodes, which contained four recording electrodes at 20-mm intervals. The cutaneous EGG arrays were validated in ten weaner pigs using simultaneous body-surface and serosal recordings, using the Cyton biosensing board and ActiveTwo acquisition systems. The serosal recordings were taken using a passive electrode array via surgical access to the stomach. Signals were filtered and compared in terms of frequency, amplitude, and phase-shift based on the classification of propagation direction from the serosal recordings. RESULTS: The data were compared over 709 cycles of slow waves, with both active cutaneous EGG arrays demonstrating comparable performance. There was an agreement between frequencies of the cutaneous EGG and serosal recordings (3.01 ± 0.03 vs 3.03 ± 0.05 cycles per minute; p = 0.75). The cutaneous EGG also demonstrated a reduction in amplitude during abnormal propagation of gastric slow waves (310 ± 50 µV vs 277 ± 9 µV; p < 0.01), while no change in phase-shift was observed (1.28 ± 0.09 s vs 1.40 ± 0.10 s; p = 0.36). CONCLUSION: A sparse linear cutaneous EGG array was capable of reliably detecting abnormalities of gastric slow waves. For more accurate characterization of gastric slow waves, a two-dimensional body-surface array will be required.

Localized gastric distension disrupts slow-wave entrainment leading to temporary ectopic propagation: a high-resolution electrical mapping study.

Gastric distension is known to affect normal slow-wave activity and gastric function, but links between slow-wave dysrhythmias and stomach function are poorly understood. Low-resolution mapping is unable to capture complex spatial properties of gastric dysrhythmias, necessitating the use of high-resolution mapping techniques. Characterizing the nature of these dysrhythmias has implications in the understanding of postprandial function and the development of new mapping devices. In this two-phase study, we developed and implemented a protocol for measuring electrophysiological responses to gastric distension in porcine experiments. In vivo, serosal high-resolution electrical mapping (256 electrodes; 36 cm2) was performed in anaesthetized pigs (n = 11), and slow-wave pattern, velocity, frequency, and amplitude were quantified before, during, and after intragastric distension. Phase I experiments (n = 6) focused on developing and refining the distension mapping methods using a surgically inserted intragastric balloon, with a variety of balloon types and distension protocols. Phase II experiments (n = 5) used barostat-controlled 500-mL isovolumetric distensions of an endoscopically introduced intragastric balloon. Dysrhythmias were consistently induced in all five gastric distensions, using refined distension protocols. Dysrhythmias appeared 23 s (SD = 5 s) after the distension and lasted 129 s (SD = 72 s), which consisted of ectopic propagation originating from the greater curvature in the region of distension. In summary, our results suggest that distension disrupts gastric entrainment, inducing temporary ectopic slow-wave propagation. These results may influence the understanding of the postprandial stomach and electrophysiological effects of gastric interventions.NEW & NOTEWORTHY This study presents the discovery of temporary dysrhythmic ectopic pacemakers in the distal stomach caused by localized gastric distension. Distension-induced dysrhythmias are an interesting physiological phenomenon that can inform the design of new interventional and electrophysiological protocols for both research and the clinic. The observation of distension-induced dysrhythmias also contributes to our understanding of stretch-sensitivity in the gut and may play an important role in normal and abnormal postprandial physiology.

Gastric ablation as a novel technique for modulating electrical conduction in the in vivo stomach.

Gastric motility is coordinated by underlying bioelectrical "slow wave" activity. Slow wave dysrhythmias are associated with motility disorders, including gastroparesis, offering an underexplored potential therapeutic target. Although ablation is widely used to treat cardiac arrhythmias, this approach has not yet been trialed for gastric electrical abnormalities. We hypothesized that ablation can create localized conduction blocks and modulate slow wave activation. Radiofrequency ablation was performed on the porcine serosa in vivo, encompassing a range of parameters (55-85°C, adjacent points forming a line, 5-10 s/point). High-resolution electrical mapping (16 × 16 electrodes; 6 × 6 cm) was applied to define baseline and acute postablation activation patterns. Tissue damage was evaluated by hematoxylin and eosin and c-Kit stains. Results demonstrated that RF ablation successfully induced complete conduction block and a full thickness lesion in the muscle layer at energy doses of 65-75°C for 5-10 s/point. Gastric ablation may hold therapeutic potential for gastric electrical abnormalities in the future.NEW & NOTEWORTHY This study presents gastric ablation as a new method for modulating slow wave activation and propagation in vivo, by creating localized electrical conduction blocks in the stomach, validated by high-resolution electrical mapping and histological tissue analysis. The results define the effective energy dose range for creating conduction blocks, while maintaining the mucosal and submucosal integrity, and demonstrate the electrophysiological effects of ablation. In future, gastric ablation can now be translated toward disrupting dysrhythmic slow wave activation.

Habitat degradation negatively affects auditory settlement behavior of coral reef fishes.

Coral reefs are increasingly degraded by climate-induced bleaching and storm damage. Reef recovery relies on recruitment of young fishes for the replenishment of functionally important taxa. Acoustic cues guide the orientation, habitat selection, and settlement of many fishes, but these processes may be impaired if degradation alters reef soundscapes. Here, we report spatiotemporally matched evidence of soundscapes altered by degradation from recordings taken before and after recent severe damage on Australia's Great Barrier Reef. Postdegradation soundscapes were an average of 15 dB re 1 µPa quieter and had significantly reduced acoustic complexity, richness, and rates of invertebrate snaps compared with their predegradation equivalents. We then used these matched recordings in complementary light-trap and patch-reef experiments to assess responses of wild fish larvae under natural conditions. We show that postdegradation soundscapes were 8% less attractive to presettlement larvae and resulted in 40% less settlement of juvenile fishes than predegradation soundscapes; postdegradation soundscapes were no more attractive than open-ocean sound. However, our experimental design does not allow an estimate of how much attraction and settlement to isolated postdegradation soundscapes might change compared with isolated predegradation soundscapes. Reductions in attraction and settlement were qualitatively similar across and within all trophic guilds and taxonomic groups analyzed. These patterns may lead to declines in fish populations, exacerbating degradation. Acoustic changes might therefore trigger a feedback loop that could impair reef resilience. To understand fully the recovery potential of coral reefs, we must learn to listen.

Memory Pattern Identification for Feedback Tracking Control in Human-Machine Systems.

OBJECTIVE: The aim of this paper was to identify the characteristics of memory patterns with respect to a visual input, perceived by the human operator during a manual control task, which consisted in following a moving target on a display with a cursor. BACKGROUND: Manual control tasks involve nondeclarative memory. The memory encodings of different motor skills have been referred to as procedural memories. The procedural memories have a pattern, which this paper sought to identify for the particular case of a one-dimensional tracking task. Specifically, data recorded from human subjects controlling dynamic systems with different fractional order were investigated. METHOD: A finite impulse response (FIR) controller was fitted to the data, and pattern analysis of the fitted parameters was performed. Then, the FIR model was further reduced to a lower order controller; from the simplified model, the stability analysis of the human-machine system in closed-loop was conducted. RESULTS: It is shown that the FIR model can be used to identify and represent patterns in human procedural memories during manual control tasks. The obtained procedural memory pattern presents a time scale of about 650 ms before decay. Furthermore, the fitted controller is stable for systems with fractional order less than or equal to 1. CONCLUSION: For systems of different fractional order, the proposed control scheme-based on an FIR model-can effectively characterize the linear properties of manual control in humans. APPLICATION: This research supports a biofidelic approach to human manual control modeling over feedback visual perceptions. Relevant applications of this research are the following: the development of shared-control systems, where a virtual human model assists the human during a control task, and human operator state monitoring.

Reducing secondary organic aerosol formation from gasoline vehicle exhaust.

On-road gasoline vehicles are a major source of secondary organic aerosol (SOA) in urban areas. We investigated SOA formation by oxidizing dilute, ambient-level exhaust concentrations from a fleet of on-road gasoline vehicles in a smog chamber. We measured less SOA formation from newer vehicles meeting more stringent emissions standards. This suggests that the natural replacement of older vehicles with newer ones that meet more stringent emissions standards should reduce SOA levels in urban environments. However, SOA production depends on both precursor concentrations (emissions) and atmospheric chemistry (SOA yields). We found a strongly nonlinear relationship between SOA formation and the ratio of nonmethane organic gas to oxides of nitrogen (NOx) (NMOG:NOx), which affects the fate of peroxy radicals. For example, changing the NMOG:NOx from 4 to 10 ppbC/ppbNOx increased the SOA yield from dilute gasoline vehicle exhaust by a factor of 8. We investigated the implications of this relationship for the Los Angeles area. Although organic gas emissions from gasoline vehicles in Los Angeles are expected to fall by almost 80% over the next two decades, we predict no reduction in SOA production from these emissions due to the effects of rising NMOG:NOx on SOA yields. This highlights the importance of integrated emission control policies for NOx and organic gases.

Fish in habitats with higher motorboat disturbance show reduced sensitivity to motorboat noise.

Anthropogenic noise can negatively impact many taxa worldwide. It is possible that in noisy, high-disturbance environments, the range and severity of impacts could diminish over time, but the influence of previous disturbance remains untested in natural conditions. This study demonstrates the effects of motorboat noise on the physiology of an endemic cichlid fish in Lake Malawi. Exposure to motorboats (driven 20-100 m from fish) and loudspeaker playback of motorboat noise both elevated the oxygen-consumption rate at a single lower-disturbance site, characterized by low historic and current motorboat activity. Repeating this assay at further lower-disturbance sites revealed a consistent effect of elevated oxygen consumption in response to motorboat disturbance. However, when similar trials were repeated at four higher-disturbance sites, no effect of motorboat exposure was detected. These results demonstrate that disturbance history can affect local population responses to noise. Action regarding noise pollution should consider the past, as well as the present, when planning for the future.

Human anti-nucleolin recombinant immunoagent for cancer therapy.

Nucleolin (NCL) is a nucleocytoplasmic protein involved in many biological processes, such as ribosomal assembly, rRNA processing, and mRNA stabilization. NCL also regulates the biogenesis of specific microRNAs (miRNAs) involved in tumor development and aggressiveness. Interestingly, NCL is expressed on the surface of actively proliferating cancer cells, but not on their normal counterparts. Therefore, NCL is an attractive target for antineoplastic treatments. Taking advantage of phage-display technology, we engineered a fully human single-chain fragment variable, named 4LB5. This immunoagent binds NCL on the cell surface, it is translocated into the cytoplasm of target cells, and it abrogates the biogenesis of NCL-dependent miRNAs. Binding of 4LB5 to NCL on the cell surface of a variety of breast cancer and hepatocellular carcinoma cell lines, but not to normal-like MCF-10a breast cells, dramatically reduces cancer cell viability and proliferation. Finally, in orthotopic breast cancer mouse models, 4LB5 administration results in a significant reduction of the tumor volume without evident side effects. In summary, here we describe, to our knowledge, the first anti-NCL single-chain fragment variable displaying antineoplastic activity against established solid tumors, which could represent the prototype of novel immune-based NCL-targeting drugs with clinical potential as diagnostic and therapeutic tools in a wide variety of human cancers.

Review of Urban Secondary Organic Aerosol Formation from Gasoline and Diesel Motor Vehicle Emissions.

Secondary organic aerosol (SOA) is formed from the atmospheric oxidation of gas-phase organic compounds leading to the formation of particle mass. Gasoline- and diesel-powered motor vehicles, both on/off-road, are important sources of SOA precursors. They emit complex mixtures of gas-phase organic compounds that vary in volatility and molecular structure-factors that influence their contributions to urban SOA. However, the relative importance of each vehicle type with respect to SOA formation remains unclear due to conflicting evidence from recent laboratory, field, and modeling studies. Both are likely important, with evolving contributions that vary with location and over short time scales. This review summarizes evidence, research needs, and discrepancies between top-down and bottom-up approaches used to estimate SOA from motor vehicles, focusing on inconsistencies between molecular-level understanding and regional observations. The effect of emission controls (e.g., exhaust aftertreatment technologies, fuel formulation) on SOA precursor emissions needs comprehensive evaluation, especially with international perspective given heterogeneity in regulations and technology penetration. Novel studies are needed to identify and quantify "missing" emissions that appear to contribute substantially to SOA production, especially in gasoline vehicles with the most advanced aftertreatment. Initial evidence suggests catalyzed diesel particulate filters greatly reduce emissions of SOA precursors along with primary aerosol.

Unspeciated organic emissions from combustion sources and their influence on the secondary organic aerosol budget in the United States.

Secondary organic aerosol (SOA) formed from the atmospheric oxidation of nonmethane organic gases (NMOG) is a major contributor to atmospheric aerosol mass. Emissions and smog chamber experiments were performed to investigate SOA formation from gasoline vehicles, diesel vehicles, and biomass burning. About 10-20% of NMOG emissions from these major combustion sources are not routinely speciated and therefore are currently misclassified in emission inventories and chemical transport models. The smog chamber data demonstrate that this misclassification biases model predictions of SOA production low because the unspeciated NMOG produce more SOA per unit mass than the speciated NMOG. We present new source-specific SOA yield parameterizations for these unspeciated emissions. These parameterizations and associated source profiles are designed for implementation in chemical transport models. Box model calculations using these new parameterizations predict that NMOG emissions from the top six combustion sources form 0.7 Tg y(-1) of first-generation SOA in the United States, almost 90% of which is from biomass burning and gasoline vehicles. About 85% of this SOA comes from unspeciated NMOG, demonstrating that chemical transport models need improved treatment of combustion emissions to accurately predict ambient SOA concentrations.

High-Energy Pacing in the Jejunum Elicits Pulsatile Segmental Contractions.

OBJECTIVE: Compromised bowel function is associated with a range of motility disorders such as post-operative ileus and chronic intestinal pseudo-obstruction. Disordered or weak motility compromise the efficient movement of luminal contents necessary for digestion and nutrient absorption. This study investigated the potential of high-energy pacing to enhance contractions in the proximal jejunum of the small intestine. METHODS: Pacing pulse parameters (pulse-width: 100 ms, 200 ms, 400 ms, pulse-amplitude: 4 mA, 6 mA, 8 mA) were systematically varied in the in vivo porcine jejunum (n = 7) and the induced contractile responses were evaluated using a video mapping system. Localized segmental contractions were quantified by measuring the intestinal diameter and thereby computing the strain. The impact of pacing parameters on contractile strain was investigated. Finally, histological studies were conducted on paced tissue to assess for potential tissue damage. RESULTS: Segmental contractions were successfully induced at all pulse-settings and evaluated across 67 pacing sessions. In response to pacing, the intestine segment at the site of pacing contracted, with diameter reduced by 6-18%. Contractile response significantly increased with increasing pulse-amplitude. However, with increasing pulse-width, the increase in contractile response was significant only between 100 ms and 400 ms. Histology showed no tissue damage occurred when maximal pacing energy (pulse-amplitude = 4-8 mA, pulse-width = 400 ms, 5 minute duration) was applied. CONCLUSION: High-energy pacing induced periodic segmental contractions in response to pacing pulses and the contractile strain was proportional to the energy applied on the intestine. The ability to enhance motility through pacing may hold promising therapeutic potential for bowel disorders and awaits clinical translation. SIGNIFICANCE: Small intestine pacing elicits localized segmental contractions which increase in magnitude with increasing pulse settings. This study marks the first adaptation of video mapping techniques to track the pacing response in the small intestine.

Electromechanical Response of Mesenteric Ischemia Defined Through Simultaneous High-Resolution Bioelectrical and Video Mapping.

Intestinal motility is governed in part by bioelectrical slow-waves and spike-bursts. Mesenteric ischemia is a substantial clinical challenge, but its electrophysiological and contractile mechanisms are not well understood. Simultaneous high-resolution bioelectrical and video mapping techniques were used to capture the changes in slow-waves, spike-bursts, and contractile activity during baseline, ischemia, and reperfusion periods. Experiments were performed on anesthetized pigs where intestinal contractions were quantified using surface strain and diameter measurements, while slow-wave and spike-bursts were quantified using frequency and amplitude. Slow-waves entrainment within the ischemic region diminished during ischemia, resulting in irregular slow-wave activity and a reduction in the frequency from 12.4 ± 3.0 cycles-per-minute (cpm) to 2.5 ± 2.7 cpm (p = 0.0006). At the end of the reperfusion period, normal slow-wave entrainment was observed at a frequency of 11.5 ± 2.9 cpm. There was an increase in spike-burst activity between the baseline and ischemia periods (1.1 ± 1.4 cpm to 8.7 ± 3.3 cpm, p = 0.0003) along with a spasm of circumferential contractions. At the end of the reperfusion period, the frequency of spike-bursts decreased to 2.7 ± 1.4 cpm, and contractions subsided. The intestine underwent tonal contraction during ischemia, with the diameter decreasing from 29.3 ± 2.6 mm to 21.2 ± 6.2 mm (p = 0.0020). At the end of the reperfusion period, the intestinal diameter increased to 27.3 ± 3.9 mm. The decrease in slow-wave activity, increase in spike-bursts, and tonal contractions can objectively identify ischemic segments in the intestine. It is anticipated that the use of electrophysiological slow-wave and spike-burst biomarkers, along with contractile measures, could identify mesenteric ischemia in surgical settings and allow an objective biomarker for successful revascularization.

Measurement and Analysis of In Vivo Gastroduodenal Slow Wave Patterns Using Anatomically-Specific Cradles and Electrodes.

OBJECTIVE: Bioelectrical 'slow waves' regulate gastrointestinal contractions. We aimed to confirm whether the pyloric sphincter demarcates slow waves in the intact stomach and duodenum. METHODS: We developed and validated novel anatomically-specific electrode cradles and analysis techniques which enable high-resolution slow wave mapping across the in vivo gastroduodenal junction. Cradles housed flexible-printed-circuit and custom cradle-specific electrode arrays during acute porcine experiments (N = 9; 44.92 kg ± 8.49 kg) and maintained electrode contact with the gastroduodenal serosa. Simultaneous gastric and duodenal slow waves were filtered independently after determining suitable organ-specific filters. Validated algorithms calculated slow wave propagation patterns and quantitative descriptions. RESULTS: Butterworth filters, with cut-off frequencies (0.0167 - 2) Hz and (0.167 - 3.33) Hz, were optimal filters for gastric and intestinal slow wave signals, respectively. Antral slow waves had a frequency of (2.76 ± 0.37) cpm, velocity of (4.83 ± 0.21) mm·s-1, and amplitude of (1.13 ± 0.24) mV, before terminating at the quiescent pylorus that was (46.54 ± 5.73) mm wide. Duodenal slow waves had a frequency of (18.13 ± 0.56) cpm, velocity of (11.66 ± 1.36) mm·s-1, amplitude of (0.32 ± 0.03) mV, and originated from a pacemaker region (7.24 ± 4.70) mm distal to the quiescent zone. CONCLUSION: Novel engineering methods enable measurement of in vivo electrical activity across the gastroduodenal junction and provide qualitative and quantitative definitions of slow wave activity. SIGNIFICANCE: The pylorus is a clinical target for a range of gastrointestinal motility disorders and this work may inform diagnostic and treatment practices.