Rebound Response Research Articles

Inflammatory rebound and postinfectious inflammatory response in children with pleural infection: A single-center retrospective study.

As pleural inflammation plays a central role in pleural infection (PI), corticosteroids are increasingly being considered as a potential therapy. However, the timing of treatment and the identification of patients who might benefit most remain unresolved. The aim of this study was therefore to investigate the inflammatory trajectories of children with PI. This retrospective single-center study included children aged 3 months to 17 years and 11 months hospitalized for PI due to Streptococcus pyogenes, Streptococcus pneumonia, and Staphylococcus aureus over 10 years. An inflammatory rebound was defined biologically as a reincrease in C-reactive protein (CRP) of at least 50 mg/L after an initial decrease in CRP of at least 50 mg/L. We included 53 cases of PI, including 16 due to S. pyogenes, 27 due to S. pneumonia, and 10 due to S. aureus. An inflammatory rebound occurred in 20 patients (38%) after a median of 4.5 (3-6) days. This inflammatory rebound occurred in 9 (56%) children with S. pyogenes, 8 (30%) children with S. pneumonia, and 3 (30%) children with S. aureus. Children with an inflammatory rebound also had a higher rate of persistent fever after Day 7 and a longer length of stay (p = .01 for both). We postulate that the inflammatory rebound identified in nearly 40% of our patients corresponds to an early postinfectious inflammatory response, and thus that corticosteroids may be most beneficial for children with PI if administered early (between Days 2 and 5).

Dynamic Recruitment of the Feedforward and Recurrent Mechanism for Black-White Asymmetry in the Primary Visual Cortex.

Black and white information is asymmetrically distributed in natural scenes, evokes asymmetric neuronal responses, and causes asymmetric perceptions. Recognizing the universality and essentiality of black-white asymmetry in visual information processing, the neural substrates for black-white asymmetry remain unclear. To disentangle the role of the feedforward and recurrent mechanisms in the generation of cortical black-white asymmetry, we recorded the V1 laminar responses and LGN responses of anesthetized cats of both sexes. In a cortical column, we found that black-white asymmetry starts at the input layer and becomes more pronounced in the output layer. We also found distinct dynamics of black-white asymmetry between the output layer and the input layer. Specifically, black responses dominate in all layers after stimulus onset. After stimulus offset, black and white responses are balanced in the input layer, but black responses still dominate in the output layer. Compared with that in the input layer, the rebound response in the output layer is significantly suppressed. The relative suppression strength evoked by white stimuli is notably stronger and depends on the location within the ON-OFF cortical map. A model with delayed and polarity-selective cortical suppression explains black-white asymmetry in the output layer, within which prominent recurrent connections are identified by Granger causality analysis. In addition to black-white asymmetry in response strength, the interlaminar differences in spatial receptive field varied dynamically. Our findings suggest that the feedforward and recurrent mechanisms are dynamically recruited for the generation of black-white asymmetry in V1.SIGNIFICANCE STATEMENT Black-white asymmetry is universal and essential in visual information processing, yet the neural substrates for cortical black-white asymmetry remain unknown. Leveraging V1 laminar recordings, we provided the first laminar pattern of black-white asymmetry in cat V1 and found distinct dynamics of black-white asymmetry between the output layer and the input layer. Comparing black-white asymmetry across three visual hierarchies, the LGN, V1 input layer, and V1 output layer, we demonstrated that the feedforward and recurrent mechanisms are dynamically recruited for the generation of cortical black-white asymmetry. Our findings not only enhance our understanding of laminar processing within a cortical column but also elucidate how feedforward connections and recurrent connections interact to shape neuronal response properties.

Deletion of the Circadian Clock Gene Per2 in the Whole Body, but Not in Neurons or Astroglia, Affects Sleep in Response to Sleep Deprivation

The sleep-wake cycle is a highly regulated behavior in which a circadian clock times sleep and waking, whereas a homeostatic process controls sleep need. Both the clock and the sleep homeostat interact, but to what extent they influence each other is not understood. There is evidence that clock genes, in particular Period2 (Per2), might be implicated in the sleep homeostatic process. Sleep regulation depends also on the proper functioning of neurons and astroglial cells, two cell-types in the brain that are metabolically dependent on each other. In order to investigate clock-driven contributions to sleep regulation we non-invasively measured sleep of mice that lack the Per2 gene either in astroglia, neurons, or all body cells. We observed that mice lacking Per2 in all body cells (Per2Brdm and TPer2 animals) display earlier onset of sleep after sleep deprivation (SD), whereas neuronal and astroglial Per2 knock-out animals (NPer2 and GPer2, respectively) were normal in that respect. It appears that systemic (whole body) Per2 expression is important for physiological sleep architecture expressed by number and length of sleep bouts, whereas neuronal and astroglial Per2 weakly impacts night-time sleep amount. Our results suggest that Per2 contributes to the timing of the regulatory homeostatic sleep response by delaying sleep onset after SD and attenuating the early night rebound response.

Liquefaction Susceptibility and Characterization of Rebound Response of Micaceous Sand

Liquefaction Susceptibility and Characterization of Rebound Response of Micaceous Sand

Effect of Lime, Kaolinite and Bentonite treatment on mechanical behaviour of micaceous sand

ABSTRACT Micaceous sands are known as problematic/undesirable soils for road/railway construction as such soils exhibit rebound action under traffic loading conditions leading to severe damage in subgrades and embankments. In the current research, three commercially available materials (Bentonite, Kaolinite and Lime) have been used independently for treating the micaceous soil to determine the appropriate stabilising agent for the overall enhancement of mechanical behaviour of micaceous soil including compatibility, cyclic stability, stiffness and strength characteristics subjected to various loading and boundary conditions. In the current research, extensive experimental research has been performed on MS treated with Bentonite/Kaolinite/Lime by conducting Compaction, Triaxial (unconsolidated undrained, consolidated undrained and consolidated drained) and cyclic triaxial tests. Bentonite treatment exhibited significant improvement in all the properties of micaceous sand (MS) as compared to Kaolinite and Lime treatment. Bentonite treatment of MS reported a marked reduction in the rebound response of micaceous soil with sustainable cyclic stability. The present research reported Bentonite treatment is the most effective, environmentally friendly and economical treatment for micaceous soil.

Modelling of strength characteristics of silica fume/glass ternary blended concrete using destructive and non-destructive testing methods

The need to promote solid waste in concrete production prompted the use of waste glass powder (WGP) and silica fume (SF) powder in partial replacement for ordinary Portland cement in ternary blended concrete. The concrete was prepared with a total binder of 350 kg (in 1 m3) with 90% of cement and 10% the combination of silica fume and waste glass powder. The water/binder ratio was 0.42, and the fine aggregate to the total aggregate was 0.4. Models of wet density and 90-day strength development were presented in terms of age, WGP, and SF. Similarly, the concrete compressive strength and elastic/shear moduli were modelled for rebound numbers and response frequencies. The impact of geometrical shape and aspect ratio was also studied using cylindrical (100 - and 75-mm diameters) and rectangular specimens with an aspect ratio of 4 and 5. Transverse response frequency decreased with an increase in sample diameter and aspect ratio. The 90-day strength of C90G2.5S7.5 had a maximum strength of 55.5 MPa. Furthermore, the ternary blended sample (C90GyS10-y) was better than glass blended concrete (C90G10S0) in terms of 28-day strength, elastic and shear moduli, while the presence of SF (C90G0S10) decreased the response frequencies of OPC concrete (C100G0S0).

Cortical mechanisms of visual brightness.

SUMMARYThe primary visual cortex signals the onset of light and dark stimuli with ON and OFF cortical pathways. Here, we demonstrate that both pathways generate similar response increments to large homogeneous surfaces and their response average increases with surface brightness. We show that, in cat visual cortex, response dominance from ON or OFF pathways is bimodally distributed when stimuli are smaller than one receptive field center but unimodally distributed when they are larger. Moreover, whereas small bright stimuli drive opposite responses from ON and OFF pathways (increased versus suppressed activity), large bright surfaces drive similar response increments. We show that this size-brightness relation emerges because strong illumination increases the size of light surfaces in nature and both ON and OFF cortical neurons receive input from ON thalamic pathways. We conclude that visual scenes are perceived as brighter when the average response increments from ON and OFF cortical pathways become stronger.

Experimental Study on Mechanical Properties of Rebar in Steel Half-Grouted Sleeve Connections with Construction Defects.

A prefabricated concrete structure is a building structure designed for sustainability and low comprehensive carbon emission. The grouted sleeve splice is a major connection method for prefabricated concrete structures. However, construction defects occur easily in the grouted sleeve splice connection at construction sites because of complex construction environments and the high connection accuracy. To determine the influence of rebar in steel half-grouted sleeve connections with construction defects, investigations were conducted using four different test groups (rebar offset, rebar bended, insufficient fluidity of grout, and control group). The load—displacement curve and load—stress curve were analyzed on 24 different specimens through uniaxial tension experiments. The experimental results showed that rebar fracture was the failure of specimens. The load—displacement curves consisted of elastic, yield, strength, and tight stages. The curves were similar to rebar under uniaxial tension, except for the rebar bended group. The axial stress and circumferential stress on the sleeve surface consistently followed a linear response before the specimen yield, whereas the axial stress and circumferential stress showed a rebound response after the specimen yielded. Different finite element models were established based on the different defects. Compared with the experimental results, the finite element analysis results coincided with those of the experimental results, and the errors were within 8% to evaluate the performance of steel half-grouted sleeve connections in construction.

Microglia are involved in the protection of memories formed during sleep deprivation

Sleep deprivation can generate inflammatory responses in the central nervous system. In turn, this inflammation increases sleep drive, leading to a rebound in sleep duration. Microglia, the innate immune cells found exclusively in the CNS, have previously been found to release inflammatory signals and exhibit altered characteristics in response to sleep deprivation. Together, this suggests that microglia may be partially responsible for the brain's response to sleep deprivation through their inflammatory activity. In this study, we ablated microglia from the mouse brain and assessed resulting sleep, circadian, and sleep deprivation phenotypes. We find that microglia are dispensable for both homeostatic sleep and circadian function and the sleep rebound response to sleep deprivation. However, we uncover a phenomenon by which microglia appear to be essential for the protection of fear-conditioning memories formed during the recovery sleep period following a period of sleep deprivation. This phenomenon occurs potentially through the upregulation of synaptic-homeostasis related genes to protect nascent dendritic spines that may be otherwise removed or downscaled during recovery sleep. These findings further expand the list of known functions for microglia in synaptic modulation.

DEM-FEM Coupling Analysis of Safe Landing of Reentry Capsule Considering Landing Attitude and Rebound Response

AbstractThis paper discusses the safe landing process of a reentry capsule in detail with respect to landing attitude and rebound response. First, the discrete-element method (DEM) of the land soil...

Rate of rebound in follicle growth after cessation of ovarian stimulation in initial non\u2010responders: a prospective cohort study

Previously anecdotally observed rebounds in follicle growth after interruption of exogenous gonadotropins in absolute non-responders were the impetus for here reported study. In a prospective cohort study, we investigated 49 consecutive patients, absolutely unresponsive to maximal exogenous gonadotropin stimulation, for a so-called rebound response to ovarian stimulation. A rebound response was defined as follicle growth following complete withdrawal of exogenous gonadotropin stimulation after complete failure to respond to maximal gonadotropin stimulation over up to 5–7 days. Median age of study patients was 40.5 ± 5.1 years (range 23–52). Women with and without rebound did not differ significantly (40.0 ± 6.0 vs. 41.0 ± 7.0 years, P = 0.41), with 24 (49.0%) recording a rebound and 25 (51.0%) not. Among the former, 21 (87.5%) reached retrieval of 1–3 oocytes and 15 (30.6%) reached embryo transfer. A successful rebound in almost half of prior non-responders was an unsuspected response rate, as was retrieval of 1–3 oocytes in over half of rebounding patients. Attempting rebounds may, thus, represent another incremental step in very poor prognosis patients before giving up on utilization of autologous oocytes. Here presented findings support further investigations into the underlying physiology leading to such an unexpectedly high rebound rate.

Landing mosquitoes bounce when engaging a substrate

In this experimental study we film the landings of Aedes aegypti mosquitoes to characterize landing behaviors and kinetics, limitations, and the passive physiological mechanics they employ to land on a vertical surface. A typical landing involves 1–2 bounces, reducing inbound momentum by more than half before the mosquito firmly attaches to a surface. Mosquitoes initially approach landing surfaces at 0.1–0.6 m/s, decelerating to zero velocity in approximately 5 ms at accelerations as high as 5.5 gravities. Unlike Dipteran relatives, mosquitoes do not visibly prepare for landing with leg adjustments or body pitching. Instead mosquitoes rely on damping by deforming two forelimbs and buckling of the proboscis, which also serves to distribute the impact force, lessening the potential of detection by a mammalian host. The rebound response of a landing mosquito is well-characterized by a passive mass-spring-damper model which permits the calculation of force across impact velocity. The landing force of the average mosquito in our study is approximately 40 upmuN corresponding to an impact velocity of 0.24 m/s. The substrate contact velocity which produces a force perceptible to humans, 0.42 m/s, is above 85% of experimentally observed landing speeds.

Development of a cyclophosphamide stress test to predict resilience to aging in mice.

The concept of resilience, defined as the ability to recover from stress, is a potential platform to predict healthy aging. However, specific stress tests for resilience have not yet been fully established in humans so investigations in animal models are of interest. The chemotherapeutic drug cyclophosphamide (Cyp) was selected as a chemical stressor to investigate resilience response in C57Bl/6 male mice at 4, 15, and 28months of age. Following a single intraperitoneal injection of Cyp (100mg/kg), tail blood was collected for counting white blood cells (WBC) every other day for 25days, and physiological performance tests performed. Cyp induced a consistent pattern in neutrophil count in all three age groups, with a nadir at day 5 and a rebound at day 7 with different rates in each group. The neutrophil to lymphocyte ratio (NLR) showed an age-dependent rebound response 7days after Cyp injection, with a similar pattern of decline back toward baseline. Mice in the 15-month age group with high pre-injection Cyp NLR had significantly higher total WBC counts after Cyp injection compared with mice with low pre-injection Cyp NLR, indicating a correlation between NLR and Cyp-altered WBC counts. In addition, mice with high pre-injection Cyp NLR showed significant learning impairment compared with mice with low pre-injection Cyp NLR, suggesting low NRL intensity can predict resilience to age-related cognitive decline. These observations provide the rationale to translate findings from the mouse to humans in developing in vitro Cyp stress tests.

Immune Responses and Performance Are Influenced by Respiratory Vaccine Antigen Type and Stress in Beef Calves.

Simple SummaryDetermining effects of physiological stress and vaccination type on performance and immune responses in cattle can be a difficult task due to the many factors that contribute to the stress response. Nonetheless, defining alterations caused by the stress response after vaccination upon feedlot arrival is vital in improving vaccination practices in the feedlot industry. Utilizing a stress model with stressors induced by current industry practices to mimic a “high-risk” cattle situation, we found that vaccination with a killed or modified-live virus vaccine induces altered immune responses in cattle that underwent industry stressors when compared to a control group. In addition, performance variables were altered in stressed cattle and those that received modified-live vaccination. We propose the feedlot industry consider these results when implementing a vaccine protocol in “high risk”, or chronically stressed, cattle during arrival processing.The study objective was to determine if a combined weaning and transportation stress model affected performance, antibody, endocrine, or hematological responses to modified-live virus (MLV) or killed virus (KV) respiratory vaccination in beef steers. In total, 48 calves (Day 0 BW = 226 ± 6.2 kg) from a single origin were used in a 2 × 2 factorial to evaluate main effects of stress model, vaccine type, and their interaction, resulting in four treatments (n = 12/treatment) including non-stress control (C) with KV (CKV), C with MLV (CMLV), stress model implementation (S) with KV (SKV), and S with MLV (SMLV). The C calves were weaned at the origin ranch on Day −37 and transported 472 km to the study site on Day −21 to allow acclimation. The S calves were weaned on Day −3, transported 460 km to a research facility on Day −2, held overnight, and transported 164 km to the study site on Day −1 to mimic the beef cattle marketing process. Vaccines were administered on Day 0 and KV was revaccinated on Day 14. The animal was the experimental unit and dependent variables were analyzed using PROC MIXED with repeated measures (day). A stress model effect (p = 0.01) existed for DMI from Day 0 to Day 7 with greater DMI for C (6.19 vs. 4.64 kg/day) when compared to S. The MLV groups had reduced (p = 0.05) ADG from Day 0 to Day 56, compared to KV. There was a vaccine type × day (p < 0.01) interaction with increased (p ≤ 0.01) PI3V- and IBRV-specific antibody titers for KV on Day 21; conversely, MLV had increased (p ≤ 0.01) BVDV titers on Days 14, 28, 35, 42, 49, and 56. Increased (p ≤ 0.05) BRSV titers were observed in a stress model × day (p < 0.01) interaction for S on Days 21, 28, 36, and 42; however, C exceeded S in BVDV-specific antibody concentration on Days 21, 28, and 49. A day effect (p < 0.01) was observed for serum haptoglobin with the greatest (p < 0.01) concentration on Day 3. Serum cortisol concentration was greater (p ≤ 0.04) for C vs. S on Days −2, 0, 1, 3, and 5. Total leukocytes were decreased for C vs. S on Days 0, 1, 3, 5, 7, 14, and 21 (p ≤ 0.02). A reduction (p ≤ 0.04) in total leukocytes was observed for MLV on Days 5, 7, and 14 vs. KV. Neutrophils and neutrophil:lymphocyte were markedly increased (p ≤ 0.01) for S on Day −2, whereas neutrophils were decreased (p ≤ 0.01) on Days 1 and 21 for S. Monocytes were decreased on Days 1, 5 and 7 for MLV (p ≤ 0.04) and Days −2 to 14 for S (p ≤ 0.03). Eosinophils were reduced (p = 0.007) for S vs. C on Day −2, yet a distinct rebound response (p = 0.03) was noted for S on Day 0. The results indicate that S and MLV vaccination more profoundly induced immunomodulation in beef calves.

Noninvasive assessment of autonomic modulation of heart rate variability in the Ts65Dn mouse model of Down syndrome: A proof of principle study.

IntroductionThe Ts65Dn mouse is the most widely used animal model of Down syndrome (DS). Differences in autonomic regulation of heart rate variability (HRV) in individuals with DS have been hypothesized. Pharmacological studies in animal models may help us understand mechanisms underlying observed changes in HRV in people with DS.ObjectiveTo investigate the use a new, noninvasive technique to assess cardiac autonomic modulation in Ts65Dn mice under the effect of adrenergic and cholinergic agonists.MethodWe recorded electrocardiograms (ECGs) from 12 Ts65Dn and 12 euploid control mice. A 30‐min baseline recording was followed by the injection of an adrenergic (isoproterenol [Iso]) or cholinergic (carbachol [CCh]) agonist. Heart rate and HRV were analyzed using a series of methods customized for mice.Results and DiscussionThe ECG apparatus described here allowed us to detect noninvasively long series of heartbeats in freely‐moving animals. During baseline conditions, the yield of detectable heartbeats was 3%–27% of the estimated total number of events, which increased to 35%–70% during the 15‐min period after either Iso or CCh injections. Ts65Dn mice displayed a robust enhanced Iso‐induced negative chronotropic rebound response compared with euploid control mice. We observed a significantly smaller CCh response in Ts65Dn versus control euploid mice in the 6‐ to 10‐min‐interval postcarbachol injection.ConclusionThis work showed that the techniques described here are sufficient for this type of study. However, future studies involving the use of more selective pharmacological agents and/or genetic manipulations will be key to advance a mechanistic understanding of cardiac autonomic regulation in DS.

Abstract IA19: Insight towards therapeutic susceptibility of KRAS-mutant cancers from MRTX1257, a novel KRAS G12C mutant-selective small-molecule inhibitor

Abstract The ability to effectively target mutated KRAS has remained elusive despite decades of research. By solving a highly informative set of ligand-complexed co-crystal structures coupled with iterative structure-based drug design, substituted tetrahydropyridopyrimidines were identified as selective, covalent inhibitors of mutant KRAS G12C. MRTX1257 emerged from this chemical series as a research tool compound that demonstrates the ability to irreversibly bind to the KRAS G12C variant, trap it in the inactive GDP-bound state, and inhibit ERK1/2 phosphorylation with an IC50 value of 1 nM. Therefore, a number of studies with MRTX1257 (and other prototype inhibitors) were designed to provide insight towards the breadth of therapeutic response and the underlying molecular mechanisms of sensitivity and resistance to KRAS inhibition. The evaluation of an extended panel of KRAS G12C mutant cell lines in cell viability and survival assays indicated that the vast majority of cell lines responded at concentrations under 50 nM, but that the concentration-response range varied by two orders of magnitude (0.2-62 nM). To extend these analyses to in vivo studies, MRTX1257 demonstrated clear evidence of dose-dependent irreversible modification of KRAS G12C and inhibition of KRAS-dependent signal transduction in multiple KRAS G12C mutant tumor models. MRTX1257 was then evaluated at a fixed dose that yielded near-complete KRAS target inhibition across an additional large panel of KRAS G12C-mutant subcutaneous cell-derived and patient-derived xenografts and demonstrated broad-spectrum antitumor activity including frank tumor regressions (often exceeding 50% tumor reduction) in approximately 80% of all models evaluated (n = 23). In contrast, MRTX1257 was inactive in non-KRAS G12C-mutant cell lines in vitro and tumor models in vivo, indicating that the antitumor activity of this molecule was mediated through binding to and inhibition of the KRAS G12C variant. The antitumor response across tumor models varied in KRAS G12C positive models from complete tumor regression with no evidence of recovery after treatment cessation, to partial response, to tumor stasis. In addition, a small subset of models demonstrated rapid initial tumor regression followed by tumor stasis, suggesting that there may be mechanisms of adaptive tolerance to MRTX1257 treatment. Based on this response pattern, temporal effects on signal transduction and molecules implicated in feedback signaling were evaluated. In a temporal pattern consistent with drug tolerance kinetics, MAP kinase pathway reactivation was observed based on rebound of pERK and pS6 signaling despite continuous treatment. Also consistent with signaling rebound dynamics and drug tolerance, downregulation of dual specificity phosphatases (DUSPs), Sprouty family (SPRY), and ETVs along with decoupling of cell cycle from KRAS regulatory constraints was observed. Based on these observations, a number of combination strategies designed to co-target signaling feedback pathways were evaluated in tumor models and provided direct insight into the importance of rebound pathways and response and the practical value of rational combination approaches. Together, these data indicate the therapeutic susceptibility and broad dependence of KRAS G12C mutation-positive tumors on KRAS for tumor cell growth and survival and provide insight toward the molecular basis of response to single-agent and combinatorial therapies. Citation Format: James G. Christensen. Insight towards therapeutic susceptibility of KRAS-mutant cancers from MRTX1257, a novel KRAS G12C mutant-selective small-molecule inhibitor [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA19.

Treatment-Emergent Influenza Virus Polymerase Acidic Substitutions Independent of Those at I38 Associated With Reduced Baloxavir Susceptibility and Virus Rebound in Trials of Baloxavir Marboxil.

Influenza viruses harboring treatment-emergent I38F/M/N/T substitutions in the polymerase acidic (PA) endonuclease exhibited reduced susceptibility to baloxavir and were associated with virus rebound and variable clinical response in clinical trials. US regulatory review of registrational trial data also identified treatment-emergent PA substitutions E23K in A/H1N1 viruses and E23G/K, A37T, and E199G in A/H3N2 viruses, which conferred reduced susceptibility to baloxavir, although to a lesser degree than I38F/M/N/T substitutions, and were associated with virus rebound. Although these non-I38 substitutions emerged less frequently than substitutions at I38, they represent alternate pathways to baloxavir virologic resistance and should be monitored accordingly.

Endocannabinoid degradation inhibitors ameliorate neuronal and synaptic alterations following traumatic brain injury.

Our previous work showed that lateral fluid percussion injury to the sensorimotor cortex (SMC) of anesthetized rats increased neuronal synaptic hyperexcitability in layer 5 (L5) neurons in ex vivo brain slices 10 days postinjury. Furthermore, endocannabinoid (EC) degradation inhibition via intraperitoneal JZL184 injection 30 min postinjury attenuated synaptic hyperexcitability. This study tested the hypothesis that traumatic brain injury (TBI) induces synaptic and intrinsic neuronal alterations of L5 SMC pyramidal neurons and that these alterations are significantly attenuated by in vivo post-TBI treatment with EC degradation inhibitors. We tested the effects of systemically administered EC degradation enzyme inhibitors (JZL184, MJN110, URB597, or JZL195) with differential selectivity for fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on electrophysiological parameters in SMC neurons of TBI- and sham-treated rats 10 days post-TBI. We recorded intrinsic neuronal properties, including resting membrane voltage, input resistance, spike threshold, spiking responses to current input, voltage "sag" (rebound response to hyperpolarization-activated inward current), and burst firing. We also measured the frequency and amplitude of spontaneous excitatory postsynaptic currents. We then used the aggregate parameter sets (intrinsic + synaptic properties) to apply a machine learning classification algorithm to quantitatively compare neural population responses from each experimental group. Collectively, our electrophysiological and computational results indicate that sham neurons are the most distinguishable from TBI neurons. Administration of EC degradation inhibitors post-TBI exerted varying degrees of rescue, approximating the neuronal phenotype of sham neurons, with neurons from TBI/JZL195 (a dual MAGL/FAAH inhibitor) being most similar to neurons from sham rats.NEW & NOTEWORTHY This study elucidates neuronal properties altered by traumatic brain injury (TBI) in layer 5 of sensorimotor cortex, which may be implicated in post-TBI circuit dysfunction. We compared effects of systemic administration of four different endocannabinoid degradation inhibitors within a clinically relevant window postinjury. Electrophysiological measures and using a machine learning classification algorithm collectively suggest that pharmacological inhibitors targeting both monoacylglycerol lipase and fatty acid amide hydrolase (e.g., JZL195) may be most efficacious in attenuating TBI-induced neuronal dysfunction at site of injury.

Hand Motor Actions of Children With Cerebral Palsy Are Associated With Abnormal Sensorimotor Cortical Oscillations

Background. The neuroimaging literature on cerebral palsy (CP) has predominantly focused on identifying the structural aberrations (eg, fiber track integrity), with very few studies examining neural activity within the key networks that serve the production of hand movements. Objective. We aimed to start to fill this knowledge gap by using magnetoencephalographic brain imaging to quantify the temporal dynamics of the sensorimotor oscillations during a hand motor action. Methods: Children with CP (n = 12; MACS [Manual Abilities Classification System] levels I-III) and typically developing (TD) children (n = 26) performed an arrow-based version of the Eriksen flanker task where a button press was performed with either the second or third digit of the right hand depending on the arrow’s direction. Results: Overall, the children with CP were less accurate and had slower reaction times compared with the TD children. These behavioral differences were closely linked with aberrant sensorimotor cortical oscillations seen in the children with CP. Compared with the TD children, the children with CP had a weaker gamma (68-82 Hz) response during motor execution and a weaker post-movement beta rebound (PMBR; 14-26 Hz) response on movement termination. Moreover, we observed a significant correlation between the amplitude of the gamma and PMBR with reaction time, with weaker gamma and PMBR responses being linked with slower reaction times. Conclusions: Overall, these results suggest that aberrations in motor-related gamma and beta cortical oscillations are associated with the impaired hand motor actions seen in children with CP.

Markedly enhanced micronucleus induction by 1,2-dimethylhydrazine dihydrochloride in colonic cells of rats with bacterial colonization in the intestine

To investigate how intestinal bacteria affect host cytogenetic alterations in the early initiation step of colon carcinogenesis, we conducted a comet assay and micronucleus (MN) test using germ-free (GF) and conventionalized (Cvd) rats after a single subcutaneous injection of the carcinogen, 1,2-dimethylhydrazine dihydrochloride (DMH). DNA damage was also determined in the liver in comet assays, as DMH is metabolized and activated in this organ. The time-response patterns of DNA damage in the liver and colon were similar in both rats, and maximum values were observed at 3 h after the treatment. In contrast, the maximum frequency of micronucleated (MNed) colonic cells was markedly higher in the Cvd rats than in the GF rats and was observed after 72 h and 120 h, respectively. The frequency of MNed cells in non-treated animals was similar in the GF and Cvd rats. In addition, we determined time-responses in the incidence of apoptosis and cell proliferation indices, i.e., the numbers of BrdU-labeled cells, mitotic cells in the crypts, and crypt column heights, using histological sections of the colons in these rats. Maximal incidence of apoptosis was observed at 6 and 24 h in the Cvd and GF rats, respectively. The value in the Cvd rats tended to be higher than that in the GF rats. Cell proliferation was suppressed until 24 and 48 h in the Cvd and GF rats, respectively, and increased subsequently. The rebound response of cell proliferation was more pronounced and occurred earlier in the Cvd rats than that in the GF rats. We demonstrated that cytogenetic alterations other than DNA damage, particularly the MNed colonic cell induction by DMH, were markedly enhanced in rats with bacterial colonization in the intestine compared to those in GF rats.