Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring. In humans, epidemiological studies suggest ...that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder. In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (T
17) cells (CD4
T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA. However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote T
17 cell differentiation. Pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria or human commensal bacteria that induce intestinal T
17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells from pregnant, but not from non-pregnant, females secrete IL-1β, IL-23 and IL-6 and stimulate T cells to produce IL-17a upon exposure to MIA. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce T
17 cells may increase the risk of neurodevelopmental disorders in the offspring of pregnant mothers undergoing immune system activation owing to infections or autoinflammatory syndromes.
In our preliminary study, the modified Marsh (M-Marsh) model caused an inadvertent underdosing of propofol in underweight patients. However, the predictive performance of the M-Marsh and Schnider ...models incorporated in commercially available target-controlled infusion (TCI) pumps was not evaluated in underweight patients.
Thirty underweight patients undergoing elective surgery were randomly allocated to receive propofol via TCI using the M-Marsh or Schnider models. The target effect-site concentrations (Ces) of propofol were, in order, 2.5, 3, 4, 5, 6 and 2 μg ml−1. Arterial blood samples were obtained at least 7 min after achieving each pseudo-steady-state.
A total of 172 plasma samples were used to determine the predictive performance of both models. The pooled median (95% confidence interval) biases and inaccuracies at a target Ce ≤ 3 μg ml−1 were −22.6 (−28.8 to −12.6) and 31.9 (24.8–36.8) for the M-Marsh model and 9.0 (1.7–16.4) and 28.5 (21.7–32.8) for the Schnider model, respectively. These values at Ce ≥ 4 μg ml−1 were −9.6 (−16.0 to −6.0) and 24.7 (21.1–27.9) for the M-Marsh model and 19.8 (12.9–25.7) and 36.2 (31.4–39.7) for the Schnider model, respectively.
The pooled biases and inaccuracies of both models were clinically acceptable. However, the M-Marsh and Schnider models consistently produced negatively and positively biased predictions, respectively, in underweight patients. In particular, the M-Marsh model showed greater inaccuracy at target Ce ≤ 3 μg ml−1 and the Schnider model showed greater inaccuracy at target Ce ≥ 4 μg ml−1. Therefore, it is necessary to develop a new pharmacokinetic model for propofol in underweight patients.
KCT0001502.
The conversion of mechanical energy into biochemical changes within living cells is process known as mechanotransduction. Bone is a quintessential tissue for studying the molecular mechanisms of ...mechanotransduction, as the skeleton's mechanical competence is crucial for vertebrate movement. Bone cell mechanotransduction is facilitated by a number of cell biological pathways, one of the most prominent of which is the Wnt signaling cascade. The Wnt co-receptor Lrp5 has been identified as a crucial protein for mechanical signaling in bone, and modifiers of Lrp5 activity play important roles in mediating signaling efficiency through Lrp5, including sclerostin, Dkk1, and the co-receptor Lrp4. Mechanical regulation of sclerostin is mediated by certain members of the Hdac family. Other mechanisms that influence Wnt signaling—some of which are mechanoresponsive—are coming to light, including R-spondins and their role in organizing the Rnf43/Znrf3 and Lgr4/5/6 complex that liberates Lrp5. While the identity of the key Wnt proteins involved in bone cell mechanical signaling are elusive, the likely pool of key players is narrowing. Identification of Wnt-based molecular targets that can be modulated pharmacologically to make mechanical stimulation (e.g., exercise) more beneficial is an emerging approach to improving skeletal integrity and reducing fracture risk.
•Wnt signaling is a key cellular mechanism in bone cells that facilitates structural adaptation in response to loading•Secreted inhibitors, transmembrane receptors, and membrane-bound facilitators, are critical for the proper response to load•Newly identified components of the Wnt pathway have unexplored roles in bone cell mechanotransduction
The topography of poly (N-isopropyl acrylamide) brushes end-grafted from initiator-terminated monolayers was imaged by atomic force microscopy, as a function of the area per chain and of solvent ...quality. Measurements were done in air and in water, below and above the lower critical solution temperature. At low grafting densities and molecular weights, area-averaged ellipsometry measurements did not detect changes in the volume of water-swollen, end-grafted polymer films above the lower critical solution temperature. However, atomic force microscopy images revealed surface features that suggest the formation of lateral aggregates or “octopus micelles”. At high grafting densities and molecular weights, the films collapsed uniformly, as detected by both AFM imaging and ellipsometry. These findings reconcile in part prior results suggesting that some poly(N-isopropyl acrylamide) chains do not collapse in poor solvent, and they also reveal more complex collapse behavior above the lower critical solution temperature than is commonly assumed. This behavior would influence the ability to tune the functional properties of poly(N-isopropyl acrylamide) coatings.
Background and purpose
Generalized cerebral ischaemia from cardiovascular dysfunction usually leads to presyncopal dizziness, but several studies reported a higher frequency of rotatory vertigo in ...cardiovascular patients. Whether generalized cerebral ischaemia due to cardiovascular disorders may produce objective vestibular dysfunction was investigated.
Methods
Thirty‐three patients with orthostatic dizziness/vertigo due to profound orthostatic hypotension and 30 controls were recruited. All participants underwent recording of eye movements during two orthostatic challenging tests: the Schellong and the squatting−standing tests. Most patients had neuroimaging, and patients with abnormal eye movements were subjected to follow‐up evaluations.
Results
Symptoms associated with orthostatic dizziness/vertigo included blurred vision, fainting and tinnitus. Ten (30%) of 33 patients developed rotatory vertigo and nystagmus during the Schellong (n = 5) or squatting−standing test (n = 5). Four of them showed pure downbeat nystagmus whilst five had downbeat and horizontal nystagmus with or without torsional component. Patients with orthostatic nystagmus had shorter duration of orthostatic intolerance than those without nystagmus (1.0 ± 1.6 vs. 11.0 ± 9.7 months, P < 0.001). In two patients, orthostatic nystagmus disappeared during follow‐up despite the persistence of profound orthostatic hypotension.
Conclusions
Generalized cerebral ischaemia caused by orthostatic hypotension induces rotatory vertigo due to objective vestibular dysfunction. The presence of orthostatic vertigo and nystagmus has an association with the duration of orthostatic intolerance.
Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This observation has been modeled in rodents subjected to maternal immune ...activation (MIA). The immune cell populations critical in the MIA model have not been identified. Using both genetic mutants and blocking antibodies in mice, we show that retinoic acid receptor–related orphan nuclear receptor gamma t (RORγt)–dependent effector T lymphocytes for example, T helper 17 (TH17) cells and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes.
Meaningful social interactions modify behavioral responses to sensory stimuli. The neural mechanisms underlying the entrainment of neutral sensory stimuli to salient social cues to produce social ...learning remain unknown. We used odor-driven behavioral paradigms to ask if oxytocin, a neuropeptide implicated in various social behaviors, plays a crucial role in the formation of learned associations between odor and socially significant cues. Through genetic, optogenetic, and pharmacological manipulations, we show that oxytocin receptor signaling is crucial for entrainment of odor to social cues but is dispensable for entrainment to nonsocial cues. Furthermore, we demonstrate that oxytocin directly impacts the piriform, the olfactory sensory cortex, to mediate social learning. Lastly, we provide evidence that oxytocin plays a role in both appetitive and aversive social learning. These results suggest that oxytocin conveys saliency of social stimuli to sensory representations in the piriform cortex during odor-driven social learning.
•Oxytocin receptor signaling is specifically required for social learning•Oxytocin neuron stimulation facilitates social learning•Oxytocin directly impacts the piriform cortex to mediate social learning•Both appetitive and aversive social learning require oxytocin receptor signaling
Choe, Reed et al. demonstrated that oxytocin receptor signaling is specifically required for learning with appetitive or aversive social cues through its direct impact on the piriform cortex. Oxytocin conveys saliency of social cues of opposing valence to sensory representations.
Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a ...possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1
; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca
/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1
; CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.
Background
Recent evidence indicates that Staphylococcus aureus, one of the most important human pathogens, secretes vesicles into the extracellular milieu.
Objective
To evaluate whether inhalation ...of S. aureus‐derived extracellular vesicles (EV) is causally related to the pathogenesis of inflammatory pulmonary diseases.
Methods
Staphylococcus aureus EV were prepared by sequential ultrafiltration and ultracentrifugation. The innate immune response was evaluated in vitro after the application of EV to airway epithelial cells and alveolar macrophages. In vivo innate and adaptive immune responses were evaluated after airway exposure to EV. Adjuvant effects of EV on the development of hypersensitivity to inhaled allergens were also evaluated after airway sensitization with S. aureus EV and ovalbumin (OVA).
Results
Staphylococcus aureus and S. aureus EV were detected in house dust. Alveolar macrophages produced both tumor necrosis α (TNF‐α) and interleukin 6 (IL‐6) after in vitro stimulation with S. aureus EV, whereas airway epithelial cells produced only IL‐6. Repeated airway exposure to S. aureus EV induced both Th1 and Th17 cell responses and neutrophilic pulmonary inflammation, mainly via a Toll‐like receptor 2 (TLR2)‐dependent mechanism. In terms of adjuvant effects, airway sensitization with S. aureus EV and OVA resulted in neutrophilic pulmonary inflammation after OVA challenge alone. This phenotype was partly reversed by the absence of interferon γ (IFN‐γ) or IL‐17.
Conclusion
Staphylococcus aureus EV can induce Th1 and Th17 neutrophilic pulmonary inflammation, mainly in a TLR2‐dependent manner. Additionally, S. aureus EV enhance the development of airway hypersensitivity to inhaled allergens.
This study examined chronic and short-term stress effects on heart rate variability (HRV), comparing time, frequency and phase domain (complexity) measures in 50 healthy adults. The hassles frequency ...subscale of the combined hassles and uplifts scale (CHUS) was used to measure chronic stress. Short-term stressor reactivity was assessed with a speech task. HRV measures were determined via surface electrocardiogram (ECG). Because respiration rate decreased during the speech task (
p
<
.001), this study assessed the influence of respiration rate changes on the effects of interest. A series of repeated-measures analyses of covariance (ANCOVA) with Bonferroni adjustment revealed that short-term stress decreased HR D2 (calculated via the pointwise correlation dimension PD2) (
p
<
.001), but increased HR mean (
p
<
.001), standard deviation of R–R (SD
RR) intervals (
p
<
.001), low (LF) (
p
<
.001) and high frequency band power (HF) (
p
=
.009). Respiratory sinus arrhythmia (RSA) and LF/HF ratio did not change under short-term stress. Partial correlation adjusting for respiration rate showed that HR D2 was associated with chronic stress (
r
=
−.35,
p
=
.019). Differential effects of chronic and short-term stress were observed on several HRV measures. HR D2 decreased under both stress conditions reflecting lowered functionality of the cardiac pacemaker. The results confirm the importance of complexity metrics in modern stress research on HRV.
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