Targeted-Neuroinflammation Mitigation Using Inflammasome-Inhibiting Nanoligomers is Therapeutic in an Experimental Autoimmune Encephalomyelitis Mouse Model.

Multiple sclerosis (MS) is a debilitating autoimmune disease that impacts millions of patients worldwide, disproportionately impacting women (4:1), and often presenting at highly productive stages of life. This disease affects the spinal cord and brain and is characterized by severe neuroinflammation, demyelination, and subsequent neuronal damage, resulting in symptoms like loss of mobility. While untargeted and pan-immunosuppressive therapies have proven to be disease-modifying and manage (or prolong the time between) symptoms in many patients, a significant fraction are unable to achieve remission. Recent work has suggested that targeted neuroinflammation mitigation through selective inflammasome inhibition can offer relief to patients while preserving key components of immune function. Here, we show a screening of potential therapeutic targets using inflammasome-inhibiting Nanoligomers (NF-κB1, TNFR1, TNF-α, IL-6) that meet or far-exceed commercially available small-molecule counterparts like ruxolitinib, MCC950, and deucravacitinib. Using the human brain organoid model, top Nanoligomer combinations (NF-κB1 + TNFR1: NI111, and NF-κB1 + NLRP3: NI112) were shown to significantly reduce neuroinflammation without any observable negative impact on organoid function. Further testing of these top Nanoligomer combinations in an aggressive experimental autoimmune encephalomyelitis (EAE) mouse model for MS using intraperitoneal (IP) injections showed that NF-κB1 and NLRP3 targeting Nanoligomer combination NI112 rescues mice without observable loss of mobility or disability, minimal inflammation in brain and spinal cord histology, and minimal to no immune cell infiltration of the spinal cord and no demyelination, similar to or at par with mice that received no EAE injections (negative control). Mice receiving NI111 (NF-κB1 + TNFR1) also showed reduced neuroinflammation compared to saline (sham)-treated EAE mice and at par/similar to other inflammasome-inhibiting small molecule treatments, although it was significantly higher than NI112 leading to subsequent worsening clinical outcomes. Furthermore, treatment with an oral formulation of NI112 at lower doses showed a significant reduction in EAE severity, albeit with higher variance owing to administration and formulation/fill-and-finish variability. Overall, these results point to the potential of further development and testing of these inflammasome-targeting Nanoliogmers as an effective neuroinflammation treatment for multiple neurodegenerative diseases and potentially benefit several patients suffering from such debilitating autoimmune diseases like MS.

Targeting Neuroinflammation by Pharmacologic Downregulation of Inflammatory Pathways Is Neuroprotective in Protein Misfolding Disorders.

Neuroinflammation plays a crucial role in the development of neurodegenerative protein misfolding disorders. This category of progressive diseases includes, but is not limited to, Alzheimer's disease, Parkinson's disease, and prion diseases. Shared pathogenesis involves the accumulation of misfolded proteins, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to irreversible neuronal loss, measurable cognitive deficits, and death. Presently, there are few to no effective treatments to halt the advancement of neurodegenerative diseases. We hypothesized that directly targeting neuroinflammation by downregulating the transcription factor, NF-κB, and the inflammasome protein, NLRP3, would be neuroprotective. To achieve this, we used a cocktail of RNA targeting therapeutics (SB_NI_112) shown to be brain-penetrant, nontoxic, and effective inhibitors of both NF-κB and NLRP3. We utilized a mouse-adapted prion strain as a model for neurodegenerative diseases to assess the aggregation of misfolded proteins, glial inflammation, neuronal loss, cognitive deficits, and lifespan. Prion-diseased mice were treated either intraperitoneally or intranasally with SB_NI_112. Behavioral and cognitive deficits were significantly protected by this combination of NF-κB and NLRP3 downregulators. Treatment reduced glial inflammation, protected against neuronal loss, prevented spongiotic change, rescued cognitive deficits, and significantly lengthened the lifespan of prion-diseased mice. We have identified a nontoxic, systemic pharmacologic that downregulates NF-κB and NLRP3, prevents neuronal death, and slows the progression of neurodegenerative diseases. Though mouse models do not always predict human patient success and the study was limited due to sample size and number of dosing methods utilized, these findings serve as a proof of principle for continued translation of the therapeutic SB_NI_112 for prion disease and other neurodegenerative diseases. Based on the success in a murine prion model, we will continue testing SB_NI_112 in a variety of neurodegenerative disease models, including Alzheimer's disease and Parkinson's disease.

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy.

Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer's disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. In this study, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old (aged 19 months) wildtype mice, and in rTg4510 tau pathology mice (aged 2 months). We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and rTg4510 mice. These effects of NF-κB/NLRP3-targeting Nanoligomers were also associated with reduced glial cell activation and pathology, favorable changes in transcriptome signatures of glia-associated inflammation (reduced) and neuronal health (increased), and positive systemic effects. Collectively, our results provide a basis for future translational studies targeting both NF-κB and NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegeneration.

Intranasally delivered mesenchymal stromal cells decrease glial inflammation early in prion disease.

Mesenchymal stromal cells (MSCs) are an intriguing avenue for the treatment of neurological disorders due to their ability to migrate to sites of neuroinflammation and respond to paracrine signaling in those sites by secreting cytokines, growth factors, and other neuromodulators. We potentiated this ability by stimulating MSCs with inflammatory molecules, improving their migratory and secretory properties. We investigated the use of intranasally delivered adipose-derived MSCs (AdMSCs) in combating prion disease in a mouse model. Prion disease is a rare, lethal neurodegenerative disease that results from the misfolding and aggregation of the prion protein. Early signs of this disease include neuroinflammation, activation of microglia, and development of reactive astrocytes. Later stages of disease include development of vacuoles, neuronal loss, abundant aggregated prions, and astrogliosis. We demonstrate the ability of AdMSCs to upregulate anti-inflammatory genes and growth factors when stimulated with tumor necrosis factor alpha (TNFα) or prion-infected brain homogenates. We stimulated AdMSCs with TNFα and performed biweekly intranasal deliveries of AdMSCs on mice that had been intracranially inoculated with mouse-adapted prions. At early stages in disease, animals treated with AdMSCs showed decreased vacuolization throughout the brain. Expression of genes associated with Nuclear Factor-kappa B (NF-κB) and Nod-Like Receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling were decreased in the hippocampus. AdMSC treatment promoted a quiescent state in hippocampal microglia by inducing changes in both number and morphology. Animals that received AdMSCs showed a decrease in both overall and reactive astrocyte number, and morphological changes indicative of homeostatic astrocytes. Although this treatment did not prolong survival or rescue neurons, it demonstrates the benefits of MSCs in combatting neuroinflammation and astrogliosis.

Eccentric exercise-induced muscle weakness abolishes sex differences in fatigability during sustained submaximal isometric contractions.

BACKGROUND: Females are typically less fatigable than males during sustained isometric contractions at lower isometric contraction intensities. This sex difference in fatigability becomes more variable during higher intensity isometric and dynamic contractions. While less fatiguing than isometric or concentric contractions, eccentric contractions induce greater and longer lasting impairments in force production. However, it is not clear how muscle weakness influences fatigability in males and females during sustained isometric contractions. METHODS: We investigated the effects of eccentric exercise-induced muscle weakness on time to task failure (TTF) during a sustained submaximal isometric contraction in young (18-30 years) healthy males (n = 9) and females (n = 10). Participants performed a sustained isometric contraction of the dorsiflexors at 35° plantar flexion by matching a 30% maximal voluntary contraction (MVC) torque target until task failure (i.e., falling below 5% of their target torque for ≥2 s). The same sustained isometric contraction was repeated 30 min after 150 maximal eccentric contractions. Agonist and antagonist activation were assessed using surface electromyography over the tibialis anterior and soleus muscles, respectively. RESULTS: Males were ∼41% stronger than females. Following eccentric exercise both males and females experienced an ∼20% decline in maximal voluntary contraction torque. TTF was ∼34% longer in females than males prior to eccentric exercise-induced muscle weakness. However, following eccentric exercise-induced muscle weakness, this sex-related difference was abolished, with both groups having an ∼45% shorter TTF. Notably, there was ∼100% greater antagonist activation in the female group during the sustained isometric contraction following exercise-induced weakness as compared to the males. CONCLUSION: This increase in antagonist activation disadvantaged females by decreasing their TTF, resulting in a blunting of their typical fatigability advantage over males.

Eccentric exercise-induced muscle weakness amplifies the history dependence of force.

INTRODUCTION: Following active lengthening or shortening contractions, isometric steady-state torque is increased (residual force enhancement; rFE) or decreased (residual force depression; rFD), respectively, compared to fixed-end isometric contractions at the same muscle length and level of activation. Though the mechanisms underlying this history dependence of force have been investigated extensively, little is known about the influence of exercise-induced muscle weakness on rFE and rFD. PURPOSE: Assess rFE and rFD in the dorsiflexors at 20%, 60%, and 100% maximal voluntary torque (MVC) and activation matching, and electrically stimulated at 20% MVC, prior to, 1 h following, and 24 h following 150 maximal eccentric dorsiflexion contractions. METHODS: Twenty-six participants (13 male, 24.7 ± 2.0y; 13 female, 22.5 ± 3.6y) were seated in a dynamometer with their right hip and knee angle set to 110° and 140°, respectively, with an ankle excursion set between 0° and 40° plantar flexion (PF). MVC torque, peak twitch torque, and prolonged low frequency force depression were used to assess eccentric exercise-induced neuromuscular impairments. History-dependent contractions consisted of a 1 s isometric (40°PF or 0°PF) phase, a 1 s shortening or lengthening phase (40°/s), and an 8 s isometric (0°PF or 40°PF) phase. RESULTS: Following eccentric exercise; MVC torque was decreased, prolonged low frequency force depression was present, and both rFE and rFD increased for all maximal and submaximal conditions. CONCLUSIONS: The history dependence of force during voluntary torque and activation matching, and electrically stimulated contractions is amplified following eccentric exercise. It appears that a weakened neuromuscular system amplifies the magnitude of the history-dependence of force.

Impaired activation of Notch-1 signaling hinders repair processes of bronchial epithelial cells exposed to cigarette smoke.

Notch-1 intervenes in the reparative processes of mucosa by controlling cell proliferation, differentiation and stem cell maintenance. Cigarette smoke alters airway epithelial homeostasis. The present study explored whether: Smokers showed altered Notch-1 expression; and whether in bronchial epithelial cells (16HBE): a) cigarette smoke extracts (CSE) altered the expression of Notch-1, of its ligand Jagged-1 (Jag-1) and the nuclear translocation of Notch-1; b) Notch-1 signaling activation as well as CSE modified Ki67, PCNA, p21, IL-33 expression, cell proliferation and repair processes. Notch-1 expression was assessed in the epithelium from large airway surgical samples from non-smoker and smoker subjects by immunohistochemistry.16HBE were cultured with/without CSE and Jag-1. A Notch-1 inhibitor (DAPT) was used as control. The expression of Notch-1, Jag-1, Ki67, PCNA, p21, IL-33 and cell proliferation (by CFSE) were all assessed by flow cytometry. Notch-1 nuclear expression was evaluated by immunofluorescence and western blot analysis. Repair processes were assessed by wound assay. Smokers had cytoplasmic but not nuclear Notch-1 expression. Although CSE increased Notch-1 expression, it counteracted Notch-1 signaling activation since it reduced Jag-1 expression and Notch-1 nuclear translocation. Notch-1 signaling activation by Jag-1 increased Ki67, PCNA and repair processes but reduced intracellular IL-33 and p21 expression without affecting cell proliferation. DAPT counteracted the effects of Notch-1 activation on PCNA and IL-33. CSE increased Ki67, PCNA, p21 and IL-33 expression but reduced cell proliferation and repair processes. In conclusion, cigarette smoke exposure, limiting Notch-1 signaling activation and hindering repair processes, amplifies injury processes in bronchial epithelial cells.

The Inhibitory Tendon-Evoked Reflex Is Increased in the Torque-Enhanced State Following Active Lengthening Compared to a Purely Isometric Contraction.

Residual torque enhancement (rTE) is a history-dependent property of muscle, which results in an increase in steady-state isometric torque production following an active lengthening contraction as compared to a purely isometric (ISO) contraction at the same muscle length and level of activation. Once thought to be only an intrinsic property of muscle, recent evidence during voluntary contractions indicates a neuromechanical coupling between motor neuron excitability and the contractile state of the muscle. However, the mechanism by which this occurs has yet to be elucidated. The purpose of this study was to investigate inhibition arising from tendon-mediated feedback (e.g., Golgi tendon organ; GTO) through tendon electrical stimulation (TStim) in the ISO and rTE states during activation-matching and torque-matching tasks. Fourteen male participants (22 ± 2 years) performed 10 activation-matching contractions at 40% of their maximum tibialis anterior electromyography amplitude (5 ISO/5 rTE) and 10 torque-matching contractions at 40% of their maximum dorsiflexion torque (5 ISO/5 rTE). During both tasks, 10 TStim were delivered during the isometric steady state of all contractions, and the resulting tendon-evoked inhibitory reflexes were averaged and analyzed. Reflex amplitude increased by ~23% in the rTE state compared to the ISO state for the activation-matching task, and no differences were detected for the torque-matching task. The current data indicate an important relationship between afferent feedback in the torque-enhanced state and voluntary control of submaximal contractions. The history-dependent properties of muscle is likely to alter motor neuron excitability through modifications in tension- or torque-mediated afferent feedback arising from the tendon.

Cigarette smoke extract modulates E-Cadherin, Claudin-1 and miR-21 and promotes cancer invasiveness in human colorectal adenocarcinoma cells.

BACKGROUND: Cigarette smoke is considered a risk factor for lung and colorectal cancer. A convincing link between epithelial-to-mesenchymal transition (EMT) with colorectal cancer progression and therapeutic resistance has emerged. Deregulated expression of E-Cadherin and Claudin-1 and increased miR-21 expression and invasiveness represent hallmarks of EMT. The effects of cigarette smoke exposure on EMT in colorectal adenocarcinoma cells are largely unknown. AIM: The aim of the study is to evaluate the effect of cigarette smoke extract (CSE) on miR-21, Claudin-1 and E-Cadherin, molecules associated to EMT in colorectal cancer cells. METHODS: A human colorectal adenocarcinoma cell line (Caco-2) was treated with CSE at different concentration (5% and 10%) and for different time points (3 h and 24 h). Metabolic activity (by MTS assay), cell necrosis/cell apoptosis (evaluating Propidium Iodide/Annexin V expression by flow cytometry), miR-21, Claudin-1 and E-Cadherin gene expression were evaluated by Real time PCR. Cell permeability, actin polymerization and cancer cell migration was assessed by Trans-Epitelial Electrical Resistance (TEER), Phalloidin expression and matrigel system, respectively. RESULTS: CSE at all the tested concentrations and at all time points reduced cell necrosis. CSE at 10% increased miR-21 and reduced the metabolic activity, cell necrosis, Claudin-1 and E-cadherin mRNA at 3 h. Cell permeability, actin polymerization and cancer cell migration were all increased upon CSE exposure. CONCLUSION: These results showed that CSE increasing miR-21, Claudin-1 and E-Cadherin and enhancing the aggressiveness of cancer cells, may concur to colorectal cancer progression.

Budesonide, Aclidinium and Formoterol in combination limit inflammaging processes in bronchial epithelial cells exposed to cigarette smoke.

Inflammation and cellular senescence (also called inflammaging) are involved in the pathogenesis of premature lung aging, a key driver of chronic obstructive pulmonary disease (COPD). Downregulation of histone deacetylases and FoxO3 expression, activation of the ERK 1/2 pathway and IL-8 increase are hallmarks of lung inflammaging. The effects of Budesonide (BUD), Aclidinium (ACL) and Formoterol (FO) on lung inflammaging are unknown. This study was aimed to assess the effects of BUD, ACL and FO in bronchial epithelial cells exposed to cigarette smoke extract (CSE) by evaluating: a) Expression of TLR4 and survivin and LPS binding by flow cytometry; b) expression of HDAC2, HDAC3, SIRT1 and FoxO3 and activation of the ERK 1/2 pathway by western blot; c) IL-8 mRNA levels and release by Real Time-PCR and ELISA, respectively. Reported results show that CSE increased TLR4 and survivin, LPS binding, ERK 1/2 activation, IL-8 release and mRNA levels but decreased SIRT1, HDAC2, HDAC3 and FoxO3 nuclear expression. Combined therapy with BUD, ACL and FO counteracted the effects of CSE on LPS binding, FoxO3 nuclear expression, ERK 1/2 activation, survivin and IL-8 release and mRNA levels. These findings suggest a new role of combination therapy with BUD, ACL and FO in counteracting inflammaging processes induced by cigarette smoke exposure.

Notch-1 signaling activation sustains overexpression of interleukin 33 in the epithelium of nasal polyps.

BACKGROUND: Alterations in the nasal epithelial barrier homeostasis and increased interleukin 33 (IL-33) expression contribute to the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). AIMS: As Notch-1 signaling is crucial in repair processes of mucosa, the current study assessed Notch-1/Jagged-1 signaling and IL-33 in the epithelium of nasal polyps biopsies from allergic (A-CRSwNP; n = 9) and not allergic (NA-CRSwNP; n = 9) subjects by immunohistochemistry. We also assessed, in a model of nasal epithelial cells, the effects of stimulation of Notch-1 with Jagged-1 on the expression of IL-33 (by flow cytometry, immunofluorescence, and immunocytochemistry), Jagged-1 (by flow cytometry), and p-CREB transcription factor (by western blot analysis). RESULTS: Ex vivo (a) in normal epithelium, the expression of Notch-1 and IL-33 were higher in NA-CRSwNP than in A-CRSwNP; (b) in metaplastic epithelium, the expression of Notch-1, Jagged-1, and IL-33 were higher in NA-CRSwNP than in A-CRSwNP; (c) in hyperplastic epithelium, the expression of Notch-1, Jagged-1, and IL-33 were higher in A-CRSwNP than in NA-CRSwNP; and (d) in basal epithelial cells, no differences were observed in the expression of Jagged-1, IL-33, and Notch-1. The expression of Notch-1 significantly correlated with the expression of IL-33. In vitro, stimulation of Notch-1 with Jagged-1 induced the expression of (a) Jagged-1; (b) IL-33; and (c) p-CREB transcription factor. The inhibitor of Notch-1, DAPT, reduced all the effects of Jagged-1 on nasal epithelial cells. CONCLUSIONS: The data herein provided support, for the first time, a putative role of Notch-1/Jagged-1 signaling in the overexpression of IL-33 in the epithelium of nasal polyps from patients with CRSwNP.

Central contributions to torque depression: an antagonist perspective.

Torque depression (TD) is the reduction in steady-state isometric torque following active muscle shortening when compared to an isometric reference contraction at the same muscle length and activation level. Central nervous system excitability differs in the TD state. While torque production about a joint is influenced by both agonist and antagonist muscle activation, investigations of corticospinal excitability have focused on agonist muscle groups. Hence, it is unknown how the TD state affects spinal and supraspinal excitability of an antagonist muscle. Eight participants (~ 24y, three female) performed 14 submaximal dorsiflexion contractions at the intensity needed to maintain a level of integrated electromyographic activity in the soleus equivalent to 15% of that recorded during a maximum plantar flexion contraction. The seven contractions of the TD protocol included a 2 s isometric phase at an ankle angle of 140°, a 1 s shortening phase at 40°/s, and a 7 s isometric phase at an angle of 100°. The seven isometric reference contractions were performed at an ankle angle of 100° for 10 s. Motor evoked potentials (MEPs), cervicomedullary motor evoked potentials (CMEPs), and maximal M-waves (Mmax) were recorded from the soleus in both conditions. In the TD compared to isometric reference state, a 13% reduction in dorsiflexor torque was accompanied by 10% lower spinal excitability (normalized CMEP amplitude; CMEP/Mmax), and 17% greater supraspinal excitability (normalized MEP amplitude; MEP/CMEP) for the soleus muscle. These findings demonstrate a neuromechanical coupling following active muscle shortening and indicate that the underlying mechanisms of TD influence antagonist activation during voluntary force production.

Ultrasensitivity dynamics of diverse aryl hydrocarbon receptor modulators in a hepatoma cell line.

The aryl hydrocarbon receptor (AhR) is a nuclear receptor that facilitates a wide transcriptional response and causes a variety of adaptive and maladaptive physiological functions. Such functions are entirely dependent on the type of ligand activating it, and therefore, the nuances in the activation of this receptor at the single-cell level have become a research interest for different pharmacological and toxicological applications. Here, we investigate the activation of the AhR by diverse classes of compounds in a Hepa1c1c7-based murine hepatoma cell line. The exogenous compounds analyzed produced different levels of ultrasensitivity in AhR activation as measured by XRE-coupled EGFP production and analyzed by both flow cytometric and computational simulation techniques. Interestingly, simulation experiments reported herein were able to reproduce and quantitate the natural single-cell stochasticity inherent to mammalian cell lines as well as the ligand-specific differences in ultrasensitivity. Classical AhR modulators 2,3,7,8-tetrachlorodibenzodioxin (10- 1-105 pM), PCB-126 (10- 1-107 pM), and benzo[a]pyrene (10- 1-107 pM) produced the greatest levels of single-cell ultrasensitivity and most maximal responses, while consumption-based ligands indole-3-carbinol (103-109 pM), 3,3'-diindolylmethane (103-108 pM), and cannabidiol (103-108 pM) caused low-level AhR activation in more purely graded single-cell fashions. All compounds were tested and analyzed over a 24 h period for consistency. The comparative quantitative results for each compound are presented within. This study aids in defining the disparity between different types of AhR modulators that produce distinctly different physiological outcomes. In addition, the simulation tool developed for this study can be used in future studies to predict the quantitative effects of diverse types of AhR ligands in the context of pharmacological therapies or toxicological concerns.

Proprioception sense in lymphedema affected upper limb.

This study aimed to provide information on proprioception alterations in lymphedema-affected limbs. Blindfolded subjects sat at a table with their forearms positioned on paddles. The hinges of the paddles were aligned with the elbow joint and an electronic goniometer was positioned to measure the angle of the forearm. Paddles were moved by an electric servomotor with a slow angular speed that was barely appreciated by the subjects. Subjects were then asked to guess the position of the affected arm in comparison with the unaffected arm to study the position sense of the lymphedema-affected arm. The study investigated 50 women affected by secondary upper limb lymphedema by measuring the difference in terms of degrees of arch of movement in comparison with the unaffected arm and also both duration of lymphedema and the circumference of the forearm. Results were matched with a control group of 50 unaffected women providing proof of compromised proprioception in lymphedema-affected arms. In addition, results also showed a correlation with duration of lymphedema but not with size (stage) of the lymphedematous arm.

Residual force enhancement during submaximal and maximal effort contractions of the plantar flexors across knee angle.

Following active muscle lengthening, steady-state isometric force is elevated compared with an isometric contraction without prior lengthening for the same muscle length and activation level. This property of muscle contraction is known as residual force enhancement (RFE). Here, we aimed to determine whether neural factors may mask some of the mechanical benefits of RFE on plantar flexion torque production. Inherent to lengthening contractions is an increase in cortical and spinal-mediated inhibition, while knee flexion places the medial gastrocnemius at a neuromechanical disadvantage. Neuromuscular properties of the plantar flexors were investigated with a Humac Norm dynamometer in 10 males (∼27 years) with a flexed (90°) and extended (180°) knee and with or without calcaneal tendon vibration (frequency range: 80-110 Hz). There was no effect for vibration (p > 0.05), but there was an effect for knee angle (p < 0.05) such that there was a 2 fold increase in RFE with the knee flexed compared with extended. During submaximal torque matching, following active lengthening there was an activation reduction (electromyography; EMG) of 7.2 and 4.7% with the knee flexed and extended, respectively for soleus as compared with the reference isometric contraction, but no difference for the medial gastrocnemius. Despite attempting to excite Ia input onto the plantar flexor motor neuron pool, vibration had no influence on RFE. Surprisingly, RFE was elevated more for the knee flexed than extended, which was possibly owing to the activation differences across the disparate muscles of the triceps surae during the plantar flexion task.

Dopamine receptor D2 (DRD2), dopamine transporter solute carrier family C6, member 4 (SLC6A3), and catechol-O-methyltransferase (COMT) genes as moderators of the relation between maternal history of maltreatment and infant emotion regulation.

Although infants less than 18 months old are capable of engaging in self-regulatory behavior (e.g., avoidance, withdrawal, and orienting to other aspects of their environment), the use of self-regulatory strategies at this age (as opposed to relying on caregivers) is associated with elevated behavioral and physiological distress. This study investigated infant dopamine-related genotypes (dopamine receptor D2 [DRD2], dopamine transporter solute carrier family C6, member 4 [SLC6A3], and catechol-O-methyltransferase [COMT]) as they interact with maternal self-reported history of maltreatment to predict observed infant independent emotion regulation behavior. A community sample (N = 193) of mother-infant dyads participated in a toy frustration challenge at infant age 15 months, and infant emotion regulation behavior was coded. Buccal cells were collected for genotyping. Maternal maltreatment history significantly interacted with infant SLC6A3 and COMT genotypes, such that infants with more 10-repeat and valine alleles of SLC6A3 and COMT, respectively, relative to infants with fewer or no 10-repeat and valine alleles, utilized more independent (i.e., maladaptive) regulatory behavior if mother reported a more extensive maltreatment history, as opposed to less. The findings indicate that child genetic factors moderate the intergenerational impact of maternal maltreatment history. The results are discussed in terms of potential mechanism of Gene × Environment interaction.

Exercise Training Increases Parietal Lobe Cerebral Blood Flow in Chronic Stroke: An Observational Study.

Exercise is increasingly recommended as an essential component of stroke rehabilitation, yet uncertainty remains with respect to its direct effect on the cerebral vasculature. The current study first demonstrated the repeatability of pseudo-continuous arterial spin labeling (ASL) magnetic resonance imaging (MRI) in older adults with stroke, and then investigated the change in cerebrovascular function following a 6-month cardiovascular rehabilitation program. In the repeatability study, 12 participants at least 3 months post-stroke underwent two ASL imaging scans 1 month apart. In the prospective observational study, eight individuals underwent ASL imaging and aerobic fitness testing before and after a 6-month cardiovascular rehabilitation program. Cerebral blood flow (CBF) and the spatial coefficient of variation of CBF (sCoV) were quantified to characterize tissue-level perfusion and large cerebral artery transit time properties, respectively. In repeat scanning, intraclass correlation (ICC) indicated moderate test-retest reliability for global gray matter CBF (ICC = 0.73) and excellent reliability for sCoV (ICC = 0.94). In the observational study, gray matter CBF increased after training (baseline: 40 ± 13 vs. 6-month: 46 ± 12 ml·100 g-1·min-1, P = 0.036). The greatest change occurred in the parietal lobe (+18 ± 12%). Gray matter sCoV, however, did not change following training (P = 0.31). This study provides preliminary evidence that exercise-based rehabilitation in chronic stroke enhances tissue-level perfusion, without changing the relative hemodynamic properties of the large cerebral arteries.

Maternal DRD2, SLC6A3, and OXTR genotypes as potential moderators of the relation between maternal history of care and maternal cortisol secretion in the context of mother-infant separation.

A mother's cortisol secretion is importantly associated with her own mental health and her infant's cortisol secretion. This study investigated the influences of maternal history of care and maternal DRD2, SLC6A3, and OXTR genotypes on maternal cortisol in the context of infant stress. A community sample of 296 mother-infant dyads completed a maternal separation at infant age 17 months. Maternal salivary cortisol, buccal cells, and self-reported history of care were collected. Multilevel models revealed that history of care had a greater influence on maternal baseline cortisol (but not cortisol trajectory) for mothers with more plasticity alleles of SLC6A3 (10R) and OXTR (G), relative to mothers with fewer or no plasticity alleles. Findings indicate that a mother's history of care is related to her cortisol secretion in anticipation of infant stress, but that this relation depends on her genetic characteristics. Findings are discussed in relation to the maternal protective system and anticipatory cortisol secretion.