Tradeoff between stability and maneuverability during whole-body movements

Background

Understanding how stability and/or maneuverability affects motor control strategies can provide insight on moving about safely in an unpredictable world. Stability in human movement has been well-studied while maneuverability has not. Further, a tradeoff between stability and maneuverability during movement seems apparent, yet has not been quantified. We proposed that greater maneuverability, the ability to rapidly and purposefully change movement direction and speed, is beneficial in uncertain environments. We also hypothesized that gaining maneuverability comes at the expense of stability and perhaps also corresponds with decreased muscle coactivation.

Materials and Methods

We used a goal-directed forward lean movement task that integrated both stability and maneuverability. Subjects (n = 11) used their center of pressure to control a cursor on a computer monitor to reach a target. We added task uncertainty by shifting the target anterior-posterior position mid-movement. We used a balance board with a narrow beam that reduced the base of support in the medio-lateral direction and defined stability as the probability that subjects could keep the balance board level during the task.

Results

During the uncertainty condition, subjects were able to change direction of their anterior-posterior center of pressure more rapidly, indicating that subjects were more maneuverable. Furthermore, medio-lateral center of pressure excursions also approached the edges of the beam and reduced stability margins, implying that subjects were less stable (i.e. less able to keep the board level). On the narrow beam board, subjects increased muscle coactivation of lateral muscle pairs and had greater muscle activity in the left leg. However, there were no statistically significant differences in muscle activity amplitudes or coactivation with uncertainty.

Conclusions/Significance

These results demonstrate that there is a tradeoff between stability and maneuverability during a goal-directed whole-body movement. Tasks with added uncertainty could help individuals learn to be more maneuverable yet sufficiently stable.     

Building excitatory and inhibitory synapses: balancing neuroligin partnerships

Processing of neural information is thought to occur by integration of excitatory and inhibitory synaptic inputs. As such, precise control mechanisms must exist to maintain an appropriate balance between each synapse type. Recent findings indicate that neuroligins and their synaptic binding partners modulate the development of both excitatory and inhibitory synapses. Here we highlight these findings and discuss a mechanism potentially involved in controlling the balance between excitation and inhibition.     

Proinflammatory cytokines (TNF-alpha and IL-6) in Egyptian patients with SLE: its correlation with disease activity

BACKGROUND: Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by a wide variety of autoantibodies, some of which are pathogenic. In recent years it has become more evident that the polyclonal B cell activation in SLE is T-cell dependent. The stimulation of the autoantibody producing B cells is likely mediated by the TH2 subtype of T cells producing IL-4, IL-5, IL-6 and IL- 10, whereas the TH1 subtype secreting IL-2 and IFN-gamma predominates in cell-mediated immune response. Tumor Necrosis Factor (TNF-alpha) is both a proinflammatory and an immunoregulatory cytokine. TNF-alpha has differential effects on B cells, on T cells and on dendritic cells as well as on the process of programmed cell death. Understanding how the immune system integrates the pleiotropic properties of TNF-alpha is a challenge, particularly so in diseases like SLE. Meanwhile the role of IL-6 in the pathogenesis of SLE is controversial. Objective: To investigate whether serum levels of TNF-alpha and IL-6 is higher in Egyptian patients with SLE than healthy control volunteers and its correlation with the clinical activity in patients with different activity scores as measured by Systemic Lupus Erythmatosus Disease Activity Index (SLEADI). Methods: Sixty individuals (40 patients with Systemic lupus Erythmatosus and 20 healthy control volunteers) were the subject of this study, they were subjected to thorough clinical examination, laboratory investigations, their clinical disease activity was scored according to SLEDAI, and serum sampling was obtained for TNF-alpha and IL-6 levels assay. Renal biopsy was carried out and examined by light microscopy by a pathologist blinded with the clinical activity. Results: The mean level of TNF-alpha was (766.95+/-357.82Pg/ml) for patients with active disease while it was (314.01+/-100.87Pg/ml) for those with inactive disease and (172.7+/-39.19Pg/ml) for the healthy control group. The difference was statistically significant (P=.002). The mean level of IL-6 was (135.4+/-54.23Pg/ml) for patients with active disease while it was (47.33+/-18.61Pg/ml) for those with inactive disease and (21.15+/-10.99Pg/ml) for the healthy control group. The difference was statistically significant (P=.002). A significant correlations between TNF-alpha and IL-6 serum levels and the SLEDAI score was observed (r=.743 and .772, respectively). Conclusion: Serum TNF-alpha and IL-6 are sensitive markers of SLE disease activity. They may be useful independent markers for prediction of SLE disease activity and to differentiate normal subjects from those having SLE. Possible therapeutic implications in the treatment of SLE in the future deserve wide scale trials.     

A preformed complex of postsynaptic proteins is involved in excitatory synapse development

Nonsynaptic clusters of postsynaptic proteins have been documented; however, their role remains elusive. We monitored the trafficking of several candidate proteins implicated in synaptogenesis, when nonsynaptic clusters of scaffold proteins are most abundant. We find a protein complex consisting of two populations that differ in their content, mobility, and involvement in synapse formation. One subpopulation is mobile and relies on actin transport for delivery to nascent and existing synapses. These mobile clusters contain the scaffolding proteins PSD-95, GKAP, and Shank. A proportion of mobile clusters that exhibits slow movement and travels short distances contains neuroligin-1. The second group consists of stationary nonsynaptic scaffold complexes that mainly contain neuroligin-1, can recruit synaptophysin-containing axonal transport vesicles, and are readily transformed to functional presynaptic contacts that recycle the vital dye FM 4-64. These results postulate a mechanism whereby preformed scaffold protein complexes serve as predetermined postsynaptic hotspots for establishment of new functional excitatory synapses.     

Phenotypic screening of hepatocyte nuclear factor (HNF) 4-gamma receptor knockout mice

Using the mouse as a model organism in pharmaceutical research presents unique advantages as its physiology in many ways resembles the human physiology, it also has a relatively short generation time, low breeding and maintenance costs, and is available in a wide variety of inbred strains. The ability to genetically modify mouse embryonic stem cells to generate mouse models that better mimic human disease is another advantage. In the present study, a comprehensive phenotypic screening protocol is applied to elucidate the phenotype of a novel mouse knockout model of hepatocyte nuclear factor (HNF) 4-gamma. HNF4-gamma is expressed in the kidneys, gut, pancreas, and testis. The first level of the screen is aimed at general health, morphologic appearance, normal cage behaviour, and gross neurological functions. The second level of the screen looks at metabolic characteristics and lung function. The third level of the screen investigates behaviour more in-depth and the fourth level consists of a thorough pathological characterisation, blood chemistry, haematology, and bone marrow analysis. When compared with littermate wild-type mice (HNF4-gamma(+/+)), the HNF4-gamma knockout (HNF4-gamma(-/-)) mice had lowered energy expenditure and locomotor activity during night time that resulted in a higher body weight despite having reduced intake of food and water. HNF4-gamma(-/-) mice were less inclined to build nest and were found to spend more time in a passive state during the forced swim test.     

Effects of polymorphisms in nucleotide-binding oligomerization domains 1 and 2 on biomarkers of the metabolic syndrome and type II diabetes

The innate immune receptor toll-like receptor 4 (TLR4) has been implicated in mediating some of the effects of dietary lipids on inflammation and type 2 diabetes (T2D). Similar to TLR4, the nucleotide-binding oligomerization domains (Nods) 1 and 2 are also proteins of innate immunity, which can respond to lipids and initiate pro-inflammatory signalling that plays a role in the aetiology of T2D. The objective was to determine the effect of Nod1 (Glu266Lys) and Nod2 (Ser268Pro) genotypes on factors associated with the metabolic syndrome (MetS), and whether they modify the association between dietary lipids and biomarkers of the MetS. Men and women (n = 998) between the ages of 20–29 years were genotyped for both polymorphisms, completed a one-month, semiquantitative food frequency questionnaire and provided a fasting blood sample. The Glu266Lys polymorphism in Nod1 was not associated with any of the biomarkers of the MetS, but modified the association between dietary saturated fat (SFA) and insulin sensitivity, as measured by HOMA-IR (p for interaction = 0.04). Individuals with the Glu/Glu or Glu/Lys genotype showed no significant relationship between dietary SFA and HOMA-IR (β = −0.002 ± 0.006, p = 0.77; and β = −0.003 ± 0.006, p = 0.61), while those with the Lys/Lys genotype showed a positive association (β = 0.033 ± 0.02, p = 0.03). The Nod2 Ser268Pro polymorphism was not associated with components of the MetS and did not modify the relationship between dietary lipid intake and the biomarkers of MetS. In summary, the Nod1 Glu266Lys polymorphism modifies the relationship between dietary SFA intake and HOMA-IR, suggesting that Nod1 may act as an intracellular lipid sensor affecting insulin sensitivity.     

Report on the levels of cadmium, lead, and mercury in imported rice grain samples

In an attempt to know whether highly consumed food might contribute to metal exposure, we analyzed cadmium, lead, and mercury in 27 rice grain samples commonly consumed in Saudi Arabia by atomic absorption spectrometry after acid digestion. The mean concentrations and ranges of cadmium, lead, and mercury in tested rice samples were 20.261 (range <DL-178.026 μg/kg), 134.819 (range 23.1–1529.0 μg/kg), and 3.186 (range <DL-43.573 μg/kg), respectively. The results showed high concentrations of metals and in some cases exceeded the Provisional Tolerance Weekly Intake (PTWI) recommended by FAO/WHO. It was also noted that different rice grain samples had varying concentrations of these metals. Because the bulk of literature warns against the cumulative effects of prolonged heavy metal exposure, regular consumption of rice by local populations might pose potential health problems.     

Mercury (Hg) Exposure in Breast-Fed Infants and Their Mothers and the Evidence of Oxidative Stress

The objective of this work was to assess exposure to mercury (Hg) and its induction of oxidative stress in 155 healthy lactating Saudi mothers and their infants. Samples of breast milk and blood were collected from the mothers, while urine was taken from both infants and mothers. Both urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) were measured in mothers and infants as biomarkers of oxidative stress. The mean concentration of Hg in breast milk was 1.19 μg/L (range 0.012–6.44 μg/L) with only one mother having Hg >4 μg/L, the upper limit established by the US Agency for Toxic Substance and Disease Registry. However, 57.4 % had Hg ≥1 μg/L, the background level for Hg in human milk. The mean urinary Hg corrected for creatinine (Hg-C) in mothers and infants was 1.47 and 7.90 μg/g creatinine, respectively, with a significant correlation between the two (p?<?0.001). Urinary Hg levels over 5 μg/g creatinine (the background level in an unexposed population) were found in 3.3 % of mothers and 50.1 % of infants. None of the mothers had total blood Hg above the US Environmental Protection Agency’s maximum reference dose of 5.8 μg/L. No correlation was noted between urinary Hg in infants and Hg in breast milk (p?>?0.05). Hg in breast milk, though, was associated with Hg in blood (p?<?0.001), suggesting the efficient transfer of Hg from blood to milk. Hg in the breast milk of mothers and in the urine of infants affected the excretion of urinary MDA and 8-OHdG, respectively, in a dose-related manner. These findings reveal for the first time lactational exposure to Hg-induced oxidative stress in breast-fed infants, which may play a role in pathogenesis, particularly during neurodevelopment. This will also contribute to the debate over the benefits of breast milk versus the adverse effects of exposure to pollutants. Nevertheless, breastfeeding should not be discouraged, but efforts should be made to identify and eliminate the source of Hg exposure in the population.     

Synthesis,antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies

A new series of NSAID thioesters were synthesized and evaluated for their in vitro antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds 2b, 3b, 6a, 7a, 7b and 8a showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. In vitro COX-1/COX-2 enzyme inhibition assay results indicated that compounds 2b, 3b, 6a, 7a, 7b, 8a and 8?b selectively inhibited the COX-2 enzyme (IC₅₀?=?～0.20–0.69?μM), with SI values of (>72.5–250) compared with celecoxib (IC₅₀?=?0.16?μM, COX-2 SI:?>?312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC₅₀?>?50?μM). On the other hand, EGFR, HER2, HER4 and cSrc kinase inhibition assays were evaluated at a 10?μM concentration. The selected candidates displayed limited activities against the various tested kinases; the compounds 2a, 3b, 6a, 7a, 7b and 8a showed no activity to weak activity (% inhibition?=?～0–10%). The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX-2. The aforementioned results indicated that thioester based on NSAID scaffolds derivatives may serve as new antitumor compounds.     

The prostaglandin EP4 receptor is a master regulator of the expression of PGE2 receptors following inflammatory activation in human monocytic cells

Prostaglandin E₂ (PGE₂) is responsible for inflammatory symptoms. However, PGE₂ also suppresses pro-inflammatory cytokine production. There are at least 4 subtypes of PGE₂ receptors, EP1–EP4, but it is unclear which of these specifically control cytokine production. The aim of this study was to determine which of the different receptors, EP1R–EP4R modulate production of tumor necrosis factor-α (TNF-α) in human monocytic cells.Human blood, or the human monocytic cell line THP-1 were stimulated with LPS. The actions of PGE₂, alongside selective agonists of EP1–EP4 receptors, were assessed on LPS-induced TNF-α, IL-1β and IL-10 release. The expression profiles of EP2R and EP4R in monocytes and THP-1 cells were characterised by RT-qPCR. In addition, the production of cytokines was evaluated following knockdown of the receptors using siRNA and over-expression of the receptors by transfection with constructs.PGE₂ and also EP2 and EP4 agonists (but not EP1 or EP3 agonists) suppressed TNF-α production in blood and THP-1 cells. LPS also up regulated expression of EP2R and EP4R but not EP1 or EP3. siRNA for either EP2R or EP4R reversed the suppressive actions of PGE₂ on cytokine production and overexpression of EP2R and EP4R enhanced the suppressive actions of PGE₂.This indicates that PGE₂ suppression of TNF-α by human monocytic cells occurs via EP2R and EP4R expression. However EP4Rs also control their own expression and that of EP2 whereas the EP2R does not affect EP4R expression. This implies that EP4 receptors have an important master role in controlling inflammatory responses.