Sialic acid plays a pivotal role in licensing Citrobacter rodentium's transition from the intestinal lumen to a mucosal adherent niche.

Enteric bacterial pathogens pose significant threats to human health; however, the mechanisms by which they infect the mammalian gut in the face of daunting host defenses and an established microbiota remain poorly defined. For the attaching and effacing (A/E) bacterial family member and murine pathogen Citrobacter rodentium, its virulence strategy likely involves metabolic adaptation to the host's intestinal luminal environment, as a necessary precursor to reach and infect the mucosal surface. Suspecting this adaptation involved the intestinal mucus layer, we found that C. rodentium was able to catabolize sialic acid, a monosaccharide derived from mucins, and utilize it as its sole carbon source for growth. Moreover, C. rodentium also sensed and displayed chemotactic activity toward sialic acid. These activities were abolished when the nanT gene, encoding a sialic acid transporter, was deleted (ΔnanT). Correspondingly, the ΔnanT C. rodentium strain was significantly impaired in its ability to colonize the murine intestine. Intriguingly, sialic acid was also found to induce the secretion of two autotransporter proteins, Pic and EspC, which possess mucinolytic and host-adherent properties. As a result, sialic acid enhanced the ability of C. rodentium to degrade intestinal mucus (through Pic), as well as to adhere to intestinal epithelial cells (through EspC). We thus demonstrate that sialic acid, a monosaccharide constituent of the intestinal mucus layer, functions as an important nutrient and a key signal for an A/E bacterial pathogen to escape the colonic lumen and directly infect its host's intestinal mucosa.

Niacin Ameliorates Neuro-Inflammation in Parkinson's Disease via GPR109A.

In this study, we used macrophage RAW264.7 cells to elucidate the molecular mechanism underlying the anti-inflammatory actions of niacin. Anti-inflammatory actions of niacin and a possible role of its receptor GPR109A have been studied previously. However, the precise molecular mechanism of niacin's action in reducing inflammation through GPR109A is unknown. Here we observed that niacin reduced the translocation of phosphorylated nuclear kappa B (p-NF-κB) induced by lipopolysaccharide (LPS) in the nucleus of RAW264.7 cells. The reduction in the nuclear translocation in turn decreased the expression of pro-inflammatory cytokines IL-1ß, IL-6 in RAW264.7 cells. We observed a decrease in the nuclear translocation of p-NF-κB and the expression of inflammatory cytokines after knockdown of GPR109A in RAW264.7 cells. Our results suggest that these molecular actions of niacin are mediated via its receptor GPR109A (also known as HCAR2) by controlling the translocation of p-NF-κB to the nucleus. Overall, our findings suggest that niacin treatment may have potential in reducing inflammation by targeting GPR109A.

The dimensionality of fatigue in Parkinson's disease.

BACKGROUND: Fatigue is a common problem among individuals with Parkinson's disease (PD). It may occur before the overt symptoms of bradykinesia, rigidity and tremor. Little is understood about how to measure fatigue in PD. Here we determined the dimensionality of the constructs of fatigue. METHODS: Four recommended scales, the Fatigue Severity Scale, Functional Assessment of Chronic Illness Therapy-Fatigue, Parkinson Fatigue Scale and Visual Analog Fatigue Scale (VAFS) were tested against quality of life measures including cognition, depression, sleep, life orientation, physical activity and PD symptoms in 22 PD subjects and 15 caregivers. RESULTS: Fatigue was associated with many quality of life variables, with the PDQ-39 summary index showing the strongest association. PD subjects agreed more strongly than caregivers that they experienced higher levels of fatigue. 27% of PD subjects rated fatigue as one of their top three most bothersome symptoms. The constructs of fatigue was captured within one dimension which explained 67% of the total variance, of which the VAFS showed the highest internal consistency. The highest likelihood ratio gave a cut-off score of < 5.5 on the VAFS. The change in scores required to produce a perceptible difference or is grossly observable ranged between 1.4 and 2.2 points respectively. CONCLUSION: The potential utility of a single measure such as the VAFS in PD that is reliably correlated with quality of life is consistent with the pursuit to develop clinical tests and measurements that are accessible, easy to use and universally interpretable across health science disciplines.

Infant locomotive development and its association with adult blood pressure.

UNLABELLED: Evidence from animal models suggests that locomotion and blood pressure share common neurophysiological regulatory systems. As a result of this common regulation, we hypothesized that the development of locomotion in human infants would be associated with blood pressure levels in adulthood. The study sample comprised 4,347 individuals with measures of locomotive and non-locomotive neuromotor development in infancy and adult blood pressure levels within a longitudinal birth cohort study, the Northern Finland Birth Cohort 1966. Later development in all three stages of locomotive development during infancy was associated with higher systolic and diastolic blood pressure levels at age 31. For age of walking without support, 0.34 (95 % CI 0.07 to 0.60)-mm Hg higher SBP and 0.38 (95 % CI 0.15 to 0.62)-mm Hg higher DBP were estimated for each month of later achievement (P = 0.012 for SBP; P = 0.001 for DBP). No association was identified for non-locomotive neuromotor development. CONCLUSION: These results highlight the positive sequelae of advanced locomotive development during infancy, suggesting that the common regulatory systems between locomotion and blood pressure may influence the development of raised blood pressure over time.

Reliability of the scapular dyskinesis test yes-no classification in asymptomatic individuals between students and expert physical therapists.

BACKGROUND: Scapular dyskinesis is considered a risk factor for the shoulder pain that may warrant screening for prevention. Clinicians of all experience screen scapular dyskinesis using the scapular dyskinesis test yes-no classification (Y-N), yet its reliability in asymptomatic individuals is unknown. We aimed to establish Y-N's intra- and inter-reliability between students and expert physical therapists. METHODS: We utilized a cross-sectional design using consecutive asymptomatic subjects. Six students and two experts rated 100 subjects using the Y-N. Cohen's kappa (κ) and Krippendorff's alpha (K-α) were calculated to determine intra- and inter-rater reliability. RESULTS: Intra- and inter-rater values for experts were κ=0.92 (95% confidence interval [CI], 0.91-0.93) and 0.85 (95% CI, 0.84-0.87) respectively; students were κ=0.77 (95% CI, 0.75-0.78) and K-α=0.63 (95% CI, 0.58-0.67). CONCLUSIONS: The Y-N is reliable in detecting scapular dyskinesis in asymptomatic individuals regardless of experience.

Niacin Enhancement for Parkinson's Disease: An Effectiveness Trial.

We previously reported that individuals with Parkinson's disease (PD) present with lower vitamin B3 levels compared to controls. It may be related to carbidopa interaction, defective tryptophan metabolism, and stresses of night sleep disorder. Vitamin B3 is the energy source for all cells by producing NAD+ and NADP+ in redox reactions of oxidative phosphorylation. Thus, some symptoms of PD such as fatigue, sleep dysfunction, and mood changes may be related to the deficiency of vitamin B3. Here, we conducted an effectiveness trial to determine the effect of 12 months of low-dose niacin (a vitamin B3 derivative) enhancement in PD individuals. An average of 9 ± 6-point improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) III (motor) score was observed after 12 months of daily niacin compared to the expected decline in score (effect size = 0.78, 95% CI = 7-11). Additionally, secondary outcome measures improved. Notably, handwriting size increased, fatigue perception decreased, mood improved, frontal beta rhythm during quiet stance increased, and stance postural sway amplitude and range of acceleration decreased. Set shifting, however, as measured by the Trail Making-B test, worsened from 66 to 96 s. Other measures did not change after 12 months, but it is not clear whether this represents a positive benefit of the vitamin. For example, while the quality of night sleep remained the same, there was a trend towards a decrease in the frequency of awakening episodes. These results suggest that niacin enhancement has the potential to maintain or improve quality of life in PD and slow disease progression.

Low-Dose Niacin Supplementation Improves Motor Function in US Veterans with Parkinson's Disease: A Single-Center, Randomized, Placebo-Controlled Trial.

A six-month double-blind, placebo-controlled randomized study was conducted to ascertain whether low-dose daily niacin supplementation would improve motor symptoms in Parkinson's disease (PD) patients. A total of 47 PD patients were assigned to receive low-dose niacin or a placebo. At the end of the double-blind phase, all participants received open-label niacin for the next six months. All patients were evaluated at baseline, after six months, and after one year of treatment. The primary outcome measure was the Unified Parkinson's Disease Rating Scale III (UPDRS III) scores. Secondary outcome measures were depression, sleep quality, mental flexibility and cognition, and physical fatigue. Niacin treatment was well-tolerated by forty-five subjects. The mean [95% CI] change in UPDRS III scores at six months of placebo was -0.05 [95% CI, -2.4 to 2.32], and niacin was -1.06 [95% CI, -3.68 to 1.57]. From six to twelve months when both groups received open-label niacin supplementation, the average UPDRS III scores significantly decreased for the placebo group by 4.58 [95% CI, -0.85 to 8.30] and the niacin group by 4.63 [95% CI, 1.42 to 7.83] points. Low-dose niacin supplementation is a well-tolerated adjunct therapy and may improve motor function in PD when taken over a longer period.

Changes in dietary fiber intake in mice reveal associations between colonic mucin O-glycosylation and specific gut bacteria.

The colonic mucus layer, comprised of highly O-glycosylated mucins, is vital to mediating host-gut microbiota interactions, yet the impact of dietary changes on colonic mucin O-glycosylation and its associations with the gut microbiota remains unexplored. Here, we used an array of omics techniques including glycomics to examine the effect of dietary fiber consumption on the gut microbiota, colonic mucin O-glycosylation and host physiology of high-fat diet-fed C57BL/6J mice. The high-fat diet group had significantly impaired glucose tolerance and altered liver proteome, gut microbiota composition, and short-chain fatty acid production compared to normal chow diet group. While dietary fiber inclusion did not reverse all high fat-induced modifications, it resulted in specific changes, including an increase in the relative abundance of bacterial families with known fiber digesters and a higher propionate concentration. Conversely, colonic mucin O-glycosylation remained similar between the normal chow and high-fat diet groups, while dietary fiber intervention resulted in major alterations in O-glycosylation. Correlation network analysis revealed previously undescribed associations between specific bacteria and mucin glycan structures. For example, the relative abundance of the bacterium Parabacteroides distasonis positively correlated with glycan structures containing one terminal fucose and correlated negatively with glycans containing two terminal fucose residues or with both an N-acetylneuraminic acid and a sulfate residue. This is the first comprehensive report of the impact of dietary fiber on the colonic mucin O-glycosylation and associations of these mucosal glycans with specific gut bacteria.

Nanobody-directed targeting of optogenetic tools to study signaling in the primary cilium.

Compartmentalization of cellular signaling forms the molecular basis of cellular behavior. The primary cilium constitutes a subcellular compartment that orchestrates signal transduction independent from the cell body. Ciliary dysfunction causes severe diseases, termed ciliopathies. Analyzing ciliary signaling has been challenging due to the lack of tools to investigate ciliary signaling. Here, we describe a nanobody-based targeting approach for optogenetic tools in mammalian cells and in vivo in zebrafish to specifically analyze ciliary signaling and function. Thereby, we overcome the loss of protein function observed after fusion to ciliary targeting sequences. We functionally localized modifiers of cAMP signaling, the photo-activated adenylyl cyclase bPAC and the light-activated phosphodiesterase LAPD, and the cAMP biosensor mlCNBD-FRET to the cilium. Using this approach, we studied the contribution of spatial cAMP signaling in controlling cilia length. Combining optogenetics with nanobody-based targeting will pave the way to the molecular understanding of ciliary function in health and disease.

An instance of reduced center of mass displacement: the Ba Gua Zhang walking gait.

The Ba Gua Zhang walking gait was examined in an accomplished practitioner to test the hypothesis that reducing the vertical oscillation of the body center of mass (CoM) conserves energy. Compared to typical walking, center-of-mass displacement and peak vertical ground reaction force decreased during Ba Gua Zhang walking. Muscle activity in the lower extremities and lower back, however, increased. The results failed to support the concept of decreasing CoM oscillations to increase efficiency.

Comparing the chemical composition of dietary fibres prepared from sugarcane, psyllium husk and wheat dextrin.

A dietary fibre prepared from sugarcane stalk was compared with psyllium husk and wheat dextrin. In contrast to the other dietary fibres, sugarcane fibre was found to contain significant amounts of insoluble dietary fibre (73-86%), lignin (18.66-20.23%), and rare minerals such as chromium (0.67-2.54 mg/100 g) and manganese (1.07-2.34 mg/100 g). Analysis of the ethanol extract also detected compounds with antioxidant activity. Characterisation of five sugarcane fibres prepared from selected strains, harvest periods (growth or storage phase), and processing conditions showed these factors influenced the final composition. Furthermore, using in vitro digestion, we found that potassium, magnesium, chromium, and zinc in were bioaccessible in sugarcane samples. Also, sodium was shown to bind to the sugarcane fibre potentially indicating bile salt binding activity. Results from this study support the use of sugarcane as a source of dietary fibre in functional foods.

Balance recovery from a forward fall: developmental aspects of sensorimotor organization and the role of supraspinal control.

We used the forward fall paradigm to test two hypotheses namely, that a supraspinal long-loop neural pathway is involved in the compensatory response, and secondly that the neural circuits underlying the performance of a balance-challenging task that requires the sequencing of several motor programs (compensatory reactions and stepping to recover balance) matures late in childhood. The first hypothesis was supported by the findings that the responses occurred earlier when the triggering signal was moved from the abdominal up to the chest level. The time required to react to the triggering signal within the supraspinal structures was also longer in children. The second hypothesis was verified by the observation of persisting soleus-tibialis coactivation in children up to 14 years old in three experimental conditions: unexpected release of the fall, voluntary release of the fall and longitudinal testing. These results suggest that the central processes involved in sequencing the postural responses do not mature until mid-adolescence. The maturation continues throughout childhood, with progressive emphasis on the central long- rather than short-latency pathways.

Factor analysis of the functional limitations test in healthy individuals.

The NeuroCom's Functional Limitations test evaluates motor performances on various dynamic movements but it is not known how the outcome variables among these movements might be related to each other. An exploratory factor analysis was conducted in healthy young individuals to identify the dimensions that contribute to the overall variance associated with the variables in the test items. Six factors comprising 18 out of 24 variables explained 76% of the overall variance. Variables from within a test item tended to be grouped in the same factor, suggesting that each item evaluates a particular set of motor skills that is required to execute the movement. The results suggest that all six items of the Functional Limitations test should to be used to estimate the overall functional motor control performance of an individual. The normative data gathered in this study using healthy individuals will allow us to compare individuals with movement limitations.

Abdominal exercise intensities on firm and compliant surfaces.

Muscle activities at 15 sites were compared within a group of healthy young adults to evaluate their relative intensities during six abdominal exercises: partial and full sit-ups on a firm surface (floor) and on an exercise ball that was either stabilized or unstabilized. The most strenuous abdominal exercise overall (i.e., whole body workout) was the full sit-up on a firm surface which included significant muscle activities in the lower extremities. Exercise intensity was also high in the full and partial sit-ups when performed on a ball. The partial sit-up on the floor was the least strenuous of the six exercises. The greatest effect on the abdominal muscles was observed in the partial sit-up on a ball (stabilized and unstabilized). Results suggest that, although abdominal exercises on a ball may be gentler on the hip and lower back, overall exercise intensity is not necessarily lower than that on the floor. Moreover, partial sit-ups, both on the floor and on a ball, also required greater neck muscle activities than full sit-ups. In deciding what type of sit-up to do, exercise surface and different muscular activities between the partial and full sit-ups should be considered.

Differential sensitivities to dioxin-like compounds PCB 126 and PeCDF between Tg(cyp1a:gfp) transgenic medaka and zebrafish larvae.

It has been intensively documented that there are species-differences in the sensitivity to dioxin-like compounds (DLCs) in mammalian and avian. However, this issue is still unclear in fish. This study aimed at evaluating the differential sensitivities to DLCs in fish larvae. Here, larvae of Tg(cyp1a:gfp) medaka and Tg(cyp1a:gfp) zebrafish were tested with 2,3,7,8-Tetrachlorodibenzodioxin (TCDD), polychlorinated biphenyl 126 (PCB 126) and 2,3,4,7,8,-Pentachlorodibenzofuran (PeCDF). Comparative analyses were performed on induction of GFP fluorescence, expression of endogenous cyp1a mRNAs and EROD activity between the two species after exposure to these chemicals. We found that PCB 126 and PeCDF exposure at high concentrations induced strong GFP expression in multiple organs (liver, head kidney and gut) in both medaka and zebrafish larvae. Moreover, the expression of endogenous cyp1a mRNA was significantly elevated in the zebrafish larvae exposed to TCDD, PCB 126 and PeCDF at different concentrations. Likewise, almost all the exposure conditions could cause prominent elevation of EROD activity in the zebrafish larvae, while the EROD activities were just slightly elevated in the medaka larvae exposed to 1 nM and 0.5 nM of TCDD as well as to 1.5 nM and 15 nM of PeCDF, but not in the medaka larvae exposed to PCB 126. Taken together, zebrafish was proved to be more sensitive than medaka to PCB 126 and to PeCDF in this study. The findings suggested species-specific sensitivity to DLCs in fish and will facilitate choosing a sensitive and reliable fish model or tool to evaluate the risk of dioxins and DLCs exposure.

Niacin modulates macrophage polarization in Parkinson's disease.

Neuroinflammation remains a central piece in Parkinson's disease (PD) pathophysiology. However, mechanisms by which PD links to the neuroinflammation remain elusive. Here, for the first time, we report that lower dose of niacin in PD patients may affect macrophage polarization from M1 (pro-inflammatory) to M2 (counter-inflammatory) profile through the niacin receptor GPR109A. Skew in the peripheral macrophages were accompanied by improved quality of life assessments in patients. Low dose niacin supplementation may be beneficial in PD, boosting anti-inflammatory processes and suppressing inflammation. Varied niacin dosages for longer durations may further reveal the potential role of anti-inflammatory interventions in PD progression.

Fiber Supplements Derived From Sugarcane Stem, Wheat Dextrin and Psyllium Husk Have Different In Vitro Effects on the Human Gut Microbiota.

There is growing public interest in the use of fiber supplements as a way of increasing dietary fiber intake and potentially improving the gut microbiota composition and digestive health. However, currently there is limited research into the effects of commercially available fiber supplements on the gut microbiota. Here we used an in vitro human digestive and gut microbiota model system to investigate the effect of three commercial fiber products; NutriKane™, Benefiber® and Psyllium husk (Macro) on the adult gut microbiota. The 16S rRNA gene amplicon sequencing results showed dramatic fiber-dependent changes in the gut microbiota structure and composition. Specific bacterial OTUs within the families Bacteroidaceae, Porphyromonadaceae, Ruminococcaceae, Lachnospiraceae, and Bifidobacteriaceae showed an increase in the relative abundances in the presence of one or more fiber product(s), while Enterobacteriaceae and Pseudomonadaceae showed a reduction in the relative abundances upon addition of all fiber treatments compared to the no added fiber control. Fiber-specific increases in SCFA concentrations showed correlation with the relative abundance of potential SCFA-producing gut bacteria. The chemical composition, antioxidant potential and polyphenolic content profiles of each fiber product were determined and found to be highly variable. Observed product-specific variations could be linked to differences in the chemical composition of the fiber products. The general nature of the fiber-dependent impact was relatively consistent across the individuals, which may demonstrate the potential of the products to alter the gut microbiota in a similar, and predictable direction, despite variability in the starting composition of the individual gut microbiota.

Hysteresis in Center of Mass Velocity Control during the Stance Phase of Treadmill Walking.

Achieving a soft landing during walking can be quantified by analyzing changes in the vertical velocity of the body center of mass (CoM) just prior to the landing of the swing limb. Previous research suggests that walking speed and step length may predictably influence the extent of this CoM control. Here we ask how stable this control is. We altered treadmill walking speed by systematically increasing or decreasing it at fixed intervals. We then reversed direction. We hypothesized that the control of the CoM vertical velocity during the late stance of the walking gait may serve as an order parameter which has an attribute of hysteresis. The presence of hysteresis implies that the CoM control is not based on simply knowing the current input conditions to predict the output response. Instead, there is also the influence of previous speed conditions on the ongoing responses. We found that the magnitudes of CoM control were different depending on whether the treadmill speed (as the control parameter) was ramped up or down. Changes in step length also influenced CoM control. A stronger effect was observed when the treadmill speed was speeded up compared to down. However, the effect of speed direction remained significant after controlling for step length. The hysteresis effect of CoM control as a function of speed history demonstrated in the current study suggests that the regulation of CoM vertical velocity during late stance is influenced by previous external conditions and constraints which combine to influence the desired behavioral outcome.

Two Mechanisms of Sensorimotor Set Adaptation to Inclined Stance.

Orientation of posture relative to the environment depends on the contributions from the somatosensory, vestibular, and visual systems mixed in varying proportions to produce a sensorimotor set. Here, we probed the sensorimotor set composition using a postural adaptation task in which healthy adults stood on an inclined surface for 3 min. Upon returning to a horizontal surface, participants displayed a range of postural orientations - from an aftereffect that consisted of a large forward postural lean to an upright stance with little or no aftereffect. It has been hypothesized that the post-incline postural change depends on each individual's sensorimotor set: whether the set was dominated by the somatosensory or vestibular system: Somatosensory dominance would cause the lean aftereffect whereas vestibular dominance should steer stance posture toward upright orientation. We investigated the individuals who displayed somatosensory dominance by manipulating their attention to spatial orientation. We introduced a distraction condition in which subjects concurrently performed a difficult arithmetic subtraction task. This manipulation altered the time course of their post-incline aftereffect. When not distracted, participants returned to upright stance within the 3-min period. However, they continued leaning forward when distracted. These results suggest that the mechanism of sensorimotor set adaptation to inclined stance comprises at least two components. The first component reflects the dominant contribution from the somatosensory system. Since the postural lean was observed among these subjects even when they were not distracted, it suggests that the aftereffect is difficult to overcome. The second component includes a covert attentional component which manifests as the dissipation of the aftereffect and the return of posture to upright orientation.

Cereal products derived from wheat, sorghum, rice and oats alter the infant gut microbiota in vitro.

The introduction of different nutrient and energy sources during weaning leads to significant changes in the infant gut microbiota. We used an in vitro infant digestive and gut microbiota model system to investigate the effect of four commercially available cereal products based on either wheat, sorghum, rice or oats, on the gut microbiota of six infants. Our results indicated cereal additions induced numerous changes in the gut microbiota composition. The relative abundance of bacterial families associated with fibre degradation, Bacteroidaceae, Bifidobacteriaceae, Lactobacillaceae, Prevotellaceae, Ruminococcaceae and Veillonellaceae increased, whilst the abundance of Enterobacteriaceae decreased with cereal additions. Corresponding changes in the production of SCFAs showed higher concentrations of acetate following all cereal additions, whilst, propionate and butyrate varied between specific cereal additions. These cereal-specific variations in the concentrations of SCFAs showed a moderate correlation with the relative abundance of potential SCFA-producing bacterial families. Overall, our results demonstrated clear shifts in the abundance of bacterial groups associated with weaning and an increase in the production of SCFAs following cereal additions.