Anion binding to a cationic europium(III) probe enables the first real-time assay of heparan sulfotransferase activity.

Sulfotransferases constitute a ubiquitous class of enzymes which are poorly understood due to the lack of a convenient tool for screening their activity. These enzymes use the anion PAPS (adenosine-3'-phosphate-5'-phosphosulfate) as a donor for a broad range of acceptor substrates, including carbohydrates, producing sulfated compounds and PAP (adenosine-3',5'-diphosphate) as a side product. We present a europium(III)-based probe that binds reversibly to both PAPS and PAP, producing a larger luminescence enhancement with the latter anion. We exploit this greater emission enhancement with PAP to demonstrate the first direct real-time assay of a heparan sulfate sulfotransferase using a multi-well plate format. The selective response of our probe towards PAP over structurally similar nucleoside phosphate anions, and over other anions, is investigated and discussed. This work opens the possibility of investigating more fully the roles played by this enzyme class in health and disease, including operationally simple inhibitor screening.

The Effects of Dual Task Cognitive Interference and Fast-Paced Walking on Gait, Turns, and Falls in Men and Women with FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a genetic neurodegenerative disorder characterized by cerebellar ataxia, tremor, and cognitive dysfunction. We examined the impact of dual-task (DT) cognitive-motor interference and fast-paced (FP) gait on gait and turning in FXTAS. Thirty participants with FXTAS and 35 age-matched controls underwent gait analysis using an inertial sensor-based 2-min walk test under three conditions: (1) self-selected pace (ST), (2) FP, and (3) DT with a concurrent verbal fluency task. Linear regression analyses were performed to assess the association between FXTAS diagnosis and gait and turn outcomes. Correlations between gait variables and fall frequency were also calculated. FXTAS participants had reduced stride length and velocity, swing time, and peak turn velocity and greater double limb support time and number of steps to turn compared to controls under all three conditions. There was greater dual task cost of the verbal fluency task on peak turn velocity in men with FXTAS compared to controls. Additionally, stride length variability was increased and cadence was reduced in FXTAS participants in the FP condition. Stride velocity variability under FP gait was significantly associated with the number of self-reported falls in the last year. Greater motor control requirements for turning likely made men with FXTAS more susceptible to the negative effects of DT cognitive interference. FP gait exacerbated gait deficits in the domains of rhythm and variability, and increased gait variability with FP was associated with increased falls. These data may inform the design of rehabilitation strategies in FXTAS.

The Effects of Phonological Short-Term Memory and Speech Perception on Spoken Sentence Comprehension in Children: Simulating Deficits in an Experimental Design.

The roles of phonological short-term memory (pSTM) and speech perception in spoken sentence comprehension were examined in an experimental design. Deficits in pSTM and speech perception were simulated through task demands while typically-developing children (N [Formula: see text] 71) completed a sentence-picture matching task. Children performed the control, simulated pSTM deficit, simulated speech perception deficit, or simulated double deficit condition. On long sentences, the double deficit group had lower scores than the control and speech perception deficit groups, and the pSTM deficit group had lower scores than the control group and marginally lower scores than the speech perception deficit group. The pSTM and speech perception groups performed similarly to groups with real deficits in these areas, who completed the control condition. Overall, scores were lowest on noncanonical long sentences. Results show pSTM has a greater effect than speech perception on sentence comprehension, at least in the tasks employed here.

Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by a repeat expansion in the fragile X mental retardation 1 (FMR1) gene. The disorder is characterized by kinetic tremor and cerebellar ataxia, shows age-dependent penetrance, and occurs more frequently in men. This paper summarizes the key emerging issues in FXTAS as presented at the Second International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2015. The topics discussed include phenotype-genotype relationships, neurobehavioral function, and updates on FXTAS genetics and imaging.

A Closer Look at Phonology as a Predictor of Spoken Sentence Processing and Word Reading.

The goal of this study was to tease apart the roles of phonological awareness (pA) and phonological short-term memory (pSTM) in sentence comprehension, sentence production, and word reading. Children 6- to 10-years of age (N = 377) completed standardized tests of pA ('Elision') and pSTM ('Nonword Repetition') from the Comprehensive Test of Phonological Processing. Concepts and Following Directions (CFD) and Formulated Sentences (FS) were taken from the Clinical Evaluation of Language Fundamentals-Fourth Edition, as measures of sentence comprehension and production, respectively. Children also completed the Word Identification (Word Id) and Word Attack (Word Att) subtests of the Woodcock Reading Mastery Test-Third Edition. Hierarchical multiple regression analyses controlling for age and nonverbal IQ revealed that Elision was the only significant predictor of CFD and FS. While Elision was the strongest predictor of Word Id and Word Att, Nonword Repetition accounted for additional variance in both reading measures. These results emphasize the usefulness of breaking down phonological processing into multiple components and they also have implications language and reading disordered populations.

Toddlers use the number feature in determiners during online noun comprehension.

Function words support many aspects of language acquisition. This study investigated whether toddlers understand the number feature of determiners and use it for noun comprehension. French offers an ideal "test case" as number is phonetically marked in determiners but not in nouns. Twenty French-learning 24-month-olds completed a split-screen experiment. Looking times to target pictures were measured under 3 trial types varying in the degree to which the determiner matched the number displayed in the object(s). Children looked longer when the determiner matched the object(s), and were confused in trials of clear mismatch. Importantly, their processing resembled that of French adults (D. Dahan, D. Swingley, M. K. Tanenhaus, & J. S. Magnuson, 2000). Thus, children understand the determiner number feature early in acquisition and use this knowledge to constrain online comprehension.

Sterically demanding macrocyclic Eu(iii) complexes for selective recognition of phosphate and real-time monitoring of enzymatically generated adenosine monophosphate.

The design of molecular receptors that bind and sense anions in biologically relevant aqueous solutions is a key challenge in supramolecular chemistry. The recognition of inorganic phosphate is particularly challenging because of its high hydration energy and pH dependent speciation. Adenosine monophosphate (AMP) represents a valuable but elusive target for supramolecular detection because of its structural similarity to the more negatively charged anions, ATP and ADP. We report two new macrocyclic Eu(iii) receptors capable of selectively sensing inorganic phosphate and AMP in water. The receptors contain a sterically demanding 8-(benzyloxy)quinoline pendant arm that coordinates to the metal centre, creating a binding pocket suitable for phosphate and AMP, whilst excluding potentially interfering chelating anions, in particular ATP, bicarbonate and lactate. The sensing selectivity of our Eu(iii) receptors follows the order AMP > ADP > ATP, which represents a reversal of the order of selectivity observed for most reported nucleoside phosphate receptors. We have exploited the unique host-guest induced changes in emission intensity and lifetime for the detection of inorganic phosphate in human serum samples, and for monitoring the enzymatic production of AMP in real-time.

Open-label pilot clinical trial of citicoline for fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that is characterized by tremor, cerebellar ataxia, frequent falls, cognitive decline, and progressive loss of motor function. There are currently no approved treatments for this disorder. The purpose of this study was to determine if citicoline was safe for the treatment of tremor and balance abnormalities and to stabilize cognitive decline in patients with FXTAS. Ten participants with diagnosed FXTAS were administered 1000 mg of citicoline once daily for 12 months. Outcome measures and neurological examination were performed at baseline, 3 months, 6 months, and 12 months. The primary outcome was the FXTAS Rating Scale score. Secondary outcomes included change in a battery of neuropsychological tests, an instrumented Timed up and go test, computerized dynamic posturography, 9-hole pegboard test, and balance confidence and psychiatric symptom questionnaires. Safety was also evaluated. Citicoline treatment resulted in minimal adverse events in all but one subject over the course of the study. There was a significant improvement in the Beck Anxiety Inventory (p = 0.03) and the Stroop Color-Word test (p = 0.03), with all other measures remaining stable over the course of 12 months. This open-label pilot trial of citicoline for individuals with FXTAS showed that it is safe and well tolerated in this population. Registration: This trial was registered at ClinicalTrials.gov. Identifier: NCT0219710.

Tremorography in fragile X-associated tremor/ataxia syndrome, Parkinson's disease and essential tremor.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease affecting carriers of a 55-200 CGG repeat in the fragile X mental retardation 1 gene, may receive an initial diagnosis of Parkinson's disease (PD) or essential tremor (ET) due to overlapping motor symptoms. Therefore, tremor and bradykinesia were compared in these disorders using quantitative tremorography. METHODS: The inertial sensor based Kinesia ™ system was used to quantify upper extremity tremor and bradykinesia in participants with FXTAS (n = 25), PD (n = 23), ET (n = 18) and controls (n = 20) and regression analysis was performed to determine whether tremorography measures distinguished between the groups. The FXTAS Rating scale (FXTAS-RS) was administered to determine whether sub-score items on the clinician rated scale correlated with tremorography variables. RESULTS: FXTAS participants had reduced finger tap speed compared to those with ET, and ET had increased kinetic tremor compared to PD. Higher kinetic tremor distinguished FXTAS from PD (p = .02), and lower finger tap speed distinguished FXTAS from ET (p = .004). FXTAS-RS tremor and bradykinesia items correlated with tremorography measures (p = .005 to <0.0001). CONCLUSIONS: This is the first quantitative study to compare tremor and bradykinesia in FXTAS, PD and ET. Kinetic tremor and bradykinesia measures using a quantitative inertial sensor system distinguished FXTAS from PD and ET, respectively. Such technologies may be useful for detecting precise tremor and bradykinesia abnormalities and distinguishing the tremor and bradykinesia profiles in each of these disorders.

Prodromal Markers of Upper Limb Deficits in FMR1 Premutation Carriers and Quantitative Outcome Measures for Future Clinical Trials in Fragile X-associated Tremor/Ataxia Syndrome.

BACKGROUND: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a rare, late-onset neurodegenerative disorder characterized by tremor and cerebellar gait ataxia, affecting premutation carriers (PMC) of CGG expansions (range, 55-200) in the fragile X mental retardation 1 (FMR1) gene. Discovery of early predictors for FXTAS and quantitative characterization of motor deficits are critical for identifying disease onset, monitoring disease progression, and determining efficacy of interventions. METHODS: A total of 39 PMC with FXTAS, 20 PMC without FXTAS, and 27 healthy controls performed a series of upper extremity (UE) motor tasks assessing tremor, bradykinesia, and rapid alternating movements that were quantified using an inertial-based sensor system (Kinesia One; Great Lakes NeuroTechnologies, Cleveland, OH, USA). Sub-scores from the clinician-rated FXTAS Rating Scale were correlated with the severity scores generated by the sensor system to determine its validity in FXTAS. RESULTS: PMC with FXTAS had significantly worse postural and kinetic tremor compared with PMC without FXTAS (P = 0.02, 0.03) and controls (P = 0.001, 0.0001), respectively, and slower finger tap (P = 0.001), hand movement (P = 0.0001), and rapid alternating movement speed (P = 0.003) and amplitude (P = 0.04) than controls. PMC without FXTAS had significantly worse right finger tap (P = 0.004), hand movement (P = 0.01), and rapid alternating movement speed (P = 0.003) and amplitude (P = 0.02) than controls. FXTAS Rating Scale subscores significantly correlated with all tremorography scores except for finger taps and left rapid alternating movement. CONCLUSIONS: These findings support the use of inertial sensor quantification systems as promising measures for preclinical FXTAS symptom detection in PMC, characterization of the natural history of FXTAS, assessment of medication responses, and outcome assessment in clinical trials.

Categorical speech perception deficits distinguish language and reading impairments in children.

We examined categorical speech perception in school-age children with developmental dyslexia or Specific Language Impairment (SLI), compared to age-matched and younger controls. Stimuli consisted of synthetic speech tokens in which place of articulation varied from 'b' to 'd'. Children were tested on categorization, categorization in noise, and discrimination. Phonological awareness skills were also assessed to examine whether these correlated with speech perception measures. We observed similarly good baseline categorization rates across all groups; however, when noise was added, the SLI group showed impaired categorization relative to controls, whereas dyslexic children showed an intact profile. The SLI group showed poorer than expected between-category discrimination rates, whereas this pattern was only marginal in the dyslexic group. Impaired phonological awareness profiles were observed in both the SLI and dyslexic groups; however, correlations between phonological awareness and speech perception scores were not significant. The results of the study suggest that in children with language and reading impairments, there is a significant relationship between receptive language and speech perception, there is at best a weak relationship between reading and speech perception, and indeed the relationship between phonological and speech perception deficits is highly complex.

Effect of sampling method on contaminant measurement in pore-water and surface water at two uranium operations: can method affect conclusions?

This paper describes a comparison of two methods of sediment pore-water sampling and two methods of surface water sampling that were used in a broader investigation of cause(s) of adverse effects on benthic invertebrate communities at two Saskatchewan uranium operations (Key Lake and Rabbit Lake). Variables measured and compared included pH, ammonia, DOC, and trace metals. The two types of sediment pore-water samples that were compared are centrifuged and 0.45-microm filtered sediment core samples vs. 0.2-microm dialysis (peeper) samples. The two types of surface water samples that were compared are 53-microm filtered Van Dorn horizontal beta samples vs. 0.2-microm dialysis (peeper) samples. Results showed that 62% of the sediment core pore water values were higher than the corresponding peeper pore-water measurements, and that 63% of the Van Dorn surface water measurements were lower than corresponding peeper surface water measurements. Furthermore, only 24% and 14% of surface water and pore-water measurements, respectively, fell within +/-10% range of one another; 73% and 50%, respectively, fell within +/-50%. Although somewhat confounded by differences in filtering method, the observed differences are believed to primarily be related to small, vertical differences in the environment sampled. Despite observed differences in concentrations of toxicologically relevant variables generated by the different sampling methods, the weight of evidence (WOE) conclusions drawn from each set of exposure data on the possible cause(s) of in situ toxicity to Hyalella azteca from a related study were the same at each uranium operation. However, this concurrence was largely due to other dominant lines of evidence. The WOE conclusions at Key Lake were dominated by the toxicity response of H. azteca in relation to exposure chemistry, where as the WOE conclusions at Rabbit Lake were informed by exposure chemistry, the toxicological response of H. azteca, and whole-body contaminant concentrations in the test organisms. Had these multiple lines of evidence not been available, differences in exposure chemistry generated by the different sampling methods could have substantially influenced the identification of potential causes of in situ toxicity.

TEM-based metrology for HfO2 layers and nanotubes formed in anodic aluminum oxide nanopore structures.

Nanotubes are fabricated by atomic layer deposition (ALD) into nanopore arrays created by anodic aluminum oxide (AAO). A transmission electron microscopy (TEM) methodology is developed and applied to quantify the ALD conformality in the nanopores (thickness as a function of depth), and the results are compared to existing models for ALD conformality. ALD HfO2 nanotubes formed in AAO templates are released by dissolution of the Al2O3, transferred to a grid, and imaged by TEM. An algorithm is devised to automate the quantification of nanotube wall thickness as a function of position along the central axis of the nanotube, by using a cylindrical model for the nanotube. Diffusion-limited depletion occurs in the lower portion of the nanotubes and is characterized by a linear slope of decreasing thickness. Experimentally recorded slopes match well with two simple models of ALD within nanopores presented in the literature. The TEM analysis technique provides a method for the rapid analysis of such nanostructures in general, and is also a means to efficiently quantify ALD profiles in nanostructures for a variety of nanodevice applications.

Cognitive function impacts gait, functional mobility and falls in fragile X-associated tremor/ataxia syndrome.

BACKGROUND: Executive function and information processing speed deficits occur in fragile X premutation carriers (PMC) with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Gait is negatively impacted by cognitive deficits in many patient populations resulting in increased morbidity and falls but these relationships have not been studied in FXTAS. RESEARCH QUESTION: We sought to investigate the associations between executive function and information processing speed and gait, turning and falls in PMC with and without FXTAS compared to healthy controls. METHODS: Global cognition and the cognitive domains of information processing speed, attention, response inhibition, working memory and verbal fluency were tested with a neuropsychological test battery in 18 PMC with FXTAS, 15 PMC without FXTAS, and 27 controls. An inertial sensor based instrumented Timed Up and Go was employed to test gait, turns and functional mobility. RESULTS: Lower information processing speed was significantly associated with shorter stride length, reflecting slower gait speed, in PMC with FXTAS (p = 0.0006) but not PMC without FXTAS or controls. Lower response inhibition was also significantly associated with slower turn-to-sit times in PMC with FXTAS (p = 0.034) but not in those without FXTAS or controls. Lower information processing speed (p = 0.012) and working memory (p = 0.004), were significantly correlated with a greater number of self-reported falls in the past year in FXTAS participants. SIGNIFICANCE: This is the first study demonstrating that worse executive function and slower information processing speed is associated with reduced gait speed and functional mobility, as well as with a higher retrospective fall history in participants with FXTAS. This information may be important in the design of cognitive and motor interventions for this neurodegenerative disorder.

Insights from child development on the relationship between episodic and semantic memory.

The present study was motivated by a recent controversy in the neuropsychological literature on semantic dementia as to whether episodic encoding requires semantic processing or whether it can proceed solely based on perceptual processing. We addressed this issue by examining the effect of age-related limitations in semantic competency on episodic memory in 4-6-year-old children (n=67). We administered three different forced-choice recognition memory tests for pictures previously encountered in a single study episode. The tests varied in the degree to which access to semantically encoded information was required at retrieval. Semantic competency predicted recognition performance regardless of whether access to semantic information was required. A direct relation between picture naming at encoding and subsequent recognition was also found for all tests. Our findings emphasize the importance of semantic encoding processes even in retrieval situations that purportedly do not require access to semantic information. They also highlight the importance of testing neuropsychological models of memory in different populations, healthy and brain damaged, at both ends of the developmental continuum.

Mismatch negativity reflects sensory and phonetic speech processing.

We examined phonetic and sensory processes in speech perception using mismatch negativity, an event-related potential component congruent with discrimination, but which occurs for unattended stimuli. Adult listeners (N=16) heard a repeated standard (the syllable 'da') that was interrupted infrequently by a phonetically different 'deviant' syllable ('ba'). The acoustic difference between standard and deviant was manipulated to create both acoustically Strong and Weak deviant stimuli. Mismatch negativities in response to the Strong deviant were significantly greater than those for the Weak deviant, in spite of the fact that both represented stable instances of the phonetic category. The data suggest that the mismatch negativity component can be strongly influenced by sensory factors beyond what is predicted by overt categorization and discrimination judgments.

Bioassays with caged hyalella azteca to determine in situ toxicity downstream of two Saskatchewan, Canada, uranium operations.

The main objectives of this in situ study were to evaluate the usefulness of an in situ bioassay to determine if downstream water bodies at the Key Lake and Rabbit Lake uranium operations (Saskatchewan, Canada) were toxic to Hyalella azteca and, if toxicity was observed, to differentiate between the contribution of surface water and sediment contamination to in situ toxicity. These objectives were achieved by performing 4-d in situ bioassays with laboratory-reared H. azteca confined in specially designed, paired, surface water and sediment exposure chambers. Results from the in situ bioassays revealed significant mortality, relative to the respective reference site, at the exposure sites at both Key Lake (p

Specific phonological impairments in dyslexia revealed by eyetracking.

Phonological deficits in dyslexia are typically assessed using metalinguistic tasks vulnerable to extraneous factors such as attention and memory. The present work takes the novel approach of measuring phonology using eyetracking. Eye movements of dyslexic children were monitored during an auditory word recognition task in which target items in a display (e.g., candle) were accompanied by distractors sharing a cohort (candy) or rhyme (sandal). Like controls, dyslexics showed slower recognition times when a cohort distractor was present than in a baseline condition with only phonologically unrelated distractors. However, unlike controls, dyslexic children did not show slowed recognition of targets with a rhyme distractor, suggesting they had not encoded rhyme relationships. This was further explored in an overt phonological awareness test of cohort and rhyme. Surprisingly, dyslexics showed normal rhyme performance but poorer judgment of initial sounds on these overt tests. The results implicate impaired knowledge of rhyme information in dyslexia; however they also indicate that testing methodology plays a critical role in how such problems are identified.

The Neuropsychiatric and Motor Profile of GBA-Associated Parkinson's Disease: A Review.

BACKGROUND: Cognitive and motor decline, along with psychiatric symptoms, have a major impact on independence, nursing home admission, caregiver burden, and mortality in Parkinson's disease (PD). The single most common genetic risk factor for developing PD is a mutation in the glucocerebrosidase (GBA) gene. METHODS: This work is a literature review regarding "GBA" and "Parkinson's disease" as conducted by PubMed search. RESULTS: There is a higher prevalence of cognitive decline and more rapid trajectory of disease progression in PD-GBA carriers, compared to noncarriers. PD-GBA carriers also have domain-specific cognitive impairment, particularly in visual memory tasks. PD-GBA carriers may also have a more aggressive motor phenotype than noncarriers. CONCLUSIONS: Early identification of PD-GBA carriers may lead to targeted therapies and development of new treatments.

Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders.

OBJECTIVE: The purpose of this paper is to review the typical cognitive and motor impairments seen in fragile X-associated tremor/ataxia syndrome (FXTAS), essential tremor (ET), Parkinson disease (PD), spinocerebellar ataxias (SCAs), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) in order to enhance diagnosis of FXTAS patients. METHODS: We compared the cognitive and motor phenotypes of FXTAS with each of these other movement disorders. Relevant neuropathological and neuroimaging findings are also reviewed. Finally, we describe the differences in age of onset, disease severity, progression rates, and average lifespan in FXTAS compared to ET, PD, SCAs, MSA, and PSP. We conclude with a flow chart algorithm to guide the clinician in the differential diagnosis of FXTAS. RESULTS: By comparing the cognitive and motor phenotypes of FXTAS with the phenotypes of ET, PD, SCAs, MSA, and PSP we have clarified potential symptom overlap while elucidating factors that make these disorders unique from one another. In summary, the clinician should consider a FXTAS diagnosis and testing for the Fragile X mental retardation 1 (FMR1) gene premutation if a patient over the age of 50 (1) presents with cerebellar ataxia and/or intention tremor with mild parkinsonism, (2) has the middle cerebellar peduncle (MCP) sign, global cerebellar and cerebral atrophy, and/or subcortical white matter lesions on MRI, or (3) has a family history of fragile X related disorders, intellectual disability, autism, premature ovarian failure and has neurological signs consistent with FXTAS. Peripheral neuropathy, executive function deficits, anxiety, or depression are supportive of the diagnosis. CONCLUSIONS: Distinct profiles in the cognitive and motor domains between these movement disorders may guide practitioners in the differential diagnosis process and ultimately lead to better medical management of FXTAS patients.