NCI Cancer Research Data Commons: Cloud-Based Analytic Resources.

The NCI's Cloud Resources (CR) are the analytical components of the Cancer Research Data Commons (CRDC) ecosystem. This review describes how the three CRs (Broad Institute FireCloud, Institute for Systems Biology Cancer Gateway in the Cloud, and Seven Bridges Cancer Genomics Cloud) provide access and availability to large, cloud-hosted, multimodal cancer datasets, as well as offer tools and workspaces for performing data analysis where the data resides, without download or storage. In addition, users can upload their own data and tools into their workspaces, allowing researchers to create custom analysis workflows and integrate CRDC-hosted data with their own. See related articles by Brady et al., p. 1384, Wang et al., p. 1388, and Kim et al., p. 1404.

NCI Cancer Research Data Commons: Lessons Learned and Future State.

More than ever, scientific progress in cancer research hinges on our ability to combine datasets and extract meaningful interpretations to better understand diseases and ultimately inform the development of better treatments and diagnostic tools. To enable the successful sharing and use of big data, the NCI developed the Cancer Research Data Commons (CRDC), providing access to a large, comprehensive, and expanding collection of cancer data. The CRDC is a cloud-based data science infrastructure that eliminates the need for researchers to download and store large-scale datasets by allowing them to perform analysis where data reside. Over the past 10 years, the CRDC has made significant progress in providing access to data and tools along with training and outreach to support the cancer research community. In this review, we provide an overview of the history and the impact of the CRDC to date, lessons learned, and future plans to further promote data sharing, accessibility, interoperability, and reuse. See related articles by Brady et al., p. 1384, Wang et al., p. 1388, and Pot et al., p. 1396.

Characterising the declarative-procedural transformation in instruction-based learning.

Many accounts of instruction-based learning assume that initial declarative representations are transformed into executable procedural ones, so as to enable instruction implementation. We tested the hypothesis that declarative-procedural transformation should be bound to a specific response modality and not transferable across different modalities. In Experiment 1, novel stimulus-response instructions had to be implemented either verbally or manually either once or three times. Modality-specific procedural encoding was probed via a subsequent implicit priming test. This involved the same stimuli but required a response that could be either compatible or incompatible with the originally instructed response using either the same or a different response modality. We found that procedural encoding was modality-specific as indicated by a stronger repetition-dependent increase of the compatibility effect when response modality was unchanged. Explicit test performance, serving as a marker of declarative encoding, was independent of modality transition and it was uncorrelated with implicit test performance. Unexpectedly, the implicit priming test also revealed a small yet significant transfer to the response modality that was previously not overtly implemented, likely reflecting covert response "simulation". To examine if covertly simulated responding occurs even when instruction implementation is omitted altogether, we conducted Experiment 2. Subjects merely viewed novel stimulus-response instructions prior to testing. Again, we found evidence for procedural encoding of the non-implemented instructions. Moreover, a direct comparison of both experiments revealed higher test scores (both implicit and explicit) for previously non-implemented instructions than for previously implemented instructions. This calls for theoretical reconciliation with diverging previous study results.

Dynamic Connectivity in Disk Graphs.

Let S⊆R2 be a set of n sites in the plane, so that every site s∈S has an associated radius rs>0. Let D(S) be the disk intersection graph defined by S, i.e., the graph with vertex set S and an edge between two distinct sites s,t∈S if and only if the disks with centers s, t and radii rs, rt intersect. Our goal is to design data structures that maintain the connectivity structure of D(S) as sites are inserted and/or deleted in S. First, we consider unit disk graphs, i.e., we fix rs=1, for all sites s∈S. For this case, we describe a data structure that has O(log2n) amortized update time and O(logn/loglogn) query time. Second, we look at disk graphs with bounded radius ratio Ψ, i.e., for all s∈S, we have 1≤rs≤Ψ, for a parameter Ψ that is known in advance. Here, we not only investigate the fully dynamic case, but also the incremental and the decremental scenario, where only insertions or only deletions of sites are allowed. In the fully dynamic case, we achieve amortized expected update time O(Ψlog4n) and query time O(logn/loglogn). This improves the currently best update time by a factor of Ψ. In the incremental case, we achieve logarithmic dependency on Ψ, with a data structure that has O(α(n)) amortized query time and O(logΨlog4n) amortized expected update time, where α(n) denotes the inverse Ackermann function. For the decremental setting, we first develop an efficient decremental disk revealing data structure: given two sets R and B of disks in the plane, we can delete disks from B, and upon each deletion, we receive a list of all disks in R that no longer intersect the union of B. Using this data structure, we get decremental data structures with a query time of O(logn/loglogn) that supports deletions in O(nlogΨlog4n) overall expected time for disk graphs with bounded radius ratio Ψ and O(nlog5n) overall expected time for disk graphs with arbitrary radii, assuming that the deletion sequence is oblivious of the internal random choices of the data structures.

Instructional load induces functional connectivity changes linked to task automaticity and mnemonic preference.

Learning new rules rapidly and effectively via instructions is ubiquitous in our daily lives, yet the underlying cognitive and neural mechanisms are complex. Using functional magnetic resonance imaging we examined the effects of different instructional load conditions (4 vs. 10 stimulus-response rules) on functional couplings during rule implementation (always 4 rules). Focusing on connections of lateral prefrontal cortex (LPFC) regions, the results emphasized an opposing trend of load-related changes in LPFC-seeded couplings. On the one hand, during the low-load condition LPFC regions were more strongly coupled with cortical areas mostly assigned to networks such as the fronto-parietal network and the dorsal attention network. On the other hand, during the high-load condition, the same LPFC areas were more strongly coupled with default mode network areas. These results suggest differences in automated processing evoked by features of the instruction and an enduring response conflict mediated by lingering episodic long-term memory traces when instructional load exceeds working memory capacity limits. The ventrolateral prefrontal cortex (VLPFC) exhibited hemispherical differences regarding whole-brain coupling and practice-related dynamics. Left VLPFC connections showed a persistent load-related effect independent of practice and were associated with 'objective' learning success in overt behavioral performance, consistent with a role in mediating the enduring influence of the initially instructed task rules. Right VLPFC's connections, in turn, were more susceptible to practice-related effects, suggesting a more flexible role possibly related to ongoing rule updating processes throughout rule implementation.

Grey matter correlates of dystonic soft signs in essential tremor.

BACKGROUND: Questionable signs of dystonia are a common finding in patients with essential tremor (ET). Brain structural alterations in ET patients plus dystonic soft signs (ET + ds) in comparison to ET patients without dystonic soft signs (ET-ds) or patients with tremor associated with manifest dystonia (TAWD) have not been examined yet. Therefore, our study aims to explore alterations of brain grey matter in patients with ET + ds. METHODS: A total of 68 elderly patients with ET-ds (n = 32), ET + ds (n = 20) or idiopathic cervical dystonia with dystonia associated action tremor of the upper limbs (TAWD, n = 16) and 42 age-matched healthy controls underwent a clinical and electrophysiological assessment and 3T MRI. For grey matter alterations T1 MRI images were analysed by voxel-based morphometry. Additionally, regression analyses with clinical parameters (tremor frequency, severity and disease duration) were performed. RESULTS: VBM showed a significant increase of grey matter in the right lentiform nucleus in ET + ds and TAWD compared to HC and ET-ds. Further, an increase of cortical grey matter in the middle frontal gyrus in ET + ds was shown. The hypertrophy of the lentiform nucleus in ET + ds was correlated with disease severity and duration. CONCLUSION: Patients with ET + ds showed grey matter brain structural alterations similar to TAWD. Our findings suggest an involvement of the basal ganglia-cortical loop in ET + ds which may indicate a pathophysiological similarity with TAWD rather than ET.

Gait and axial postural abnormalities correlations in Parkinson's disease: A multicenter quantitative study.

INTRODUCTION: Gait and axial postural abnormalities (PA) are common and disabling symptoms of Parkinson's disease (PD). The interplay between them has been poorly explored. METHODS: A standardized protocol encompassing videos and photos for posture and gait analysis of PD patients with a clinically defined PA (MDS-UPDRS-III item 3.13 > 0) was used in 6 movement disorder centers. A comprehensive evaluation was performed to clarify the association between gait performance and the presence and severity of PA. RESULTS: 225 PD patients were enrolled: 57 had severe PA, 149 mild PA, and 19 did not meet criteria for PA, according to a recent consensus agreement on PA definition. PD patients with severe PA were significantly older (p:0.001), with longer disease duration (p:0.007), worse MDS-UPDRS-II and -III scores and axial sub-scores (p < 0.0005), higher LEDD (p:0.002) and HY stage (p < 0.0005), and a significantly lower velocity (p < 0.001) and cadence (p:0.021), if compared to mild PA patients. The multiple regression analysis evaluating gait parameters and degrees of trunk/neck flexion showed that higher degrees of lumbar anterior trunk flexion were correlated with lower step length (OR -0.244; p:0.014) and lower velocity (OR -0.005; p:0.028). CONCLUSIONS: Our results highlight the possible impact of severe anterior trunk flection on PD patients' gait, with a specific detrimental effect on gait velocity and step length. Personalized rehabilitation strategies should be elaborated based on the different features of PA, aiming to target a combined treatment of postural and specifically related gait pattern alterations.

Postural abnormalities in Asian and Caucasian Parkinson's disease patients: A multicenter study.

INTRODUCTION: Postural abnormalities (PA) are disabling features of Parkinson's disease (PD). Indirect analyses suggested a higher prevalence of PA among Asian patients compared to Caucasian ones, but no direct comparisons have been performed so far. METHODS: An international, multicenter, cross-sectional study was performed in 6 European and Asian movement disorders centers with the aim to clarify differences and similarities of prevalence and characteristics of PA in Asian vs. Caucasian PD patients. Axial PA, encompassing antecollis (AC), camptocormia (CC), and Pisa syndrome (PS), and appendicular PA (appPA) were systematically searched and analysed in consecutive patients. RESULTS: 88 (27%) of 326 PD patients had PA (29.1% in Asians and 24.3% in Caucasians, p: 0.331). Prevalence of axial PA was 23.6% in Asians and 24.3% in Caucasians (p = 0.886), in spite of a longer disease duration among Caucasians, but a longer PA duration among Asians. No differences in prevalence between AC, CC, and PS were found between the two ethnicities. The prevalence of appPA was higher in Asians (p = 0.036), but the regression analysis did not confirm a significant difference related to ethnicity. Considering the whole population, male gender (OR, 4.036; 95% CI, 1.926-8.456; p < 0.005), a longer disease duration (OR, 2.61; 95% CI, 1.024-6.653; p = 0.044), and a higher axial score (OR, 1.242; 95% CI, 1.122-1.375; p < 0.0005) were the factors associated with axial PA. CONCLUSION: The prevalence of axial PA in PD patients is not influenced by ethnicity. However, Asian PD patients tend to develop PA earlier in the disease course, particularly AC.

Neural Correlates of Executed Compared to Imagined Writing and Drawing Movements: A Functional Magnetic Resonance Imaging Study.

Objective: In this study we used functional magnetic resonance imaging (fMRI) to investigate whether motor imagery (MI) of handwriting and circle drawing activates a similar handwriting network as writing and drawing itself. Methods: Eighteen healthy right-handed participants wrote the German word "Wellen" and drew continuously circles in a sitting (vertical position) and lying position (horizontal position) to capture kinematic handwriting parameters such as velocity, pressure and regularity of hand movements. Afterward, they performed the same tasks during fMRI in a MI and an executed condition. Results: The kinematic analysis revealed a general correlation of handwriting parameters during sitting and lying except of pen pressure during drawing. Writing compared to imagined writing was accompanied by an increased activity of the ipsilateral cerebellum and the contralateral sensorimotor cortex. Executed compared to imagined drawing revealed elevated activity of a fronto-parieto-temporal network. By contrasting writing and drawing directly, executed writing induced an enhanced activation of the left somatosensory and premotor area. The comparison of the MI of these tasks revealed a higher involvement of occipital activation during imagined writing. Conclusion: The kinematic results pointed to a high comparability of writing in a vertical and horizontal position. Overall, we observed highly overlapping cortical activity except of a higher involvement of motor control areas during motor execution. The sparse difference between writing and drawing can be explained by highly automatized writing in healthy individuals.

Never too little: Grip and lift forces following probabilistic weight cues in patients with writer's cramp.

OBJECTIVE: Planning of voluntary object-related movements requires the estimation of the most probable object properties. We investigated how 14 writer's cramp (WC) patients compared to 14 controls use probabilistic weight cues in a serial grip-lift task. METHODS: In every grip-lift trial, an object of either light, medium or heavy weight had to be grasped and lifted after a visual cue gave a probabilistic prediction of the object weights (e.g. 32.5% light, 67.5% medium, 0 % heavy). We determined peak (1) grip force GF, (2) load force LF, (3) grip force rate GFR, (4) load force rate LFR, while we registered brain activity with functional magnetic resonance imaging. RESULTS: In both groups, GFR, LFR and GF increased when a higher probability of heavy weights was announced. When a higher probability of light weights was indicated, controls reduced GFR, LFR and GF, while WC patients did not downscale their forces. There were no inter-group differences in blood oxygenation level dependent activation. CONCLUSIONS: WC patients could not utilize the decision range in motor planning and adjust their force in a probabilistic cued fine motor task. SIGNIFICANCE: The results support the pathophysiological model of a hyperfunctional dopamine dependent direct basal ganglia pathway in WC.

Abnormal effective connectivity in the sensory network in writer's cramp.

BACKGROUND: Writer's cramp (WC), a task specific form of dystonia, is considered to be a motor network disorder, but abnormal sensory tactile processing has also been acknowledged. The sensory spatial discrimination threshold (SDT) can be determined with a spatial acuity test (JVP domes). In addition to increased SDT, patients with WC exhibited dysfunctional sensory processing in the sensory cortex, insula, basal ganglia and cerebellum in a functional magnetic resonance imaging (fMRI) study while performing the spatial acuity test. OBJECTIVES: To assess whether effective connectivity (EC) in the sensory network including cortical, basal ganglia, thalamic and cerebellar regions of interest in WC patients is abnormal. METHODS: We used fMRI and applied a block design, while 19 WC patients and 13 age-matched healthy controls performed a spatial discrimination task. Before we assessed EC using dynamic causal modelling, we compared three model structures based on the current literature. We enclosed regions of interest that are established for sensory processing during right hand stimulation: Left thalamus, somatosensory, parietal and insular cortex, posterior putamen, and right cerebellum. RESULTS: The EC analysis revealed task-dependent decreased unidirectional connectivity between the insula and the posterior putamen. The connectivity involving the primary sensory cortex, parietal cortex and cerebellum were not abnormal in WC. The two groups showed no differences in their behavioural data. CONCLUSIONS: Perception and integration of sensory information requires the exchange of information between the insula cortex and the putamen, a sensory process that was disturbed in WC patients.

Degraded Arabinogalactans and Their Binding Properties to Cancer-Associated Human Galectins.

Galectins represent ß-galactoside-binding proteins with numerous functions. Due to their role in tumor progression, human galectins-1, -3 and -7 (Gal-1, -3 and -7) are potential targets for cancer therapy. As plant derived glycans might act as galectin inhibitors, we prepared galactans by partial degradation of plant arabinogalactan-proteins. Besides commercially purchased galectins, we produced Gal-1 and -7 in a cell free system and tested binding capacities of the galectins to the galactans by biolayer-interferometry. Results for commercial and cell-free expressed galectins were comparable confirming functionality of the cell-free produced galectins. Our results revealed that galactans from Echinacea purpurea bind to Gal-1 and -7 with KD values of 1-2 µM and to Gal-3 slightly stronger with KD values between 0.36 and 0.70 µM depending on the sensor type. Galactans from the seagrass Zostera marina with higher branching of the galactan and higher content of uronic acids showed stronger binding to Gal-3 (0.08-0.28 µM) compared to galactan from Echinacea. The results contribute to knowledge on interactions between plant polysaccharides and galectins. Arabinogalactan-proteins have been identified as a new source for production of galactans with possible capability to act as galectin inhibitors.

Arabinogalactan-proteins from non-coniferous gymnosperms have unusual structural features.

Arabinogalactan-proteins (AGPs), important signalling molecules of the plant cell wall, are structurally extensively investigated in angiosperms, but information on AGPs in gymnosperms is still limited. We characterized AGPs from the gymnosperms Ginkgo biloba, Ephedra distachya, Encephalartos longifolius and Cycas revoluta. The protein contents are comparable to that of angiosperm AGPs. Hydroxyproline is the site of linking the carbohydrate part and was detected in all AGPs with highest concentration in Cycas AGP (1.1 % of the AGP). Interestingly, with the exception of Cycas, all AGPs contained the monosaccharide 3-O-methylrhamnose not present in angiosperm polysaccharides. The carbohydrate moieties of Cycas and Ephredra showed the main components 1,3,6-linked galactose and terminal arabinose typical of angiosperm AGPs, whereas that of Ginkgo AGP was unique with 1,4-linked galactose as dominant structural element. Bioinformatic search for glycosyltransferases in Ginkgo genome also revealed a lower number of galactosyltransferases responsible for biosynthesis of the 1,3-Gal/1,6-Gal AGP backbone.

A structural variation reference for medical and population genetics.

Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

Arabinogalactan-proteins in spore-producing land plants.

Arabinogalactan-proteins (AGPs) are proteoglycans of the extracellular matrix of plants that were first isolated and described in the 1970s. Today, the consensus is that the following features are regarded as typical for these molecules: In contrast to broad knowledge on AGPs in seed plants, insight in occurrence and structure of AGPs in spore-producing land plants (bryophytes, lycophytes and monilophytes) is very limited, although these plants are the closest living relatives to seed plants. In general, understanding of cell wall evolution is incomplete due to limited knowledge of cell wall structure of non-flowering plants. In this review, current knowledge on AGPs of mosses, clubmosses and ferns is summarized, possible functions are discussed and suggestions for future investigations are given.

Neural Correlates of Hypokinetic Dysarthria and Mechanisms of Effective Voice Treatment in Parkinson Disease.

BACKGROUND: Hypokinetic dysarthria is highly prevalent in idiopathic Parkinson disease (PD), and effectiveness of high-intensity voice treatment is well established. However, the neural correlates remain largely unknown. OBJECTIVE: We aimed to specify cerebral pathophysiology of hypokinetic dysarthria and treatment-induced changes using functional magnetic resonance imaging (fMRI). METHODS: We used fMRI to investigate healthy controls (HCs) and patients with idiopathic PD-associated dysarthria before and after treatment according to the Lee Silverman Voice Treatment LOUD (LSVT). During fMRI, participants covertly read sentences with normal (eg, conversation in a quiet room) or high (eg, shouting on a windy beach) intensity. In addition, we tested LSVT effects on intelligibility and different speech features (intensity, pitch, articulation). RESULTS: LSVT effectively improved intelligibility, articulation, and pitch in patients. Covert high-intensity speech compared with covert normal-intensity speech led to increased activation of mainly secondary motor areas and bilateral superior and medial temporal regions. Prior to LSVT, patients showed less activity in several speech-associated areas compared with HCs. As a neural correlate of effective LSVT, increased right-sided superior temporal activity correlated with improved intelligibility. CONCLUSION: This is the first brain imaging study using a covert speech paradigm in PD, which revealed cortical hypoactivation as correlate of hypokinetic dysarthria. Furthermore, cortical correlates of effective LSVT treatment colocalized with the neuronal network, showing increased activation during high- versus normal-intensity speech generation.

The Aurora-Kinase A Phe31-Ile polymorphism as possible predictor of response to treatment in head and neck squamous cell carcinoma.

Recently the Aurora-Kinases (Aurk) moved into the focus as novel disease related biomarkers and therapeutic targets. Elevated Aurora-Kinase expression has been found in a number of malignancies, amongst them HNSCC. For esophageal cancer, the AurkA Phe31-Ile polymorphism has previously been associated with tumor progression. Here we evaluated the treatment efficiency of HNSCC cell radiation as a function of Aurora-Kinases in HNSCC cell lines. Moreover, we investigated a potential sensitization to radiation by a cell treatment with the inhibitors Alisertib, Barasertib, Docetaxel and VX-680. In parallel the radiation dependent expression and regulation of AurkA/B, p-Akt Ser 473 and Survivin and the AurkA polymorphism were investigated in primary tumor samples. We identified a high-risk collective with elevated AurkA and Survivin or AurkA and p-Akt Ser 473 expression. High AurkA, AurkB, and p-Akt Ser 473 expression was exclusively found in the heterozygous cell line. We found a polymorphism dependent sensitivity to treatments with different Aurk inhibitors: The homozygous cell line UD-SCC-5 could be sensitized to radiation with Docetaxel in combination with any of the Aurora-Kinase inhibitors. In contrast, treatment with Docetaxel or radiation did not enhance the inhibitory effect of Barasertib or VX-680 in the heterozygous SAS cell line. These findings indicate that the Aurora-Kinase A Phe31-Ile-polymorphism is a possibly predictive factor for response to radiation in combination with Docetaxel and Aurora-Kinase inhibitor treatments.