Interactive Rhythmic Auditory Stimulation Reinstates Natural 1/f Timing in Gait of Parkinson's Patients

Parkinson's disease (PD) and basal ganglia dysfunction impair movement timing, which leads to gait instability and falls. Parkinsonian gait consists of random, disconnected stride times—rather than the 1/f structure observed in healthy gait—and this randomness of stride times (low fractal scaling) predicts falling. Walking with fixed-tempo Rhythmic Auditory Stimulation (RAS) can improve many aspects of gait timing; however, it lowers fractal scaling (away from healthy 1/f structure) and requires attention. Here we show that interactive rhythmic auditory stimulation reestablishes healthy gait dynamics in PD patients. In the experiment, PD patients and healthy participants walked with a) no auditory stimulation, b) fixed-tempo RAS, and c) interactive rhythmic auditory stimulation. The interactive system used foot sensors and nonlinear oscillators to track and mutually entrain with the human's step timing. Patients consistently synchronized with the interactive system, their fractal scaling returned to levels of healthy participants, and their gait felt more stable to them. Patients and healthy participants rarely synchronized with fixed-tempo RAS, and when they did synchronize their fractal scaling declined from healthy 1/f levels. Five minutes after removing the interactive rhythmic stimulation, the PD patients' gait retained high fractal scaling, suggesting that the interaction stabilized the internal rhythm generating system and reintegrated timing networks. The experiment demonstrates that complex interaction is important in the (re)emergence of 1/f structure in human behavior and that interactive rhythmic auditory stimulation is a promising therapeutic tool for improving gait of PD patients

Variation in Tropical Reef Symbiont Metagenomes Defined by Secondary Metabolism

The complex evolution of secondary metabolism is important in biology, drug development, and synthetic biology. To examine this problem at a fine scale, we compared the genomes and chemistry of 24 strains of uncultivated cyanobacteria, Prochloron didemni, that live symbiotically with tropical ascidians and that produce natural products isolated from the animals. Although several animal species were obtained along a >5500 km transect of the Pacific Ocean, P. didemni strains are >97% identical across much of their genomes, with only a few exceptions concentrated in secondary metabolism. Secondary metabolic gene clusters were sporadically present or absent in identical genomic locations with no consistent pattern of co-occurrence. Discrete mutations were observed, leading to new chemicals that we isolated from animals. Functional cassettes encoding diverse chemicals are exchanged among a single population of symbiotic P. didemni that spans the tropical Pacific, providing the host animals with a varying arsenal of secondary metabolites

Investigating the Effect of Galaxy Interactions on the Enhancement of Active Galactic Nuclei at 0.5 < z < 3.0

Galaxy interactions and mergers are thought to play an important role in the evolution of galaxies. Studies in the nearby universe show a higher AGN fraction in interacting and merging galaxies than their isolated counterparts, indicating that such interactions are important contributors to black hole growth. To investigate the evolution of this role at higher redshifts, we have compiled the largest known sample of major spectroscopic galaxy pairs (2381 with $\Delta V <5000$ km s$^{-1}$) at $0.5<z<3.0$ from observations in the COSMOS and CANDELS surveys. We identify X-ray and IR AGN among this kinematic pair sample, a visually identified sample of mergers and interactions, and a mass-, redshift-, and environment-matched control sample for each in order to calculate AGN fractions and the level of AGN enhancement as a function of relative velocity, redshift, and X-ray luminosity. While we see a slight increase in AGN fraction with decreasing projected separation, overall, we find no significant enhancement relative to the control sample at any separation. In the closest projected separation bin ($<25$ kpc, $\Delta V <1000$ km s$^{-1}$), we find enhancements of a factor of 0.94$^{+0.21}_{-0.16}$ and 1.00$^{+0.58}_{-0.31}$ for X-ray and IR-selected AGN, respectively. While we conclude that galaxy interactions do not significantly enhance AGN activity on average over $0.5<z<3.0$ at these separations, given the errors and the small sample size at the closest projected separations, our results would be consistent with the presence of low-level AGN enhancement

The Cytoplasmic Domain of MUC1 Induces Hyperplasia in the Mammary Gland and Correlates with Nuclear Accumulation of β-Catenin

MUC1 is an oncoprotein that is overexpressed in up to 90% of breast carcinomas. A previous in vitro study by our group demonstrated that the cytoplasmic domain of MUC1 (MUC1-CD), the minimal functional unit of MUC1, contributes to the malignant phenotype in cells by binding directly to β-catenin and protecting β-catenin from GSK3β-induced degradation. To understand the in vivo role of MUC1-CD in breast development, we generated a MUC1-CD transgenic mouse model under the control of the MMTV promoter in a C57BL/6J background, which is more resistant to breast tumor. We show that the expression of MUC1-CD in luminal epithelial cells of the mammary gland induced a hyperplasia phenotype characterized by the development of hyper-branching and extensive lobuloalveoli in transgenic mice. In addition to this hyperplasia, there was a marked increase in cellular proliferation in the mouse mammary gland. We further show that MUC1-CD induces nuclear localization of β-catenin, which is associated with a significant increase of β-catenin activity, as shown by the elevated expression of cyclin D1 and c-Myc in MMTV-MUC1-CD mice. Consistent with this finding, we observed that overexpression of MUC1-C is associated with β-catenin nuclear localization in tumor tissues and increased expression of Cyclin D1 and c-Myc in breast carcinoma specimens. Collectively, our data indicate a critical role for MUC1-CD in the development of mammary gland preneoplasia and tumorigenesis, suggesting MUC1-CD as a potential target for the diagnosis and chemoprevention of human breast cancer

Food-associated cues alter forebrain functional connectivity as assessed with immediate early gene and proenkephalin expression

<p>Abstract</p> <p>Background</p> <p>Cues predictive of food availability are powerful modulators of appetite as well as food-seeking and ingestive behaviors. The neurobiological underpinnings of these conditioned responses are not well understood. Monitoring regional immediate early gene expression is a method used to assess alterations in neuronal metabolism resulting from upstream intracellular and extracellular signaling. Furthermore, assessing the expression of multiple immediate early genes offers a window onto the possible sequelae of exposure to food cues, since the function of each gene differs. We used immediate early gene and proenkephalin expression as a means of assessing food cue-elicited regional activation and alterations in functional connectivity within the forebrain.</p> <p>Results</p> <p>Contextual cues associated with palatable food elicited conditioned motor activation and corticosterone release in rats. This motivational state was associated with increased transcription of the activity-regulated genes <it>homer1a</it>, <it>arc</it>, <it>zif268</it>, <it>ngfi-b </it>and c-<it>fos </it>in corticolimbic, thalamic and hypothalamic areas and of proenkephalin within striatal regions. Furthermore, the functional connectivity elicited by food cues, as assessed by an inter-regional multigene-expression correlation method, differed substantially from that elicited by neutral cues. Specifically, food cues increased cortical engagement of the striatum, and within the nucleus accumbens, shifted correlations away from the shell towards the core. Exposure to the food-associated context also induced correlated gene expression between corticostriatal networks and the basolateral amygdala, an area critical for learning and responding to the incentive value of sensory stimuli. This increased corticostriatal-amygdalar functional connectivity was absent in the control group exposed to innocuous cues.</p> <p>Conclusion</p> <p>The results implicate correlated activity between the cortex and the striatum, especially the nucleus accumbens core and the basolateral amygdala, in the generation of a conditioned motivated state that may promote excessive food intake. The upregulation of a number of genes in unique patterns within corticostriatal, thalamic, and hypothalamic networks suggests that food cues are capable of powerfully altering neuronal processing in areas mediating the integration of emotion, cognition, arousal, and the regulation of energy balance. As many of these genes play a role in plasticity, their upregulation within these circuits may also indicate the neuroanatomic and transcriptional correlates of extinction learning.</p

A basal lithostrotian titanosaur (Dinosauria: Sauropoda) with a complete skull: Implications for the evolution and paleobiology of titanosauria

We describe Sarmientosaurus musacchioi gen. et sp. nov., a titanosaurian sauropod dinosaur from the Upper Cretaceous (Cenomanian - Turonian) Lower Member of the Bajo Barreal Formation of southern Chubut Province in central Patagonia, Argentina. The holotypic and only known specimen consists of an articulated, virtually complete skull and part of the cranial and middle cervical series. Sarmientosaurus exhibits the following distinctive features that we interpret as autapomorphies: (1) maximum diameter of orbit nearly 40% rostrocaudal length of cranium; (2) complex maxilla - lacrimal articulation, in which the lacrimal clasps the ascending ramus of the maxilla; (3) medial edge of caudal sector of maxillary ascending ramus bordering bony nasal aperture with low but distinct ridge; (4) ´tongue-like´ ventral process of quadratojugal that overlaps quadrate caudally; (5) separate foramina for all three branches of the trigeminal nerve; (6) absence of median venous canal connecting infundibular region to ventral part of brainstem; (7) subvertical premaxillary, procumbent maxillary, and recumbent dentary teeth; (8) cervical vertebrae with ´strut-like´ centroprezygapophyseal laminae; (9) extremely elongate and slender ossified tendon positioned ventrolateral to cervical vertebrae and ribs. The cranial endocast of Sarmientosaurus preserves some of the most complete information obtained to date regarding the brain and sensory systems of sauropods. Phylogenetic analysis recovers the new taxon as a basal member of Lithostrotia, as the most plesiomorphic titanosaurian to be preserved with a complete skull. Sarmientosaurus provides a wealth of new cranial evidence that reaffirms the close relationship of titanosaurs to Brachiosauridae. Moreover, the presence of the relatively derived lithostrotian Tapuiasaurus in Aptian deposits indicates that the new Patagonian genus represents a ´ghost lineage´ with a comparatively plesiomorphic craniodental form, the evolutionary history of which is missing for at least 13 million years of the Cretaceous. The skull anatomy of Sarmientosaurus suggests that multiple titanosaurian species with dissimilar cranial structures coexisted in the early Late Cretaceous of southern South America. Furthermore, the new taxon possesses a number of distinctive morphologies - such as the ossified cervical tendon, extremely pneumatized cervical vertebrae, and a habitually downward- facing snout - that have rarely, if ever, been documented in other titanosaurs, thus broadening our understanding of the anatomical diversity of this remarkable sauropod clade. The latter two features were convergently acquired by at least one penecontemporaneous diplodocoid, and may represent mutual specializations for consuming low-growing vegetation.Fil: Martínez, Rubén Darío. Universidad Nacional de la Patagonia; ArgentinaFil: Lamanna, Matthew C.. Carnegie Museum Of Natural History; Estados UnidosFil: Novas, Fernando Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "bernardino Rivadavia"; ArgentinaFil: Ridgely, Ryan C.. Ohio University College Of Osteopathic Medicine; Estados UnidosFil: Casal, Gabriel. Universidad Nacional de la Patagonia; ArgentinaFil: Martínez, Javier E.. Hospital Regional de Comodoro Rivadavia; ArgentinaFil: Vita, Javier R.. Resonancia Magnética Borelli; ArgentinaFil: Witmer, Lawrence M.. Ohio University College Of Osteopathic Medicine; Estados Unido

Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the ZNF804A Pathway

Importance: We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. Objectives To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. Design, Setting, and Participants: Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). Main Outcomes and Measures: Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. Results: Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. Conclusions and Relevance: These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64–1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58–1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen. Conclusions No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences