Cerebellar encoding of multiple candidate error cues in the service of motor learning

or learning to occur through trial and error, the nervous system must effectively detect and encode performance errors. To examine this process, we designed a set of oculomotor learning tasks with more than one visual object providing potential error cues, as would occur in a natural visual scene. A task-relevant visual target and a task-irrelevant visual background both influenced vestibulo-ocular reflex learning in rhesus monkeys. Thus, motor learning does not identify a single error cue based on behavioral relevance, but can be simultaneously influenced by more than one cue. Moreover, the relative weighting ofthe differentcues could vary. Ifthe speed ofthe visual target's motion on the retina was low (≪1°/s), background motion dominated learning, but if target speed was high, the effects of the background were suppressed. The target and background motion had similar, nonlinear effects on the putative neural instructive signals carried by cerebellar climbing fibers, but with a stronger influence ofthe backgroundon the climbing fibers than on learning. In contrast, putative neuralinstructive signals carriedby the simple spikes of Purkinje cells were influenced solely by the motion of the visual target. Because they are influenced by different cues during training, joint control of learning by the climbing fibers and Purkinje cells may expand the learning capacity of the cerebellar circuit

Does Smile help detect the UK’s Price Leadership Change after MiFID?

We investigate intraday realised volatility, trading volume, and information transmission following a series of changes to the Markets in Financial Instruments Directive (MiFID) in the UK. We find that multilateral trading facilities attract order flows from the London Stock Exchange (LSE) and hence introduce new dynamics to market provisions, such as volatility and information transmission. In addition, the structure of the order books and market depth changed after the introduction of MiFID in the UK. However, our novel study conveying smile patterns of volatility and volume suggests that the LSE continues to lead the rest of the multilateral venues. This shows that although MiFID has led to market segmentation, there is still clear price discovery among multilateral trading facilities

Network-selective vulnerability of the human cerebellum to Alzheimer’s disease and frontotemporal dementia

Neurodegenerative diseases are associated with distinct and distributed patterns of atrophy in the cerebral cortex. Emerging evidence suggests that these atrophy patterns resemble intrinsic connectivity networks in the healthy brain, supporting the network-based degeneration framework where neuropathology spreads across connectivity networks. An intriguing yet untested possibility is that the cerebellar circuits, which share extensive connections with the cerebral cortex, could be selectively targeted by major neurodegenerative diseases. Here we examined the structural atrophy in the cerebellum across common types of neurodegenerative diseases, and characterized the functional connectivity patterns of these cerebellar atrophy regions. Our results showed that Alzheimer’s disease and frontotemporal dementia are associated with distinct and circumscribed atrophy in the cerebellum. These cerebellar atrophied regions share robust and selective intrinsic connectivity with the atrophied regions in the cerebral cortex. These findings for the first time demonstrated the selective vulnerability of the cerebellum to common neurodegenerative disease, extending the network-based degeneration framework to the cerebellum. Our work also has direct implications on the cerebellar contribution to the cognitive and affective processes that are compromised in neurodegeneration as well as the practice of using the cerebellum as reference region for ligand neuroimaging studies

Intrinsic connectivity network disruption in progressive supranuclear palsy

Objective Progressive supranuclear palsy (PSP) has been conceptualized as a large-scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP. Methods Using task-free functional magnetic resonance imaging, we mapped intrinsic connectivity to the dorsal midbrain tegmentum (dMT), a region that shows focal atrophy in PSP. Two healthy control groups (1 young, 1 older) were used to define and replicate the normal connectivity pattern, and patients with PSP were compared to an independent matched healthy control group on measures of network connectivity. Results Healthy young and older subjects showed a convergent pattern of connectivity to the dMT, including brainstem, cerebellar, diencephalic, basal ganglia, and cortical regions involved in skeletomotor, oculomotor, and executive control. Patients with PSP showed significant connectivity disruptions within this network, particularly within corticosubcortical and cortico-brainstem interactions. Patients with more severe functional impairment showed lower mean dMT network connectivity scores. Interpretation This study defines a PSP-related intrinsic connectivity network in the healthy brain and demonstrates the sensitivity of network-based imaging methods to PSP-related physiological and clinical changes. Ann Neurol 2013;73:603-61

All-cause mortality and long-term exposure to low level air pollution in the ‘45 and up study’ cohort, Sydney, Australia, 2006–2015

Epidemiological studies show that long-term exposure to ambient air pollution reduces life expectancy. Most studies have been in environments with relatively high concentrations such as North America, Europe and Asia. Associations at the lower end of the concentration-response function are not well defined.We assessed associations between all-cause mortality and exposure to annual average particulate matte

Loss of 5-hydroxymethylcytosine correlates with increasing morphologic dysplasia in melanocytic tumors

DNA methylation is the most well studied epigenetic modification in cancer biology. 5-hydroxymethylcytosine is an epigenetic mark that can be converted from 5-methylcytosine by the ten-eleven translocation gene family. We recently reported the loss of 5-hydroxymethylcytosine in melanoma compared to benign nevi and suggested that loss of this epigenetic marker is correlated with tumor virulence based on its association with a worse prognosis. In this study we further characterize the immunoreactivity patterns of 5-hydroxymethylcytosine in the full spectrum of melanocytic lesions to further validate the potential practical application of this epigenetic marker. 175 cases were evaluated: 18 benign nevi, 20 dysplastic nevi (10 low-grade and 10 high-grade lesions), 10 atypical Spitz nevi, 20 borderline tumors, 5 melanomas arising within nevi, and 102 primary melanomas. Progressive loss of 5-hydroxymethylcytosine from benign dermal nevi to high-grade dysplastic nevi to borderline melanocytic neoplasms to melanoma was observed. In addition, an analysis of the relationship of nuclear diameter to 5-hydroxymethylcytosine staining intensity within lesional cells revealed a significant correlation between larger nuclear diameter and decreased levels of 5-hydroxymethylcytosine. Furthermore, borderline lesions uniquely exhibited a diverse spectrum of staining of each individual case. This study further substantiates the association of 5-hydroxymethylcytosine loss with dysplastic cytomorphologic features and tumor progression and supports the classification of borderline lesions as a biologically distinct category of melanocytic lesions

Hierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor

After birth, cardiomyocytes (CM) acquire numerous adaptations in order to efficiently pump blood throughout an animal’s lifespan. How this maturation process is regulated and coordinated is poorly understood. Here, we perform a CRISPR/Cas9 screen in mice and identify serum response factor (SRF) as a key regulator of CM maturation. Mosaic SRF depletion in neonatal CMs disrupts many aspects of their maturation, including sarcomere expansion, mitochondrial biogenesis, transverse-tubule formation, and cellular hypertrophy. Maintenance of maturity in adult CMs is less dependent on SRF. This stage-specific activity is associated with developmentally regulated SRF chromatin occupancy and transcriptional regulation. SRF directly activates genes that regulate sarcomere assembly and mitochondrial dynamics. Perturbation of sarcomere assembly but not mitochondrial dynamics recapitulates SRF knockout phenotypes. SRF overexpression also perturbs CM maturation. Together, these data indicate that carefully balanced SRF activity is essential to promote CM maturation through a hierarchy of cellular processes orchestrated by sarcomere assembly

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance

Oyster Reefs at Risk and Recommendations for Conservation, Restoration, and Management

Native oyster reefs once dominated many estuaries, ecologically and economically. Centuries of resource extraction exacerbated by coastal degradation have pushed oyster reefs to the brink of functional extinction worldwide. We examined the condition of oyster reefs across 144 bays and 44 ecoregions; our comparisons of past with present abundances indicate that more than 90% of them have been lost in bays (70%) and ecoregions (63%). In many bays, more than 99% of oyster reefs have been lost and are functionally extinct. Overall, we estimate that 85% of oyster reefs have been lost globally. Most of the world\u27s remaining wild capture of native oysters (\u3e 75%) comes from just five ecoregions in North America, yet the condition of reefs in these ecoregions is poor at best, except in the Gulf of Mexico. We identify many cost-effective solutions for conservation, restoration, and the management of fisheries and nonnative species that could reverse these oyster losses and restore reef ecosystem services

Dominant hemisphere lateralization of cortical parasympathetic control as revealed by frontotemporal dementia.

The brain continuously influences and perceives the physiological condition of the body. Related cortical representations have been proposed to shape emotional experience and guide behavior. Although previous studies have identified brain regions recruited during autonomic processing, neurological lesion studies have yet to delineate the regions critical for maintaining autonomic outflow. Even greater controversy surrounds hemispheric lateralization along the parasympathetic-sympathetic axis. The behavioral variant of frontotemporal dementia (bvFTD), featuring progressive and often asymmetric degeneration that includes the frontoinsular and cingulate cortices, provides a unique lesion model for elucidating brain structures that control autonomic tone. Here, we show that bvFTD is associated with reduced baseline cardiac vagal tone and that this reduction correlates with left-lateralized functional and structural frontoinsular and cingulate cortex deficits and with reduced agreeableness. Our results suggest that networked brain regions in the dominant hemisphere are critical for maintaining an adaptive level of baseline parasympathetic outflow