The representation of priors and decisions in the human parietal cortex

Animals actively sample their environment through orienting actions such as saccadic eye movements. Saccadic targets are selected based both on sensory evidence immediately preceding the saccade, and a “salience map” or prior built-up over multiple saccades. In the primate cortex, the selection of each individual saccade depends on competition between target-selective cells that ramp up their firing rate to saccade release. However, it is less clear how a cross-saccade prior might be implemented, either in neural firing or through an activity-silent mechanism such as modification of synaptic weights on sensory inputs. Here, we present evidence from magnetoencephalography for 2 distinct processes underlying the selection of the current saccade, and the representation of the prior, in human parietal cortex. While the classic ramping decision process for each saccade was reflected in neural firing rates (measured in the event-related field), a prior built-up over multiple saccades was implemented via modulation of the gain on sensory inputs from the preferred target, as evidenced by rapid frequency tagging. A cascade of computations over time (initial representation of the prior, followed by evidence accumulation and then an integration of prior and evidence) provides a mechanism by which a salience map may be built up across saccades in parietal cortex. It also provides insight into the apparent contradiction that inactivation of parietal cortex has been shown not to affect performance on single-trials, despite the presence of clear evidence accumulation signals in this region

Excavation: Recent Photographs by Stanley Greenberg Exhibition Catalogue

https://digitalcommons.fairfield.edu/greenberg-ephemera/1000/thumbnail.jp

P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>The purinergic receptor P2x7 is expressed on myeloid cells as well as on CNS glial cells, and P2x7 activation has been shown to increase both glial and T-cell activation. These properties suggest a role in the development of autoimmune disease including multiple sclerosis.</p> <p>Methods</p> <p>The animal model of MS, experimental autoimmune encephalomyelitis (EAE) using myelin oligodendrocyte glycoprotein (MOG) peptide residues 35–55 was induced in wildtype C57BL6 mice and in P2x7 deficient mice ('P2x7 mice') that were backcrossed to C57BL6 mice. Disease progression was monitored by appearance of clinical signs, immunocytochemical staining to assess brain inflammation and neuronal damage, and by measurement of Tcell cytokine production.</p> <p>Results</p> <p>The incidence of EAE disease in P2x7 mice was reduced 4-fold compared to the wildtype mice; however the P2x7 mice that became ill had similar days of onset and clinical scores as the wildtype mice. Splenic T-cells isolated from P2x7 null mice produced greater IFNγ and IL-17 (from 3 to 12 fold greater levels) than wildtype cells, however cytokine production from P2x7 derived cells was not increased by a selective P2x7 agonist as was cytokine production from wildtype cells. Although infiltrating cells were detected in brains of both the P2x7 and wildtype mice, astroglial activation and axonal damage was reduced versus wildtype mice, and the distribution of astroglial activation was markedly distinct in the two strains. In contrast, microglial activation was similar in the two strains.</p> <p>Conclusion</p> <p>P2x7 deficiency resulted in compensatory changes leading to increased T-cell cytokine production, and activated T-cells were detected in the brains of P2x7 null mice with no clinical signs. However, the greatly reduced incidence of disease suggests that an initiating event is absent in these mice, and points to a role for astroglial P2x7 in development of EAE disease.</p

Highly robust model of transcription regulator activity predicts breast cancer overall survival

Background: While several multigene signatures are available for predicting breast cancer prognosis, particularly in early stage disease, effective molecular indicators are needed, especially for triple-negative carcinomas, to improve treatments and predict diagnostic outcomes. The objective of this study was to identify transcriptional regulatory networks to better understand mechanisms giving rise to breast cancer development and to incorporate this information into a model for predicting clinical outcomes. Methods: Gene expression profiles from 1097 breast cancer patients were retrieved from The Cancer Genome Atlas (TCGA). Breast cancer-specific transcription regulatory information was identified by considering the binding site information from ENCODE and the top co-expressed targets in TCGA using a nonlinear approach. We then used this information to predict breast cancer patient survival outcome. Result: We built a multiple regulator-based prediction model for breast cancer. This model was validated in more than 5000 breast cancer patients from the Gene Expression Omnibus (GEO) databases. We demonstrated our regulator model was significantly associated with clinical stage and that cell cycle and DNA replication related pathways were significantly enriched in high regulator risk patients. Conclusion: Our findings demonstrate that transcriptional regulator activities can predict patient survival. This finding provides additional biological insights into the mechanisms of breast cancer progression

MAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB

Autophagy is the major cellular pathway by which macromolecules are degraded, and amino acid depletion powerfully activates autophagy. MAP4K3, or germinal-center kinase-like kinase, is required for robust cell growth in response to amino acids, but the basis for MAP4K3 regulation of cellular metabolic disposition remains unknown. Here we identify MAP4K3 as an amino acid-dependent regulator of autophagy through its phosphorylation of transcription factor EB (TFEB), a transcriptional activator of autophagy, and through amino acid starvation-dependent lysosomal localization of MAP4K3. We document that MAP4K3 physically interacts with TFEB and MAP4K3 inhibition is sufficient for TFEB nuclear localization, target gene transactivation, and autophagy, even when mTORC1 is activated. Moreover, MAP4K3 serine 3 phosphorylation of TFEB is required for TFEB interaction with mTORC1-Rag GTPase-Ragulator complex and TFEB cytosolic sequestration. Our results uncover a role for MAP4K3 in the control of autophagy and reveal MAP4K3 as a central node in nutrient-sensing regulation

Oxidation of Fish Oil Oleogels Formed by Natural Waxes in Comparison With Bulk Oil

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143663/1/ejlt201700378.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143663/2/ejlt201700378_am.pd

Impact of Scotland’s comprehensive, smoke-free legislation on stroke

&lt;p&gt;Background: Previous studies have reported a reduction in acute coronary events following smoke-free legislation. Evidence is lacking on whether stroke is also reduced. The aim was to determine whether the incidence of stroke, overalland by sub-type, fell following introduction of smoke-free legislation across Scotland on 26 March 2006.&lt;/p&gt; &lt;p&gt;Methods and Findings: A negative binomial regression model was used to determine whether the introduction of smokefree legislation resulted in a step and/or slope change in stroke incidence. The model was adjusted for age-group, sex, socioeconomic deprivation quintile, urban/rural residence and month. Interaction tests were also performed. Routine hospital administrative data and death certificates were used to identify all hospital admissions and pre-hospital deaths due to stroke (ICD10 codes I61, I63 and I64) in Scotland between 2000 and 2010 inclusive. Prior to the legislation, rates of all stroke, intracerebral haemorrhage and unspecified stroke were decreasing, whilst cerebral infarction was increasing at 0.97% per annum. Following the legislation, there was a dramatic fall in cerebral infarctions that persisted for around 20 months. No visible effect was observed for other types of stroke. The model confirmed an 8.90% (95% CI 4.85, 12.77, p,0.001) stepwise reduction in cerebral infarction at the time the legislation was implemented, after adjustment for potential cofounders.&lt;/p&gt; &lt;p&gt;Conclusions: Following introduction of national, comprehensive smoke-free legislation there was a selective reduction in cerebral infarction that was not apparent in other types of stroke.&lt;/p&gt

Multiple reassortment events in the evolutionary history of H1N1 influenza A virus since 1918

The H1N1 subtype of influenza A virus has caused substantial morbidity and mortality in humans, first documented in the global pandemic of 1918 and continuing to the present day. Despite this disease burden, the evolutionary history of the A/H1N1 virus is not well understood, particularly whether there is a virological basis for several notable epidemics of unusual severity in the 1940s and 1950s. Using a data set of 71 representative complete genome sequences sampled between 1918 and 2006, we show that segmental reassortment has played an important role in the genomic evolution of A/H1N1 since 1918. Specifically, we demonstrate that an A/H1N1 isolate from the 1947 epidemic acquired novel PB2 and HA genes through intra-subtype reassortment, which may explain the abrupt antigenic evolution of this virus. Similarly, the 1951 influenza epidemic may also have been associated with reassortant A/H1N1 viruses. Intra-subtype reassortment therefore appears to be a more important process in the evolution and epidemiology of H1N1 influenza A virus than previously realized