Occasion setters determine responses of putative dopamine neurons to discriminative stimuli

Midbrain dopamine (DA) neurons are involved in the processing of rewards and reward-predicting stimuli, possibly analogous to reinforcement learning reward prediction errors. Here we studied the activity of putative DA neurons (n=41) recorded in the ventral tegmental area of rats (n=6) performing a behavioural task involving occasion setting. In this task an occasion setter (OS) indicated that the relationship between a discriminative stimulus (DS) and reinforcement is in effect, so that reinforcement of bar pressing occurred only after the OS (tone or houselight) was followed by the DS (houselight or tone). We found that responses of putative DA cells to the DS were enhanced when preceded by the OS, as were behavioural responses to obtain rewards. Surprisingly though, we did not find a population response of putative DA neurons to the OS, contrary to predictions of standard temporal-difference models of DA neurons. However, despite the absence of a population response, putative DA neurons exhibited a heterogeneous response on a single unit level, so that some units increased and others decreased their activity as a response to the OS. Similarly, putative non-DA cells did not respond to the DS on a population level, but with heterogeneous responses on a single unit level. The heterogeneity in the responses of putative DA cells may reflect how DA neurons encode context and point to local differences in DA signalling

Is there a silver lining to the Zika virus epidemic in the Americas?

It is hard to find anything positive to say about an epidemic of an emerging virus that infects pregnant women, targets developing fetuses’ neural progenitor cells, and disrupts the sequence of neural development to cause a devastating syndrome resulting in lifelong disabilities. Infants with microcephaly became the faces of the Zika virus epidemic in the Americas, which affected almost all countries in the western hemisphere in 2014–17. By the end of 2017, Zika virus has nearly disappeared from the Americas as quickly as it emerged. Now that the dust is settling, what have the scientific and public health communities learned? Is there a silver lining to Zika’s devastation

The Power of Proofs: New Algorithms for Timed Automata Model Checking (with Appendix)

This paper presents the first model-checking algorithm for an expressive modal mu-calculus over timed automata, $L^{\mathit{rel}, \mathit{af}}_{\nu,\mu}$, and reports performance results for an implementation. This mu-calculus contains extended time-modality operators and can express all of TCTL. Our algorithmic approach uses an "on-the-fly" strategy based on proof search as a means of ensuring high performance for both positive and negative answers to model-checking questions. In particular, a set of proof rules for solving model-checking problems are given and proved sound and complete; we encode our algorithm in these proof rules and model-check a property by constructing a proof (or showing none exists) using these rules. One noteworthy aspect of our technique is that we show that verification performance can be improved with \emph{derived rules}, whose correctness can be inferred from the more primitive rules on which they are based. In this paper, we give the basic proof rules underlying our method, describe derived proof rules to improve performance, and compare our implementation of this model checker to the UPPAAL tool.Comment: This is the preprint of the FORMATS 2014 paper, but this is the full version, containing the Appendix. The final publication is published from Springer, and is available at http://link.springer.com/chapter/10.1007%2F978-3-319-10512-3_9 on the Springer webpag

Misclassification in defining and diagnosing microcephaly

Background: Several health agencies define microcephaly for surveillance purposes using a single criterion, a percentile or Z-score cut-off for newborn head circumference. This definition, however, conflicts with the reported prevalence of microcephaly even in populations with endemic Zika virus. Objective: We explored possible reasons for this conflict, hypothesising that the definition of microcephaly used in some studies may be incompletely described, lacking the additional clinical criteria that clinicians use to make a formal diagnosis. We also explored the potential for misclassification that can result from differences in these definitions, especially when applying a percentile cut-off definition in the presence of the much lower observed prevalence estimates that we believe to be valid. Methods: We conducted simulations under a theoretical bimodal distribution of head circumference. For different definitions of microcephaly, we calculated the sensitivity and specificity using varying cut-offs of head circumference. We then calculated and plotted the positive predictive value for each of these definitions by prevalence of microcephaly. Results: Simple simulations suggest that if the true prevalence of microcephaly is approximately what is reported in peer-reviewed literature, then relying on cut-off-based definitions may lead to very poor positive predictive value under realistic conditions. Conclusions: While a simple head circumference criterion may be used in practice as a screening or surveillance tool, the definition lacks clarification as to what constitutes true pathological microcephaly and may lead to confusion about the true prevalence of microcephaly in Zika-endemic areas, as well as bias in aetiologic studies

Symmetries and Elasticity of Nematic Gels

A nematic liquid-crystal gel is a macroscopically homogeneous elastic medium with the rotational symmetry of a nematic liquid crystal. In this paper, we develop a general approach to the study of these gels that incorporates all underlying symmetries. After reviewing traditional elasticity and clarifying the role of broken rotational symmetries in both the reference space of points in the undistorted medium and the target space into which these points are mapped, we explore the unusual properties of nematic gels from a number of perspectives. We show how symmetries of nematic gels formed via spontaneous symmetry breaking from an isotropic gel enforce soft elastic response characterized by the vanishing of a shear modulus and the vanishing of stress up to a critical value of strain along certain directions. We also study the phase transition from isotropic to nematic gels. In addition to being fully consistent with approaches to nematic gels based on rubber elasticity, our description has the important advantages of being independent of a microscopic model, of emphasizing and clarifying the role of broken symmetries in determining elastic response, and of permitting easy incorporation of spatial variations, thermal fluctuations, and gel heterogeneity, thereby allowing a full statistical-mechanical treatment of these novel materials.Comment: 21 pages, 4 eps figure

Effects of T- and P-odd weak nucleon interaction in nuclei: renormalizations due to residual strong interaction, matrix elements between compound states and their correlations with P-violating matrix elements

Manifestations of P-,T-odd weak interaction between nucleons in nucleus are considered. Renormalization of this interaction due to residual strong interaction is studied. Mean squared matrix elements of P-,T-odd weak interaction between compound states are calculated. Correlators between P-,T-odd and P-odd, T-even weak interaction matrix elements between compound states are considered and estimates for these quantities are obtained.Comment: Submitted to Phys. Rev. C; 21 pages, REVTEX 3, no figure

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Neurodevelopmental Outcomes of Children following in Utero Exposure to Zika in Nicaragua

Background: Neurodevelopmental outcomes of asymptomatic children exposed to Zika virus (ZIKV) in utero are not well characterized. Methods: We prospectively followed 129 newborns without evidence of congenital Zika syndrome (CZS) up to 24 months of age. Participants were classified as ZIKV exposed or ZIKV unexposed. The Mullen Scales of Early Learning (MSEL) was administered in the participants' homes at 6, 12, 15, 18, 21, and 24 months of age by trained psychologists. Sociodemographic data, medical history, and infant anthropometry at birth were collected at each home visit. Our primary outcome was the Mullen Early Learning Composite Score (ECL) at 24 months of age between our 2 exposure groups. Secondary outcomes were differences in MSEL subscales over time and at 24 months. Results: Of 129 infants in whom exposure status could be ascertained, 32 (24.8%) met criteria for in utero ZIKV exposure and 97 (75.2%) did not. There were no differences in maternal age, maternal educational attainment, birthweight, or gestational age at birth between the 2 exposure groups. The adjusted means and standard errors (SEs) for the ELC score between the ZIKV-exposed children compared to ZIKV-unexposed children were 91.4 (SE, 3.1) vs 96.8 (SE, 2.4) at 12 months and 93.3 (SE, 2.9) vs 95.9 (SE, 2.3) at 24 months. In a longitudinal mixed model, infants born to mothers with an incident ZIKV infection (P =. 01) and low-birthweight infants (<2500 g) (P =. 006) had lower composite ECL scores. Conclusions: In this prospective cohort of children without CZS, children with in utero ZIKV exposure had lower neurocognitive scores at 24 months

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy