Striatal topography of probability and magnitude information for decisions under uncertainty

Most decisions involve some element of uncertainty. When the outcomes of these decisions have different likelihoods of occurrence, the decision-maker must consider both the magnitude of each outcome and the probability of its occurrence, but how do individual decision makers combine the two dimensions of magnitude and probability? Here, we approach the problem by separating in time the presentation of magnitude and probability information, and focus the analysis of fMRI activations on the first piece of information only. Thus, we are able to identify distinct neural circuits for the two dimensions without the confounding effect of divided attention or the cognitive operation of combining them. We find that magnitude information correlates with the size of the response of the ventral striatum while probability information correlates with the response in the dorsal striatum. The relative responsiveness of these two striatal regions correlates with the behavioral tendency to weight one more than the other. The results are consistent with a second-order process of information aggregation in which individuals make separate judgments for magnitude and probability and then integrate those judgments

Evaluation of cisplatin-induced pathology in the larval zebrafish lateral line

Cisplatin is an effective anticancer agent, but also causes permanent hearing loss by damaging hair cells-the sensory receptors essential for hearing. There is an urgent clinical need to protect cochlear hair cells in patients undergoing cisplatin chemotherapy. The zebrafish lateral line organ contains hair cells and has been frequently used in studies to screen for otoprotective compounds. However, these studies have employed a wide range of cisplatin dosages and exposure times. We therefore performed a comprehensive evaluation of cisplatin ototoxicity in the zebrafish lateral line with the goal of producing a standardized, clinically relevant protocol for future studies. To define the dose- and time-response patterns of cisplatin-induced hair-cell death, we treated 6-day-old larvae for 2 h in 50 µM-1 mM cisplatin and allowed them to recover. We observed delayed hair cell death, which peaked at 4-8 h post-exposure. Cisplatin also activated a robust inflammatory response, as determined by macrophage recruitment and phagocytosis of hair cells. However, selective depletion of macrophages did not affect hair cell loss. We also examined the effect of cisplatin treatment on fish behavior and found that cisplatin-induced lateral line injury measurably impaired rheotaxis. Finally, we examined the function of remaining hair cells that appeared resistant to cisplatin treatment. We observed significantly reduced uptake of the cationic dye FM1-43 in these cells relative to untreated controls, indicating that surviving hair cells may be functionally impaired. Cumulatively, these results indicate that relatively brief exposures to cisplatin can produce hair cell damage and delayed hair cell death. Our observations provide guidance on standardizing methods for the use of the zebrafish model in studies of cisplatin ototoxicity

Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix.

Metastasis requires tumor cells to navigate through a stiff stroma and squeeze through confined microenvironments. Whether tumors exploit unique biophysical properties to metastasize remains unclear. Data show that invading mammary tumor cells, when cultured in a stiffened three-dimensional extracellular matrix that recapitulates the primary tumor stroma, adopt a basal-like phenotype. Metastatic tumor cells and basal-like tumor cells exert higher integrin-mediated traction forces at the bulk and molecular levels, consistent with a motor-clutch model in which motors and clutches are both increased. Basal-like nonmalignant mammary epithelial cells also display an altered integrin adhesion molecular organization at the nanoscale and recruit a suite of paxillin-associated proteins implicated in invasion and metastasis. Phosphorylation of paxillin by Src family kinases, which regulates adhesion turnover, is similarly enhanced in the metastatic and basal-like tumor cells, fostered by a stiff matrix, and critical for tumor cell invasion in our assays. Bioinformatics reveals an unappreciated relationship between Src kinases, paxillin, and survival of breast cancer patients. Thus adoption of the basal-like adhesion phenotype may favor the recruitment of molecules that facilitate tumor metastasis to integrin-based adhesions. Analysis of the physical properties of tumor cells and integrin adhesion composition in biopsies may be predictive of patient outcome

Groundwater and resilience to drought in the Ethiopian Highlands

During drought, groundwater is often relied on to provide secure drinking water, particularly in rural Africa where other options are limited. However, the technology chosen to access groundwater significantly affects local water security. Here we examine the performance of springs, hand-dug- wells and boreholes in northern Ethiopia through direct high frequency monitoring of water-levels (n=19) and water quality (n=48) over an 18-month period and gathering information on community impacts of declining water access during the El Niño 2015/2016 drought. We found that shallow boreholes equipped with handpumps were the most reliable water supply, recovering within hours to daily abstraction throughout all conditions. Recovery and performance of most hand-dug-wells and springs declined significantly throughout the extended dry season, although in specific aquifer conditions they were reliable. All sources types had negligible measured contamination from Thermo-tolerant Coliforms through the extended dry season, but were contaminated during the rains marking drought cessation. Boreholes were least affected, median 10 cfu/100ml, compared to 190 and 59 cfu/100ml for hand-dug-wells and springs respectively. Many communities who relied solely on springs, wells or rivers experienced severe water shortage in the El Niño drought with mean daily collection times up to 12 hours and volumes collected reducing to 3-5 litre- per-capita- per-day. This led to reports of violent conflict, missed meals, reduction in school attendance and farm activity and increased health impacts. From this study there is a clear case for improving resilience to drought by installing boreholes equipped with handpumps where feasible even if collection times are >30 minutes

The price of your soul: neural evidence for the non-utilitarian representation of sacred values

Sacred values, such as those associated with religious or ethnic identity, underlie many important individual and group decisions in life, and individuals typically resist attempts to trade off their sacred values in exchange for material benefits. Deontological theory suggests that sacred values are processed based on rights and wrongs irrespective of outcomes, while utilitarian theory suggests that they are processed based on costs and benefits of potential outcomes, but which mode of processing an individual naturally uses is unknown. The study of decisions over sacred values is difficult because outcomes cannot typically be realized in a laboratory, and hence little is known about the neural representation and processing of sacred values. We used an experimental paradigm that used integrity as a proxy for sacredness and which paid real money to induce individuals to sell their personal values. Using functional magnetic resonance imaging (fMRI), we found that values that people refused to sell (sacred values) were associated with increased activity in the left temporoparietal junction and ventrolateral prefrontal cortex, regions previously associated with semantic rule retrieval. This suggests that sacred values affect behaviour through the retrieval and processing of deontic rules and not through a utilitarian evaluation of costs and benefits

Defining success in graduate school

[Response to Weiner OD (2014) How should we be selecting our graduate students. Mol Biol Cell 25:429–430. doi: 10.1091/mbc.E13-11-0646.

High-throughput microfluidic micropipette aspiration device to probe time-scale dependent nuclear mechanics in intact cells

The mechanical properties of the cell nucleus are increasingly recognized as critical in many biological processes. The deformability of the nucleus determines the ability of immune and cancer cells to migrate through tissues and across endothelial cell layers, and changes to the mechanical properties of the nucleus can serve as novel biomarkers in processes such as cancer progression and stem cell differentiation. However, current techniques to measure the viscoelastic nuclear mechanical properties are often time consuming, limited to probing one cell at a time, or require expensive, highly specialized equipment. Furthermore, many current assays do not measure time-dependent properties, which are characteristic of viscoelastic materials. Here, we present an easy-to-use microfluidic device that applies the well-established approach of micropipette aspiration, adapted to measure many cells in parallel. The device design allows rapid loading and purging of cells for measurements, and minimizes clogging by large particles or clusters of cells. Combined with a semi-automated image analysis pipeline, the microfluidic device approach enables significantly increased experimental throughput. We validated the experimental platform by comparing computational models of the fluid mechanics in the device with experimental measurements of fluid flow. In addition, we conducted experiments on cells lacking the nuclear envelope protein lamin A/C and wild-type controls, which have well-characterized nuclear mechanical properties. Fitting time-dependent nuclear deformation data to power law and different viscoelastic models revealed that loss of lamin A/C significantly altered the elastic and viscous properties of the nucleus, resulting in substantially increased nuclear deformability. Lastly, to demonstrate the versatility of the devices, we characterized the viscoelastic nuclear mechanical properties in a variety of cell lines and experimental model systems, including human skin fibroblasts from an individual with a mutation in the lamin gene associated with dilated cardiomyopathy, healthy control fibroblasts, induced pluripotent stem cells (iPSCs), and human tumor cells. Taken together, these experiments demonstrate the ability of the microfluidic device and automated image analysis platform to provide robust, high throughput measurements of nuclear mechanical properties, including time-dependent elastic and viscous behavior, in a broad range of applications.This work was supported by awards from the National Institutes of Health [R01 HL082792 and U54 CA210184 to JL], the Department of Defense Breast Cancer Research Program [Breakthrough Award BC150580 to JL], the National Science Foundation [CBET-1254846 and MCB-1715606 to JL; GRFP- 2014163403 to GRF], La Ligue contre le cancer [REMX17751 to PMD] the Fondation ARC [PDF20161205227 to PMD], and a ministerial doctoral fellowship of Paris Saclay University to SDM. This work was performed in part at Cornell NanoScale Facility (CNF), an NNCI member supported by NSF Grant NNCI- 1542081. The authors thank Elisa di Pasquale and Gianluigi Condorelli for the human iPSCs and laminopathy patient fibroblasts, Colin Stewart for the lamin A/C-deficient and wild- type MEFs. The authors thank Karine Guevorkian and Francoise Brochard for helpful discussions

Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of meier-gorlin syndrome

Mutations in ORC1, ORC4, ORC6, CDT1, and CDC6, which encode proteins required for DNA replication origin licensing, cause Meier-Gorlin syndrome (MGS), a disorder conferring microcephaly, primordial dwarfism, underdeveloped ears, and skeletal abnormalities. Mutations in ATR, which also functions during replication, can cause Seckel syndrome, a clinically related disorder. These findings suggest that impaired DNA replication could underlie the developmental defects characteristic of these disorders. Here, we show that although origin licensing capacity is impaired in all patient cells with mutations in origin licensing component proteins, this does not correlate with the rate of progression through S phase. Thus, the replicative capacity in MGS patient cells does not correlate with clinical manifestation. However, ORC1-deficient cells from MGS patients and siRNA-mediated depletion of origin licensing proteins also have impaired centrosome and centriole copy number. As a novel and unexpected finding, we show that they also display a striking defect in the rate of formation of primary cilia. We demonstrate that this impacts sonic hedgehog signalling in ORC1-deficient primary fibroblasts. Additionally, reduced growth factor-dependent signaling via primary cilia affects the kinetics of cell cycle progression following cell cycle exit and re-entry, highlighting an unexpected mechanism whereby origin licensing components can influence cell cycle progression. Finally, using a cell-based model, we show that defects in cilia function impair chondroinduction. Our findings raise the possibility that a reduced efficiency in forming cilia could contribute to the clinical features of MGS, particularly the bone development abnormalities, and could provide a new dimension for considering developmental impacts of licensing deficiency

Methane Throughout the Atmosphere of the Warm Exoplanet WASP-80b

The abundances of major carbon and oxygen bearing gases in the atmospheres of giant exoplanets provide insights into atmospheric chemistry and planet formation processes. Thermochemistry suggests that methane should be the dominant carbon-bearing species below $\sim$1000 K over a range of plausible atmospheric compositions; this is the case for the Solar System planets and has been confirmed in the atmospheres of brown dwarfs and self-luminous directly imaged exoplanets. However, methane has not yet been definitively detected with space-based spectroscopy in the atmosphere of a transiting exoplanet, but a few detections have been made with ground-based, high-resolution transit spectroscopy including a tentative detection for WASP-80b. Here we report transmission and emission spectra spanning 2.4-4.0 micrometers of the 825 K warm Jupiter WASP-80b taken with JWST's NIRCam instrument, both of which show strong evidence for methane at greater than 6-sigma significance. The derived methane abundances from both viewing geometries are consistent with each other and with solar to sub-solar C/O and ~5$\times$ solar metallicity, which is consistent with theoretical predictions.Comment: 23 pages, 10 figures, 3 tables. This preprint has been submitted to and accepted in principle for publication in Nature without significant change

Characteristics of the National Applicant Pool for Clinical Informatics Fellowships (2016-2017)

We conducted a national study to assess the numbers and diversity of applicants for 2016 and 2017 clinical informatics fellowship positions. In each year, we collected data on the number of applications that programs received from candidates who were ultimately successful vs. unsuccessful. In 2017, we also conducted an anonymous applicant survey. Successful candidates applied to an average of 4.2 and 5.5 programs for 2016 and 2017, respectively. In the survey, unsuccessful candidates reported applying to fewer programs. Assuming unsuccessful candidates submitted between 2-5 applications each, the total applicant pool numbered 42-69 for 2016 (competing for 24 positions) and 52-85 for 2017 (competing for 30 positions). Among survey respondents (n=33), 24% were female, 1 was black and none were Hispanic. We conclude that greater efforts are needed to enhance interest in clinical informatics among medical students and residents, particularly among women and members of underrepresented minority groups