Dataset from: Lapses in perceptual decisions reflect exploration.

Perceptual decision-makers often display a constant rate of errors independent of evidence strength. These “lapses” are treated as a nuisance arising from noise tangential to the decision, e.g. inattention or motor errors. Here, we use a multisensory decision task in rats to demonstrate that these explanations cannot account for lapses’ stimulus dependence. We propose a novel explanation: lapses reflect a strategic trade-off between exploiting known rewarding actions and exploring uncertain ones. We tested the model’s predictions by selectively manipulating one action’s reward magnitude or probability. As uniquely predicted by this model, changes were restricted to lapses associated with that action. Finally, we show that lapses are a powerful tool for assigning decision-related computations to neural structures based on disruption experiments (here, posterior striatum and secondary motor cortex). These results suggest that lapses reflect an integral component of decision-making and are informative about action values in normal and disrupted brain states

Dataset from: Visual evidence accumulation guides decision-making in unrestrained mice.

The ability to manipulate neural activity with precision is an asset in uncovering neural circuits for decision-making. Diverse tools for manipulating neurons are available for mice, but their feasibility remains unclear, especially when decisions require accumulating visual evidence. For example, whether mice' decisions reflect leaky accumulation is unknown, as are the relevant/irrelevant factors that influence decisions. Further, causal circuits for visual evidence accumulation are poorly understood. To address this, we measured decisions in mice judging the fluctuating rate of a flash sequence. An initial analysis (>500,000 trials, 29 male and female mice) demonstrated that information throughout the 1000 ms trial influenced choice, with early information most influential. This suggests that information persists in neural circuits for ∼1000 ms with minimal accumulation leak. Next, in a subset of animals, we probed strategy more extensively and found that although animals were influenced by stimulus rate, they were unable to entirely suppress the influence of stimulus brightness. Finally, we identified anteromedial (AM) visual area via retinotopic mapping and optogenetically inhibited it using JAWS. Light activation biased choices in both injected and uninjected animals, demonstrating that light alone influences behavior. By varying stimulus–response contingency while holding stimulated hemisphere constant, we surmounted this obstacle to demonstrate that AM suppression biases decisions. By leveraging a large dataset to quantitatively characterize decision-making behavior, we establish mice as suitable for neural circuit manipulation studies. Further, by demonstrating that mice accumulate visual evidence, we demonstrate that this strategy for reducing uncertainty in decision-making is used by animals with diverse visual systems

Biofunctionalised bacterial cellulose scaffold supports the patterning and expansion of human embryonic stem cell-derived dopaminergic progenitor cells.

BACKGROUND: Stem cell-based therapies for neurodegenerative diseases like Parkinson's disease are a promising approach in regenerative medicine and are now moving towards early stage clinical trials. However, a number of challenges remain including the ability to grow stem cells in vitro on a 3-dimensional scaffold, as well as their loss, by leakage or cell death, post-implantation. These issues could, however, be helped through the use of scaffolds that support the growth and differentiation of stem cells both in vitro and in vivo. The present study focuses on the use of bacterial cellulose as an in vitro scaffold to promote the growth of different stem cell-derived cell types. Bacterial cellulose was used because of its remarkable properties such as its wettability, ability to retain water and low stiffness, all of which is similar to that found in brain tissue. METHODS: We cultured human embryonic stem cell-derived progenitor cells on bacterial cellulose with growth factors that were covalently functionalised to the surface via silanisation. Epifluorescence microscopy and immunofluorescence were used to detect the differentiation of stem cells into dopaminergic ventral midbrain progenitor cells. We then quantified the proportion of cells that differentiated into progenitor cells and compared the effect of growing cells on biofunctionalised cellulose versus standard cellulose. RESULTS: We show that the covalent functionalisation of bacterial cellulose sheets with bioactive peptides improves the growth and differentiation of human pluripotent stem cells into dopaminergic neuronal progenitors. CONCLUSIONS: This study suggests that the biocompatible material, bacterial cellulose, has potential applications in cell therapy approaches as a means to repair damage to the central nervous system, such as in Parkinson's disease but also in tissue engineering

Loss of hSef promotes metastasis through upregulation of EMT in prostate cancer

We have previously reported that the negative signaling regulator Similar Expression to FGF (hSef) is downregulated in prostate cancer and its loss is associated with clinical metastasis. Here, we explored the mechanistic basis of this finding. We first confirmed our clinical observation by testing hSef manipulation in an $\textit{in vivo}$ metastasis model. hSef stable expressing cells (PC3M-hSef) or empty vector controls (PC3M-EV) were injected subcutaneously into the lateral thoracic walls of NOD-SCID gamma mice and lungs were harvested at autopsy. In this model, 6/7 PC3M-EV xenografts had definitive lung micro-metastasis whilst only 1/6 PC3M-hSef xenografts exhibited metastasis recapitulating the clinical scenario ($\textit{p}$ = 0.03). Gene expression studies revealed key perturbations in genes involved in cell motility and epithelial to mesenchymal transition (EMT) along with alterations in cognate signaling pathways. These results were validated in an EMT specific PCR array whereby hSef over-expression and silencing reciprocally altered E-Cadherin expression ($\textit{p}$ = <0.001) amongst other EMT markers. Immunohistochemistry of excised tumors from the xenografts also confirmed the effect of hSef in suppressing E-Cadherin expression at the protein level. Phosphokinase arrays further demonstrated a role for hSef in attenuating signaling of not only ERK-MAPK but also the JNK and p38 pathways as well. Taken together, these data suggest evidence that loss of hSef may be a critical event facilitating tumor dissemination of prostate cancer through alteration of EMT. Detection of downregulated hSef, along with other negative regulators, may therefore be a useful biomarker heralding a transition to a metastatic phenotype and warrants further exploration in this context.Grant sponsor: Medical Research Council/The Prostate Cancer Charity Clinical Research Training Fellowship (S.H.); Grant number: G1001961; Grant sponsor: The Royal College of Surgeons Surgical Research Fellowship (S.H.), Addenbrooke’s Charitable Trust Oncology Research Fellowship (S.H.) and the University of Cambridge Raymond and Beverly Sackler Studentship (S.H.) DOI: 10.1002/ijc.30604

Assessing Human Embryonic Stem Cell-Derived Dopaminergic Neuron Progenitor Transplants Using Non-invasive Imaging Techniques

Abstract: Purpose: Human pluripotent stem cell (hPSC)-derived dopaminergic neuron progenitor cells (DAPCs) are a potential therapy for Parkinson’s disease (PD). However, their intracranial administration raises safety concerns including uncontrolled proliferation, migration and inflammation. Here, we apply a bimodal imaging approach to investigate the fate of DAPC transplants in the rat striatum. Procedures: DAPCs co-expressing luciferase and ZsGreen or labelled with micron-sized particles of iron oxide (MPIOs) were transplanted in the striatum of RNU rats (n = 6 per group). DAPCs were tracked in vivo using bioluminescence and magnetic resonance (MR) imaging modalities. Results: Transgene silencing in differentiating DAPCs accompanied with signal attenuation due to animal growth rendered the bioluminescence undetectable by week 2 post intrastriatal transplantation. However, MR imaging of MPIO-labelled DAPCs showed that transplanted cells remained at the site of injection for over 120 days. Post-mortem histological analysis of DAPC transplants demonstrated that labelling with either luciferase/ZsGreen or MPIOs did not affect the ability of cells to differentiate into mature dopaminergic neurons. Importantly, labelled cells did not elicit increased glial reactivity compared to non-labelled cells. Conclusions: In summary, our findings support the transplantation of hPSC-derived DAPCs as a safe treatment for PD

A reference human induced pluripotent stem cell line for large-scale collaborative studies

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field

Opportunities and challenges in the use of coal fly ash for soil improvements – a review

Coal fly ash (CFA), a by-product of coal combustion has been regarded as a problematic solid waste, mainly due to its potentially toxic trace elements, PTEs (e.g. Cd, Cr, Ni, Pb) and organic compounds (e.g. PCBs, PAHs) content. However, CFA is a useful source of essential plant nutrients (e.g. Ca, Mg, K, P, S, B, Fe, Cu and Zn). Uncontrolled land disposal of CFA is likely to cause undesirable changes in soil conditions, including contamination with PTEs, PAHs and PCBs. Prudent CFA land application offers considerable opportunities, particularly for nutrient supplementation, pH correction and ameliorating soil physical conditions (soil compaction, water retention and drainage). Since CFA contains little or no N and organic carbon, and CFA-borne P is not readily plant available, a mixture of CFA and manure or sewage sludge (SS) is better suited than CFA alone. Additionally, land application of such a mixture can mitigate the mobility of SS-borne PTEs, which is known to increase following cessation of SS application. Research analysis further shows that application of alkaline CFA with or without other amendments can help remediate at least marginally metal contaminated soils by immobilisation of mobile metal forms. CFA land application with SS or other source of organic carbon, N and P can help effectively reclaim/restore mining-affected lands. Given the variability in the nature and composition of CFA (pH, macro- and micro-nutrients) and that of soil (pH, texture and fertility), the choice of CFA (acidic or alkaline and its application rate) needs to consider the properties and problems of the soil. CFA can also be used as a low cost sorbent for the removal of organic and inorganic contaminants from wastewater streams; the disposal of spent CFA however can pose further challenges. Problems in CFA use as a soil amendment occur when it results in undesirable change in soil pH, imbalance in nutrient supply, boron toxicity in plants, excess supply of sulphate and PTEs. These problems, however, are usually associated with excess or inappropriate CFA applications. The levels of PAHs and PCBs in CFA are generally low; their effects on soil biota, uptake by plants and soil persistence, however, need to be assessed. In spite of this, co-application of CFA with manure or SS to land enhances its effectiveness in soil improvements

Access and benefit sharing: Issues related to marine genetic resources

Since the entry into force of the CBD in 1993, countries have struggled to find answers to several questions related to ABS issues and have spent considerable amounts of time, energy and money in understanding how to operationalise these principles. One critical area that is beginning to appear during the discussions under the international regime is the status of marine genetic resources with a particular emphasis emerging on genetic resources available in areas beyond national jurisdiction. This paper presents some key legal and policy issues that negotiators of the international regime on ABS need to consider in relation to marine genetic resources. © 2008, RIS

Decision Activity in Parietal Cortex - Leader or Follower?

Katz and colleagues demonstrate that inactivating the primate lateral intraparietal area (LIP) spares visual motion decisions, even though these same decisions strongly modulate LIP neurons. This work is the latest addition to an intense effort spanning sensory modalities, animals, and techniques to understand which structures comprise the circuits responsible for interpreting sensory signals to make decisions

Visual evidence accumulation guides decision-making in unrestrained mice

The ability to manipulate neural activity with precision is an asset in uncovering neural circuits for decision-making. Diverse tools for manipulating neurons are available for mice, but their feasibility remains unclear, especially when decisions require accumulating visual evidence. For example, whether mice' decisions reflect leaky accumulation is unknown, as are the relevant/irrelevant factors that influence decisions. Further, causal circuits for visual evidence accumulation are poorly understood. To address this, we measured decisions in mice judging the fluctuating rate of a flash sequence. An initial analysis (>500,000 trials, 29 male and female mice) demonstrated that information throughout the 1000ms trial influenced choice, with early information most influential. This suggests that information persists in neural circuits for approximately 1000ms with minimal accumulation leak. Next, in a subset of animals, we probed strategy more extensively and found that although animals were influenced by stimulus rate, they were unable to entirely suppress the influence of stimulus brightness. Finally, we identified anteromedial (AM) visual area via retinotopic mapping and optogenetically inhibited it using JAWS. Light activation biased choices in both injected and uninjected animals, demonstrating that light alone influences behavior. By varying stimulus-response contingency while holding stimulated hemisphere constant, we surmounted this obstacle to demonstrate that AM suppression biases decisions. By leveraging a large dataset to quantitatively characterize decision-making behavior, we establish mice as suitable for neural circuit manipulation studies. Further, by demonstrating that mice accumulate visual evidence, we demonstrate that this strategy for reducing uncertainty in decision-making is employed by animals with diverse visual systems.Significance statementTo connect behaviors to their underlying neural mechanism, a deep understanding of behavioral strategy is needed. This understanding is incomplete for mice. To surmount this, we measured the outcome of over 500,000 decisions made by 29 mice trained to judge visual stimuli and performed behavioral/optogenetic manipulations in smaller subsets. Our analyses offer new insights into mice' decision-making strategies and compares them with those of other species. We then disrupted neural activity in a candidate neural structure and examined the effect on decisions. Our findings establish mice as suitable for visual accumulation of evidence decisions. Further, the results highlight similarities in decision-making strategies across very different species