In depth characterization of midbrain organoids derived from wild type iPSC lines.

The ability to model human neurological tissues in vitro has been a major hurdle to effective drug development for neurological disorders. iPSC-derived brain organoids have emerged as a compelling solution to this problem as they have the potential to relevantly model the protein expression pattern and physiology of specific brain regions. Although many protocols now exist for the production of brain organoids, few attempts have been made to do an in-depth kinetic evaluation of expression of mature regiospecific markers of brain organoids.

Generation and characterization of NGLY1 patient-derived midbrain organoids.

NGLY1 deficiency is an ultra-rare, autosomal recessive genetic disease caused by mutations in the gene encoding N-glycanase one that removes N-linked glycan. Patients with pathogenic mutations in NGLY1 have complex clinical symptoms including global developmental delay, motor disorder and liver dysfunction. To better understand the disease pathogenesis and the neurological symptoms of the NGLY1 deficiency we generated and characterized midbrain organoids using patient-derived iPSCs from two patients with distinct disease-causing mutations-one homozygous for p.

High-Content Drug Discovery Targeting Molecular Bladder Cancer Subtypes.

Molecular subtypes of muscle-invasive bladder cancer (MIBC) display differential survival and drug sensitivities in clinical trials. To date, they have not been used as a paradigm for phenotypic drug discovery. This study aimed to discover novel subtype-stratified therapy approaches based on high-content screening (HCS) drug discovery.

Design, Synthesis, and Biological Evaluation of the First Inhibitors of Oncogenic CHD1L.

Chromodomain helicase DNA-binding protein 1 like (CHD1L) is an oncogene implicated in tumor progression, multidrug resistance, and metastasis in many types of cancer. In this article, we described the optimization of the first lead CHD1L inhibitors (CHD1Li) through drug design and medicinal chemistry. More than 30 CHD1Li were synthesized and evaluated using a variety of colorectal cancer (CRC) tumor organoid models and functional assays.

The distributional outcomes of rights-based management in fisheries.

Fisheries managers have increasingly adopted rights-based management (i.e., "catch shares" or "individual transferable quotas" [ITQs]) to address economic and biological management challenges under prior governance regimes.

Recommendation as generalization: Using big data to evaluate cognitive models.

The explosion of data generated during human interactions online presents an opportunity for psychologists to evaluate cognitive models outside the confines of the laboratory. Moreover, the size of these online data sets can allow researchers to construct far richer models than would be feasible with smaller in-lab behavioral data. In the current article, we illustrate this potential by evaluating 3 popular psychological models of generalization on 2 web-scale online data sets typically used to build automated recommendation systems.

Covalent inhibition of NSD1 histone methyltransferase.

The nuclear receptor-binding SET domain (NSD) family of histone methyltransferases is associated with various malignancies, including aggressive acute leukemia with NUP98-NSD1 translocation. While NSD proteins represent attractive drug targets, their catalytic SET domains exist in autoinhibited conformation, presenting notable challenges for inhibitor development. Here, we employed a fragment-based screening strategy followed by chemical optimization, which resulted in the development of the first-in-class irreversible small-molecule inhibitors of the nuclear receptor-binding SET domain protein 1 (NSD1) SET domain.

First-in-Class Inhibitors of Oncogenic CHD1L with Preclinical Activity against Colorectal Cancer.

Since the discovery of CHD1L in 2008, it has emerged as an oncogene implicated in the pathology and poor prognosis of a variety of cancers, including gastrointestinal cancers. However, a mechanistic understanding of CHD1L as a driver of colorectal cancer has been limited. Until now, there have been no reported inhibitors of CHD1L, also limiting its development as a molecular target.

Fishing to live or living to fish: Job satisfaction and identity of west coast fishermen.

Fishing is a dangerous and financially risky way to make a living, but it attracts many participants that prefer it to higher paying and safer jobs. Based on a survey of over 1400 U.S.

Evaluating (and Improving) the Correspondence Between Deep Neural Networks and Human Representations.

Decades of psychological research have been aimed at modeling how people learn features and categories. The empirical validation of these theories is often based on artificial stimuli with simple representations. Recently, deep neural networks have reached or surpassed human accuracy on tasks such as identifying objects in natural images.

Status-quo management of marine recreational fisheries undermines angler welfare.

Recreational fisheries can have a significant impact on fish populations and can suffer from the same symptoms of open access as commercial fisheries. However, recreational fisheries receive little attention compared with their commercial counterparts. Regulations designed to allocate scarce fish, such as seasonal closures and bag limits, can result in significant losses of value to anglers.

Bond-orientational order and Frank's constant in two-dimensional colloidal hard spheres.

Recently, the full phase behaviour of 2D colloidal hard spheres was experimentally established, and found to involve a first order liquid to hexatic transition and a continuous hexatic to crystal transition (Thorneywork et al 2017 Phys. Rev. Lett.

Ecosystem-based management and the wealth of ecosystems.

We merge inclusive wealth theory with ecosystem-based management (EBM) to address two challenges in the science of sustainable management of ecosystems. First, we generalize natural capital theory to approximate realized shadow prices for multiple interacting natural capital stocks (species) making up an ecosystem. These prices enable ecosystem components to be better included in wealth-based sustainability measures.

Biological origins of color categorization.

The biological basis of the commonality in color lexicons across languages has been hotly debated for decades. Prior evidence that infants categorize color could provide support for the hypothesis that color categorization systems are not purely constructed by communication and culture. Here, we investigate the relationship between infants' categorization of color and the commonality across color lexicons, and the potential biological origin of infant color categories.

Two-Dimensional Melting of Colloidal Hard Spheres.

We study the melting of quasi-two-dimensional colloidal hard spheres by considering a tilted monolayer of particles in sedimentation-diffusion equilibrium. In particular, we measure the equation of state from the density profiles and use time-dependent and height-resolved correlation functions to identify the liquid, hexatic, and crystal phases. We find that the liquid-hexatic transition is first order and that the hexatic-crystal transition is continuous.

Testing the feasibility of a hypothetical whaling-conservation permit market in Norway.

A cap-and-trade system for managing whale harvests represents a potentially useful approach to resolve the current gridlock in international whale management. The establishment of whale permit markets, open to both whalers and conservationists, could reveal the strength of conservation demand, about which little is known. This lack of knowledge makes it difficult to predict the outcome of a hypothetical whale permit market.

Focal colors across languages are representative members of color categories.

Focal colors, or best examples of color terms, have traditionally been viewed as either the underlying source of cross-language color-naming universals or derived from category boundaries that vary widely across languages. Existing data partially support and partially challenge each of these views. Here, we advance a position that synthesizes aspects of these two traditionally opposed positions and accounts for existing data.

Exploring Human Cognition Using Large Image Databases.

Most cognitive psychology experiments evaluate models of human cognition using a relatively small, well-controlled set of stimuli. This approach stands in contrast to current work in neuroscience, perception, and computer vision, which have begun to focus on using large databases of natural images. We argue that natural images provide a powerful tool for characterizing the statistical environment in which people operate, for better evaluating psychological theories, and for bringing the insights of cognitive science closer to real applications.

Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.

Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated.

Measuring the value of groundwater and other forms of natural capital.

Valuing natural capital is fundamental to measuring sustainability. The United Nations Environment Programme, World Bank, and other agencies have called for inclusion of the value of natural capital in sustainability metrics, such as inclusive wealth. Much has been written about the importance of natural capital, but consistent, rigorous valuation approaches compatible with the pricing of traditional forms of capital have remained elusive.

Random walks on semantic networks can resemble optimal foraging.

When people are asked to retrieve members of a category from memory, clusters of semantically related items tend to be retrieved together. A recent article by Hills, Jones, and Todd (2012) argued that this pattern reflects a process similar to optimal strategies for foraging for food in patchy spatial environments, with an individual making a strategic decision to switch away from a cluster of related information as it becomes depleted. We demonstrate that similar behavioral phenomena also emerge from a random walk on a semantic network derived from human word-association data.

Associations between food environment around schools and professionally measured weight status for middle and high school students.

Background: Obesity rates among school-age children remain high. Access to energy-dense foods at home, in schools, in stores, and restaurants around homes and schools is of concern. Research on the relationship between food environment around schools and students' weight status is inconclusive.

What are we protecting? Fisher behavior and the unintended consequences of spatial closures as a fishery management tool.

Spatial closures like marine protected areas (MPAs) are prominent tools for ecosystem-based management in fisheries. However, the adaptive behavior of fishermen, the apex predator in the ecosystem, to MPAs may upset the balance of fishing impacts across species. While ecosystem-based management (EBM) emphasizes the protection of all species in the environment, the weakest stock often dominates management attention.