Cell death is a complex process that plays a vital role in development, homeostasis, and disease. Our understanding of and ability to control cell death is impeded by an incomplete characterization of the full range of cell death processes that occur in mammalian systems, especially in response to exogenous perturbations. We present here a general approach to address this problem, which we call modulatory profiling. Modulatory profiles are composed of the changes in potency and efficacy of lethal compounds produced by a second cell death-modulating agent in human cell lines. We show that compounds with the same characterized mechanism of action have similar modulatory profiles. Furthermore, clustering of modulatory profiles revealed relationships not evident when clustering lethal compounds based on gene expression profiles alone. Finally, modulatory profiling of compounds correctly predicted three previously uncharacterized compounds to be microtubule-destabilizing agents, classified numerous compounds that act nonspecifically, and identified compounds that cause cell death through a mechanism that is morphologically and biochemically distinct from previously established ones.apoptosis | chemical biology | small molecules C ell death has historically been viewed as a binary phenomenon. Cells were described to die in one of two ways-through a controlled and ordered process (apoptosis) or an unregulated and chaotic process (necrosis) (1, 2). Not only were these often considered the only two possible mechanisms, but they were also frequently viewed as morphologically and biochemically uniform (3, 4). A great deal of research in recent decades has not only shown the complexity and heterogeneity of apoptotic and necrotic signaling, but also that cells can die in physiological and nonphysiological contexts through processes morphologically and biochemically distinct from both apoptosis and necrosis.Activation of caspases, a family of cysteine proteases, is essential for producing the full morphological characteristics of apoptosis. There are at least three distinct pathways that can lead to the activation of effector caspases-the extrinsic death receptor pathway, the intrinsic mitochondrial pathway, and the Granzyme B pathway (5)-but numerous mechanisms feed into these three pathways. There is substantial evidence that necrosis, long considered to be a disorganized and unregulated process, can proceed through an evolutionarily conserved pathway in a highly orchestrated fashion. Necrosis-like morphology has been observed after death receptor stimulation (6-12), after treatment with DNA-damaging agents (13-15), and in Caenorhabditis elegans in response to a variety of stresses (16,17). These examples illustrate the heterogeneity of cell death processes resembling necrosis. A widely debated nonapoptotic, nonnecrotic cell death mechanism is autophagic cell death, which has been implicated in vivo in the involution of the salivary gland in Drosophila (18) and in death because of the hypersensitivity response in Arabidopsi...

Synaptic dysfunction is thought to play a major role in memory impairment in Alzheimer's disease (AD). PARP-1 has been identified as an epigenetic regulator of plasticity and memory. Thus, we hypothesize that PARP-1 may be altered in postmortem hippocampus of individuals with AD compared to age-matched controls without neurologic disease. We found a reduced level of PARP-1 nucleolar immunohistochemical staining in hippocampal pyramidal cells in AD. Nucleolar PARP-1 staining ranged from dispersed and less intense to entirely absent in AD compared to the distinct nucleolar localization in hippocampal pyramidal neurons in controls. In cases of AD, the percentage of hippocampal pyramidal cells with nucleoli that were positive for both PARP-1 and the nucleolar marker fibrillarin was significantly lower than in controls. PARP-1 nucleolar expression emerges as a sensitive marker of functional changes in AD and suggests a novel role for PARP-1 dysregulation in AD pathology.

Thirty states and the District of Columbia have legalized the use of cannabis for medicinal and/or recreational use by either formally or informally de‐criminalizing its use. However, cannabis remains a Schedule 1 drug under the Federal Controlled Substances Act (21 U.S.C. Sections 801 through 812), leaving federal law in conflict with the laws of over half of the states. As a result, market participants in legal cannabis businesses face risks due to the industry's unique legal status within the United States. We examine the risks and challenges deemed by the cannabis industry as the top risks facing the industry's continued future growth and its sustainability. In addition to general risks inherent in a nascent industry, a legal cannabis business faces additional risks, such as risks in its banking and finance activity, placement of insurance, payment of taxes, and managing its supply chain. These legal businesses also face true legal risk from the possibility of being shut down by the federal government and seizure of assets and product under the CSA. This paper also examines whether the cannabis industry would benefit from a futures market to mitigate price risk.

There is a growing appreciation for differences in epidemiology, treatment, and outcomes of cardiovascular conditions by sex. Historically, cardiovascular clinical trials have under-represented females, but findings have nonetheless been applied to clinical care in a sex-agnostic manner. Thus, much of the collective knowledge about sex-specific cardiovascular outcomes result from post hoc and secondary analyses. In some cases, these investigations have revealed important sex-based differences with implications for optimizing care for female patients with arrhythmias. This review explores the available evidence related to cardiac arrhythmia care among females, with emphasis on areas in which important sex differences are known or suggested. Considerations related to improving female enrollment in clinical trials as a way to establish more robust clinical evidence for the treatment of females are discussed. Areas of remaining evidence gaps are provided, and recommendations for areas of future research and specific action items are suggested. The overarching goal is to improve appreciation for sex-based differences in cardiac arrhythmia care as 1 component of a comprehensive plan to optimize arrhythmia care for all patients.