Box Drawings for Learning with Imbalanced Data

The vast majority of real world classification problems are imbalanced, meaning there are far fewer data from the class of interest (the positive class) than from other classes. We propose two machine learning algorithms to handle highly imbalanced classification problems. The classifiers constructed by both methods are created as unions of parallel axis rectangles around the positive examples, and thus have the benefit of being interpretable. The first algorithm uses mixed integer programming to optimize a weighted balance between positive and negative class accuracies. Regularization is introduced to improve generalization performance. The second method uses an approximation in order to assist with scalability. Specifically, it follows a \textit{characterize then discriminate} approach, where the positive class is characterized first by boxes, and then each box boundary becomes a separate discriminative classifier. This method has the computational advantages that it can be easily parallelized, and considers only the relevant regions of feature space

Nanotechnology for Cell–Substrate Interactions

In the pursuit to understand the interaction between cells and their underlying substrates, the life sciences are beginning to incorporate micro- and nanotechnology-based tools to probe and measure cells. The development of these tools portends endless possibilities for new insights into the fundamental relationships between cells and their surrounding microenvironment that underlie the physiology of human tissue. Here, we review techniques and tools that have been used to study how a cell responds to the physical factors in its environment. We also discuss unanswered questions that could be addressed by these approaches to better elucidate the molecular processes and mechanical forces that dominate the interactions between cells and their physical scaffolds

Sexual dysfunction in patients with schizophrenia treated with conventional antipsychotics or risperidone

Hong Liu-Seifert1, Bruce J Kinon1, Christopher J Tennant2, Jennifer Sniadecki1, Jan Volavka31Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA; 2CJT Biomedical Consulting, South Lake Tahoe, CA, USA; 3New York University, New York, NY, USAObjective: To better understand sexual dysfunction in patients with schizophrenia and its associations with prolactin and reproductive hormones.Methods: This was a secondary analysis of an open-label, one-day study (N = 402). The primary objective of the study was to assess the prevalence of hyperprolactinemia in patients with schizophrenia who had been treated with conventional antipsychotics or risperidone. Other atypical antipsychotics available at the time of the study were not included due to a more favorable prolactin profile.Results: The majority of patients (59% of females and 60% of males) reported impairment of sexual function. In postmenopausal females, risk of impaired sexual interest was increased by 31% for every 10 ng/ml increase in prolactin (p = 0.035). In males, lower testosterone was associated with higher prolactin (p < 0.001) and with orgasmic (p = 0.004) and ejaculatory dysfunction (p = 0.028).Conclusion: These findings suggest that hyperprolactinemia may be associated with sexual dysfunction. They also provide more information on the relationships between prolactin, reproductive hormones, and sexual dysfunction. Sexual dysfunction is an understudied yet important consideration in the treatment of schizophrenia. More attention is warranted in this area as it may provide opportunities for improved quality of life and adherence to treatment for patients.Keywords: sexual dysfunction, schizophrenia, hyperprolactinemia, antipsychotics, risperidon

Magnetic microposts as an approach to apply forces to living cells

Cells respond to mechanical forces whether applied externally or generated internally via the cytoskeleton. To study the cellular response to forces separately, we applied external forces to cells via microfabricated magnetic posts containing cobalt nanowires interspersed among an array of elastomeric posts, which acted as independent sensors to cellular traction forces. A magnetic field induced torque in the nanowires, which deflected the magnetic posts and imparted force to individual adhesions of cells attached to the array. Using this system, we examined the cellular reaction to applied forces and found that applying a step force led to an increase in local focal adhesion size at the site of application but not at nearby nonmagnetic posts. Focal adhesion recruitment was enhanced further when cells were subjected to multiple force actuations within the same time interval. Recording the traction forces in response to such force stimulation revealed two responses: a sudden loss in contractility that occurred within the first minute of stimulation or a gradual decay in contractility over several minutes. For both types of responses, the subcellular distribution of loss in traction forces was not confined to locations near the actuated micropost, nor uniformly across the whole cell, but instead occurred at discrete locations along the cell periphery. Together, these data reveal an important dynamic biological relationship between external and internal forces and demonstrate the utility of this microfabricated system to explore this interaction. Supporting materials: http://www.pnas.org/cgi/content/full/0611613104/DC

SARS-CoV-2 Infects Human Pluripotent Stem Cell-Derived Cardiomyocytes, Impairing Electrical and Mechanical Function

COVID-19 patients often develop severe cardiovascular complications, but it remains unclear if these are caused directly by viral infection or are secondary to a systemic response. Here, we examine the cardiac tropism of SARS-CoV-2 in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and smooth muscle cells (hPSC-SMCs). We find that that SARS-CoV-2 selectively infects hPSC-CMs through the viral receptor ACE2, whereas in hPSC-SMCs there is minimal viral entry or replication. After entry into cardiomyocytes, SARS-CoV-2 is assembled in lysosome-like vesicles and egresses via bulk exocytosis. The viral transcripts become a large fraction of cellular mRNA while host gene expression shifts from oxidative to glycolytic metabolism and upregulates chromatin modification and RNA splicing pathways. Most importantly, viral infection of hPSC-CMs progressively impairs both their electrophysiological and contractile function, and causes widespread cell death. These data support the hypothesis that COVID-19-related cardiac symptoms can result from a direct cardiotoxic effect of SARS-CoV-2