Hematopoietic stem cells (HSCs) are generated during embryonic development and possess the ability to reconstitute all adult blood lineages and self-renew for the life of an organism. Despite efforts to generate HSCs in vitro in a manner that recapitulates embryonic development, all attempts to date have failed indicating that our knowledge of this process is incomplete. Cell signaling pathways are crucial for the formation of HSCs during embryonic development. Understanding the requirements for cell signaling are complicated by the fact that there is crosstalk between pathways during development, necessitating a clear understanding of these relationships. Notch signaling is essential for HSC formation, as evidenced by the fact that many Notch pathway proteins are required for this process including the specific Notch1 receptor that functions cell- autonomously in mouse. Additionally, recent data from the zebrafish indicate that Notch signaling downstream of the non-canonical Wnt protein Wnt16 is also required in the somitic environment for HSC and sclerotome specification, suggesting that these two developmental events are related. We asked if the remaining Notch receptors perform any role in HSC emergence, here we present evidence that Notch3 is required in zebrafish. Tissue and temporal- specific activation of Notch intracellular domain (NICD) rescue experiments in Notch3 knockdown embryos indicate that Notch3 is required in somitic tissues for the generation of HSCs and sclerotome well before establishment of the HSC program, conversely Notch1 homologues Notch1a and Notch1b are required in the endothelium for dorsal aorta (DA) and HSC specification just before HSCs are generated. We identified that the function of Notch3 lies downstream of Wnt16, Dlc, and Dld in a linear genetic pathway. In contrast, endothelial expression of Notch1b requires the activity of Pdgfra receptor in a distinct signaling cascade from Wnt16- Notch3. Collectively, these findings demonstrate that multiple inputs from the Notch pathway are required at different times and places during development, with distinct inputs regulated by specific signaling pathway

Minoxidil is a strong oral vasodilator that is used to treat patients with hypertension refractoryto first-line medications. We report a case of minoxidil-associated subacute cardiac tamponadediagnosed by point-of-care ultrasound (POCUS) in a hypertensive patient. A 30-year-old male witha past medical history of poorly controlled hypertension (treated with minoxidil) and chronic kidneydisease presented with 2-3 days of chest pain and shortness of breath with markedly elevated bloodpressures. A point-of-care transthoracic echocardiogram revealed a massive pericardial effusion withsonographic tamponade physiology. We review the risk factors for developing pericardial effusionsthat progress to cardiac tamponade, the utility of diagnosing these patients by POCUS, and theincidence of patients who present with sonographic signs of cardiac tamponade without hypotension.

Visualizations are frequently used as a means to understand trends and gather insights from datasets, but often take a long time to generate. In this paper, we focus on the problem of rapidly generating approximate visualizations while preserving crucial visual properties of interest to analysts. Our primary focus will be on sampling algorithms that preserve the visual property of ordering; our techniques will also apply to some other visual properties. For instance, our algorithms can be used to generate an approximate visualization of a bar chart very rapidly, where the comparisons between any two bars are correct. We formally show that our sampling algorithms are generally applicable and provably optimal in theory, in that they do not take more samples than necessary to generate the visualizations with ordering guarantees. They also work well in practice, correctly ordering output groups while taking orders of magnitude fewer samples and much less time than conventional sampling schemes.

Neuropeptides, especially oxytocin (OT) and arginine vasopressin (AVP), have been implicated in several features of monogamy including alloparenting. The purpose of the present study was to examine the role of OT and AVP in alloparental behavior in reproductively naïve male prairie voles. Males received intracerebroventricular (ICV) injections of artificial cerebrospinal fluid (aCSF), OT, an OT receptor antagonist (OTA), AVP, an AVP receptor antagonist (AVPA), or combinations of OTA and AVPA and were subsequently tested for parental behavior. Approximately 45 min after treatment, animals were tested for behavioral responses to stimulus pups. In a 10-min test, spontaneous alloparental behavior was high in control animals. OT and AVP did not significantly increase the number of males that showed parental behavior, although more subtle behavioral changes were observed. Combined treatment with AVPA and OTA (10 ng each) significantly reduced male parental behavior and increased attacks; following a lower dose (1 ng OTA/1 ng AVPA), males were less likely to display kyphosis and tended to be slower to approach pups than controls. Since treatment with only one antagonist did not interfere with the expression of alloparenting, these results suggest that access to either OT or AVP receptors may be sufficient for the expression of alloparenting.

The inhibition of unwanted behaviors is considered an effortful and controlled ability. However, inhibition also requires the detection of contexts indicating that old behaviors may be inappropriate--in other words, inhibition requires the ability to monitor context in the service of goals, which we refer to as context-monitoring. Using behavioral, neuroimaging, electrophysiological and computational approaches, we tested whether motoric stopping per se is the cognitively-controlled process supporting response inhibition, or whether context-monitoring may fill this role. Our results demonstrate that inhibition does not require control mechanisms beyond those involved in context-monitoring, and that such control mechanisms are the same regardless of stopping demands. These results challenge dominant accounts of inhibitory control, which posit that motoric stopping is the cognitively-controlled process of response inhibition, and clarify emerging debates on the frontal substrates of response inhibition by replacing the centrality of controlled mechanisms for motoric stopping with context-monitoring.

Tumor growth is not solely a consequence of autonomous tumor cell properties. Rather, tumor cells act upon and are acted upon by their microenvironment. It is tumor tissue biology that ultimately determines tumor growth. Thus, we developed a compound library screen for agents that could block essential tumor-promoting effects of the glioblastoma (GBM) perivascular stem cell niche (PVN). We modeled the PVN with three-dimensional primary cultures of human brain microvascular endothelial cells in Matrigel. We previously demonstrated stimulated growth of GBM cells in this PVN model and used this to assay PVN function. We screened the Microsource Spectrum Collection library for drugs that specifically blocked PVN function, without any direct effect on GBM cells themselves. Three candidate PVN-disrupting agents, Iridin, Tigogenin and Triacetylresveratrol (TAR), were identified and evaluated in secondary in vitro screens against a panel of primary GBM isolates as well as in two different in vivo intracranial models. Iridin and TAR significantly inhibited intracranial tumor growth and prolonged survival in these mouse models. Together these data identify Iridin and TAR as drugs with novel GBM tissue disrupting effects and validate the importance of preclinical screens designed to address tumor tissue function rather than the mechanisms of autonomous tumor cell growth.

Hematopoietic stem cells (HSCs) underlie the production of blood and immune cells for the lifetime of an organism. In vertebrate embryos, HSCs arise from the unique transdifferentiation of hemogenic endothelium comprising the floor of the dorsal aorta during a brief developmental window. To date, this process has not been replicated in vitro from pluripotent precursors, partly because the full complement of required signaling inputs remains to be determined. Here, we show that TNFR2 via TNF? activates the Notch and NF-?B signaling pathways to establish HSC fate, indicating a requirement for inflammatory signaling in HSC generation. We determine that primitive neutrophils are the major source of TNF?, assigning a role for transient innate immune cells in establishing the HSC program. These results demonstrate that proinflammatory signaling, in the absence of infection, is utilized by the developing embryo to generate the lineal precursors of the adult hematopoietic system.