Flow distributed oscillation, flow velocity modulation and resonance

We examine the effects of a periodically varying flow velocity on the standing and travelling wave patterns formed by the flow-distributed oscillation (FDO) mechanism. In the kinematic (or diffusionless) limit, the phase fronts undergo a simple, spatiotemporally periodic longitudinal displacement. On the other hand, when the diffusion is significant, periodic modulation of the velocity can disrupt the wave pattern, giving rise in the downstream region to travelling waves whose frequency is a rational multiple of the velocity perturbation frequency. We observe frequency locking at ratios of 1:1, 2:1 and 3:1, depending on the amplitude and frequency of the velocity modulation. This phenomenon can be viewed as a novel, rather subtle type of resonant forcing.Comment: submitted to Phys. Rev.

A zinc transporter gene required for development of the nervous system.

The essentiality of zinc for normal brain development is well established. It has been suggested that primary and secondary zinc deficiencies can contribute to the occurrence of numerous human birth defects, including many involving the central nervous system. In a recent study, we searched for zinc transporter genes that were critical for neurodevelopment. We confirmed that ZIP12 is a zinc transporter encoded by the gene slc39a12 that is highly expressed in the central nervous systems of human, mouse, and frog (Xenopus tropicalis).Using loss-of-function methods, we determined that ZIP12 is required for neuronal differentiation and neurite outgrowth and necessary for neurulation and embryonic viability. These results highlight an essential need for zinc regulation during embryogenesis and nervous system development. We suggest that slc39a12 is a candidate gene for inherited neurodevelopmental defects in humans

Extracellular electrical fields direct wound healing and regeneration

Author Posting. © Marine Biological Laboratory, 2011. This article is posted here by permission of Marine Biological Laboratory for personal use, not for redistribution. The definitive version was published in Biological Bulletin 221 (2011): 79-92.Endogenous DC electric fields (EFs) are important, fundamental components of development, regeneration, and wound healing. The fields are the result of polarized ion transport and current flow through electrically conductive pathways. Nullification of endogenous EFs with pharmacological agents or applied EFs of opposite polarity disturbs the aforementioned processes, while enhancement increases the rate of wound closure and the extent of regeneration. EFs are applied to humans in the clinic, to provide an overwhelming signal for the enhancement of healing of chronic wounds. Although clinical trials, spanning a course of decades, have shown that applied EFs enhance healing of chronic wounds, the mechanisms by which cells sense and respond to these weak cues remains unknown. EFs are thought to influence many different processes in vivo. However, under more rigorously controlled conditions in vitro, applied EFs induce cellular polarity and direct migration and outgrowth. Here we review the generation of endogenous EFs, the results of their alteration, and the mechanisms by which cells may sense these weak fields. Understanding the mechanisms by which native and applied EFs direct development and repair will enable current and future therapeutic applications to be optimized.This work has been supported by The Eugene and Millicent Bell Fellowship Fund in Tissue Engineering (M.A.M.), the Hermann Foundation Research Development Fund Award (M.A.M.), the NIH:NCRR grant P41 RR001395 (PI Peter JS Smith) and the Regenerative Biology Center at the MBL GM092374 (PI Gary Borisy)

Spatial manipulation of cells and organelles using single electrode dielectrophoresis

Author Posting. © Author(s), 2012. This article is posted here by permission of Informa Healthcare USA, for personal use, not for redistribution. The definitive version was published in BioTechniques 52 (2012): 39-43, doi:10.2144/000113802.The selection, isolation, and accurate positioning of single cells in three dimensions are increasingly desirable in many areas of cell biology and tissue engineering. We describe the application of a simple and low cost dielectrophoretic device for picking out and relocating single target cells. The device consists of a single metal electrode and an AC signal generator. It does not require microfabrication technologies or sophisticated electronics. The dielectrophoretic manipulator also discriminates between live and dead cells and is capable of redistributing intracellular organelles.This research was funded by NIH-NCRR grant P41 RR001395 and supported by The Eugene and Millicent Bell Fellowship Fund in Tissue Engineering, the Hermann Foundation Research Development Fund Award, the Dennis and Alix Robinson Memorial, and the MBL Bell Center, grant GM092374.2012-07-0

Cisplatin resistant spheroids model clinically relevant survival mechanisms in ovarian tumors

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS 11 (2016): e0151089, doi: 10.1371/journal.pone.0151089 .The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05) (S2 Table). Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition.This work was funded by the NIH NCRR supplement grant P41 RR001395-27S1 (J.W.H.), NSF DBI-1005378 “REU Site: Biological Discovery in Woods Hole”, faculty startup funds from the Office of Research at Oklahoma State University (W.C.), and the Mary Kay Foundation (A.S.B.)

Transformative decisions

Some of the most fundamental decisions we make in our lives – such as becoming a parent or moving to a different part of the world – are transformative. According to Laurie Paul (2014), transformative decisions pose a major problem to us because they fall outside the realm of rationality. Her argument in favor of that conclusion rests on the premise that the subjective value (i.e., the value of experiencing a certain outcome of a decision) plays the central role in transformative decisions. This paper challenges that premise and hence the overall conclusion that transformative decisions usually are not rational. In the theoretical part, we specify the conditions under which transformative decisions are possibly rational and likely to be rational. The data we present in the empirical part reveal that subjective value often plays only a minor role in people’s decision-making process. Putting both parts together, we argue that people have a great chance of making rational transformative choices

Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials

Neprilysin is a neutral endopeptidase and its inhibition increases bioavailability of natriuretic peptides, bradykinin, and substance P, resulting in natriuretic, vasodilatatory, and anti-proliferative effects. In concert, these effects are prone to produce a powerful ventricular unloading and antihypertensive response. LCZ696 (Valsartan/sacubitril) is a first-in-class angiotensin II-receptor neprilysin inhibitor. LCZ696 is a novel drug not only for the treatment of heart failure but it is also likely to be a useful antihypertensive drug and may have a preferential effect on systolic pressure. This review discusses (i) the mechanism of action, pharmacokinetics, and pharmacodynamics of this novel drug, (ii) the efficacy, safety, and tolerability of LCZ696 in treatment of hypertension from the available trials, (iii) evidence from other contemporary trials on combined Neprilysin inhibitors, (iv) future trials and areas of research to identify hypertensive patient populations that would most benefit from LCZ69

How Not to Characterise a Hard Choice

People are often faced with so called hard choices – also known as hard cases of comparison. In trying to characterize these hard choices, philosophers have made two central claims. First, failure of transitivity underlies hard cases of comparison. Second, using a random procedure is considered inappropriate in order to arrive at a decision in hard cases. While having some argumentative support, both claims primarily rely on expert intuitions. The results of the experiments we present in this paper challenge both claims, as well as the representativeness of expert intuitions that support these claims, by showing that most people (i) violate transitivity only if a hard choice is important, and (ii) find it appropriate to use a random procedure even in hard cases of comparison

Limnogeologúa de Laguna Chungará y cambio climático durante el Holoceno superior en el altiplano chileno septentrional

[Resumen] El estudio sísmico de la Laguna Chungará (69° 30' O, 18° 15'S, 4520 m. s.n.m, Altiplano chileno septentrional) y el análisis sedimentológico de varios sondeos ha permitido reconstruir la evolución de la sedimentación lacustre en el lago durante el Holoceno Superior. Se han identificado dos asociaciones de facies: i) litoral, más somera, compuesta por facies de turbera y in plataforma lacustre, más profunda, compuesta por facies con abundantes fragmentos de Characeae. Estas facies alternan en tres ciclos sedimentarios provocados por fluctuaciones en el nivel del lago. Estas variaciones hidrológicas en la laguna han sido causadas por cambios en el balance hídrico que a su vez reflejan importantes fluctuaciones climáticas durante el Holoceno Superior.[Abstract] We reconstruct the Late Holocene sedimentary history of Laguna Chungará (69° 30' W, 18° 10'5, 4520 m.a.s.l., northern Chilean Altiplano) based on high resolution seismic profiling and sedimentologic analyses of cores. Two sedimentary facies associations have been defined and interpreted: n macrophytedominant littoral, composed of black muds with macrophyte remains and peaty muds, and in Characeae-dominant lacustrine self, composed of gray muds and sands with abundant Characeae remains. The two facies associations define three cycles caused by oscillations in the lake level from shallower (macrophyte) to deeper (Characeae) conditions. Changes in the hydrology of Laguna Chungará reflect variations in the effective moisture (precipitation - evaporation) in the Altiplano during the Late Holocene