Silencing disease genes in the laboratory and the clinic

Synthetic nucleic acids are commonly used laboratory tools for modulating gene expression and have the potential to be widely used in the clinic. Progress towards nucleic acid drugs, however, has been slow and many challenges remain to be overcome before their full impact on patient care can be understood. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the two most widely used strategies for silencing gene expression. We first describe these two approaches and contrast their relative strengths and weaknesses for laboratory applications. We then review the choices faced during development of clinical candidates and the current state of clinical trials. Attitudes towards clinical development of nucleic acid silencing strategies have repeatedly swung from optimism to depression during the past 20 years. Our goal is to provide the information needed to design robust studies with oligonucleotides, making use of the strengths of each oligonucleotide technology

Texas Guinan

Texas Guinan’s lasting fame derives from her reign as New York City’s Prohibition-era “queen of the nightclubs,” who greeted patrons with the famous cry, “Hello, sucker!” This is the persona displayed in Incendiary Blonde (1945), the flashy Hollywood biopic about Guinan starring Betty Hutton, and by Guinan playing herself in a few early Talkies, including the now-lost Queen of the Night Clubs (1929). But Guinan, born in Waco, Texas, obviously the source of her nickname, first achieved national prominence in the ostensibly masculine domain of the silent film Western, where she was promoted as the “female William S. Hart.” “Texas Guinan to Typify West” promised an early ad campaign for a series of her films, and, playing a tough “gun woman” rather than a timid schoolmarm in need of rescue, Guinan tailored her defiantly unglamorous image as a rowdy cowgirl who tames men as easily as horses. Moreover, her success as a performer allowed her to assume off-screen control of her career, first as the department head of the unit producing her films at Bull’s Eye/Reelcraft in 1919, and most significantly in 1921 by forming Texas Guinan Productions, her own independent company, to make The Code of the West (1921) and Texas of the Mounted (1921), her final silent films before her successful reinvention as a night club hostess. Some evidence suggests that the company may have produced additional films. According to her biographer Louise Berliner, Guinan was an innovative and energetic producer, choosing to cast each film rather than employ a stock company, helping to inaugurate states-rights distribution of her films, and supervising the publicity campaigns (including staging live skits before screenings) for her new company

Jane Austen\u27s clergymen: Fact or fiction

The substance and the life that produced the novelist Janes Austen were of rare quality. Oscar Firkins states that: the general absence of criticism of her family is remarkable in a person of quick eyesight and brusque tongue. Jane Austen liked her lot in ife and that life was mostly kinsfolk

Functional characterization of synthetic leukotriene B and its stereochemical isomers.

Leukotriene B (LTB), a potent lipid chemotactic factor for neutrophils, is 5S,12R-dihydroxy-6,14-cis,8,10-trans-eicosatetraenoic acid (Fig 1), based upon direct comparison of natural LTB with synthetic 5S,12R-dihydroxy-6,8,10,14-eicosatetraenoic acid (5,12-di-HETE) stereoisomers in three biological assays. Of the six synthetic stereoisomers evaluated, only the 5S,12R,6,14-cis,8,10-trans compound had chemotactic potency for human neutrophils in vitro that was comparable to that of natural LTB, with a concentration of 3 X 10(9-9) M eliciting a one-half maximum response. In contrast, the racemic mixture of 5R,12R- and 5S,12S-6,10-trans,8,14-cis, the racemic mixture of 5S,12R- and 5R,12S-6,10-trans,8,14-cis, the 5S,12R-6,8-trans,10,14-cis, the 5S,12R-6,8,10-trans,14-cis, and the 5S,12S-6,8,10-trans,14-cis stereoisomers required concentrations of 3 X 10(-7) to 1 X 10(-6) M to elicit comparable responses. Only natural LTB and its synthetic counterpart elicited a local neutrophil infiltration when injected into the skin of the rhesus monkey at 10 ng and 100 ng per site. Natural and synthetic LTB at a concentration of 3 X 10(-8) M each provoked an EC25 contractile response of guinea pig pulmonary parenchymal strips in vitro, whereas the other four tested stereoisomers of 5,12-di-HETE were inactive at this concentration. Structure-function analyses suggest that the neutrophil chemotactic activity depends critically upon the C-1 to C-12 domain, including the stereochemistry of the 6-,8-,and 10-olefinic bonds and the presence of both hydroxyl groups

Applications of vortex gas models to tornadogenesis and maintenance

Processes related to the production of vorticity in the forward and rear flank downdrafts and their interaction with the boundary layer are thought to play a role in tornadogenesis. We argue that an inverse energy cascade is a plausible mechanism for tornadogenesis and tornado maintenance and provide supporting evidence which is both numerical and observational. We apply a three-dimensional vortex gas model to supercritical vortices produced at the surface boundary layer possibly due to interactions of vortices brought to the surface by the rear flank downdraft and also to those related to the forward flank downdraft. Two-dimensional and three-dimensional vortex gas models are discussed, and the three-dimensional vortex gas model of Chorin, developed further by Flandoli and Gubinelli, is proposed as a model for intense small- scale subvortices found in tornadoes and in recent numerical studies by Orf et al. In this paper, the smaller scales are represented by intense, supercritical vortices, which transfer energy to the larger-scale tornadic flows (inverse energy cascade). We address the formation of these vortices as a result of the interaction of the flow with the surface and a boundary layer.Comment: 20 pages, 6 figure

Being 'In The Room Where It Happens:' Supporting Information Needs of Students in Experiential Learning Programs

Presentation at 2016 LEPE (Leaders of Experiential Project-Based Education) Conference “Real-World Possibilities to Motivate Learning” UCLA Anderson Tuesday, June 21 – Thursday, June 23, 2016As business schools embrace experiential learning, many service units have grown their offerings to better serve students in these programs. An important role needed to support experiential learning programs is to ensure that students have access to information resources needed to address the problem they are asked to solve. This is in stark contrast to the minimal role that libraries and librarians play to support students working through business cases where students typically have all the information needed to work through the problem. On the other hand, students working on experiential learning projects have few pre-packaged sets of business information, leaving them potentially grasping for straws. With experiential learning projects, students often start off with little background information and might be left to their own to find resources that help solve complicated and narrow problems for their sponsor. Instead of feeling adrift, student teams can connect with librarians to assist them in finding and utilizing information resources that reflect the needs and scope of the project. A number of business schools have created structures and dedicated librarians to support students on these projects. Most importantly, it enables students to focus on the larger issues of the project and gain an appreciation for the value of information resources in business. These embedded librarian programs have a tremendous opportunity to provide both information instruction and support for the students as they work in the field. The value is demonstrated by having the librarians work with students in the 'room where it happens.' In this presentation, the library directors for UCLA Anderson and Michigan Ross will share information on how their staff support experiential learning at their respective schools. Among the topics to be discussed will include: working with and supporting student teams, balancing work between librarians, communication with student groups, connections to the library post-project, and other topics. Attendees will hear proven ways research support from these two schools’ libraries elevates the quality of deliverables to each team’s client.http://deepblue.lib.umich.edu/bitstream/2027.42/120937/1/Horne_Seeman_LEPE_UCLA2016.pptxhttp://deepblue.lib.umich.edu/bitstream/2027.42/120937/2/Horne_Seeman_LEPE_UCLA2016_2Page.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/120937/3/Horne_Seeman_LEPE_UCLA2016_6Page.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/120937/4/LEPE2016LibraryServicesHandout.pdfDescription of Horne_Seeman_LEPE_UCLA2016.pptx : PowerPoint Slides (pptx)Description of Horne_Seeman_LEPE_UCLA2016_2Page.pdf : PowerPoint Handout (2 slides per page) pdf fileDescription of Horne_Seeman_LEPE_UCLA2016_6Page.pdf : PowerPoint Handout (6 slides per page) pdf fileDescription of LEPE2016LibraryServicesHandout.pdf : Handout with Minicases (pdf

Unrestricted sexuality promotes distinctive short- and long-term mate preferences in women

The dual-sexual strategy hypothesis claims that women select different men for short- and long-term relationships. In short-term relationships, women are attracted to good genes (e.g., masculinity, attractiveness); in long-term relationships, material traits (e.g., good income, patient) are favoured. A potential predictor of women's mating strategy is sociosexuality, a measure of an individual's willingness to engage in casual, uncommitted sex. We asked whether women high in sociosexuality (i.e., unrestricted sexuality) would demonstrate greater distinctiveness between short- and long-term mate preferences. In an online study, participants (N = 459) from India and the USA were apportioned a ‘mate budget’ to construct their ideal short- and long-term partners. Mate Dollars could be spent on either genetic or material traits. As expected, genetic traits were favoured for short-term relationships; material traits were favoured for long-term relationships. However, women with a more restricted sexuality preferred short-term mates who closely resembled their long-term preferences. Women from the USA (with typically less restricted sexuality) showed more distinctive preferences than in India (with typically more restricted sexuality). Thus, a woman's sociosexuality influences the distinctiveness of her short- and long-term mate preferences

Do Gender Differences in Perceived Prototypical Computer Scientists and Engineers Contribute to Gender Gaps in Computer Science and Engineering?

Women are vastly underrepresented in the fields of computer science and engineering (CS&E). We examined whether women might view the intellectual characteristics of prototypical individuals in CS&E in more stereotype-consistent ways than men might and, consequently, show less interest in CS&E. We asked 269 U.S. college students (187, 69.5% women) to describe the prototypical computer scientist (Study 1) or engineer (Study 2) through open-ended descriptions as well as through a set of trait ratings. Participants also rated themselves on the same set of traits and rated their similarity to the prototype. Finally, participants in both studies were asked to describe their likelihood of pursuing future college courses and careers in computer science (Study 1) or engineering (Study 2). Across both studies, we found that women offered more stereotype-consistent ratings than did men of the intellectual characteristics of prototypes in CS (Study 1) and engineering (Study 2). Women also perceived themselves as less similar to the prototype than men did. Further, the observed gender differences in prototype perceptions mediated the tendency for women to report lower interest in CS&E fields relative to men. Our work highlights the importance of prototype perceptions for understanding the gender gap in CS&E and suggests avenues for interventions that may increase women’s representation in these vital fields

Dimensionality reduction for hand-independent dexterous robotic grasping

In this paper, we build upon recent advances in neuroscience research which have shown that control of the human hand during grasping is dominated by movement in a configuration space of highly reduced dimensionality. We extend this concept to robotic hands and show how a similar dimensionality reduction can be defined for a number of different hand models. This framework can be used to derive planning algorithms that produce stable grasps even for highly complex hand designs. Furthermore, it offers a unified approach for controlling different hands, even if the kinematic structures of the models are significantly different. We illustrate these concepts by building a comprehensive grasp planner that can be used on a large variety of robotic hands under various constraints