Intuition, hypothesis, and reality.

Realism about the external, natural world is an overarching empirical hypothesis. The method of hypothetical realism rejects as an excessive concession to the skeptic these two assumptions of constructivist intuitionism: first, that everything real must be exhaustively inspectable; and second, that our beliefs are to be justified to the point of certainty. We prefer to say that nothing is ever known directly; that all of our contact with the world is mediated by thoughts, words, and percepts construed as signs having referents distinct from themselves. We organize these signs into meaningful and possibly true hypotheses as we speculate--in practice, science and metaphysics--about a world we have not made

Improved Bounds on Information Dissemination by Manhattan Random Waypoint Model

With the popularity of portable wireless devices it is important to model and predict how information or contagions spread by natural human mobility -- for understanding the spreading of deadly infectious diseases and for improving delay tolerant communication schemes. Formally, we model this problem by considering $M$ moving agents, where each agent initially carries a \emph{distinct} bit of information. When two agents are at the same location or in close proximity to one another, they share all their information with each other. We would like to know the time it takes until all bits of information reach all agents, called the \textit{flood time}, and how it depends on the way agents move, the size and shape of the network and the number of agents moving in the network. We provide rigorous analysis for the \MRWP model (which takes paths with minimum number of turns), a convenient model used previously to analyze mobile agents, and find that with high probability the flood time is bounded by $O\big(N\log M\lceil(N/M) \log(NM)\rceil\big)$, where $M$ agents move on an $N\times N$ grid. In addition to extensive simulations, we use a data set of taxi trajectories to show that our method can successfully predict flood times in both experimental settings and the real world.Comment: 10 pages, ACM SIGSPATIAL 2018, Seattle, U

Differences in the Experience of Caregiving Between Spouse and Adult Child Caregivers in Dementia With Lewy Bodies.

Background and objectivesDementia caregiving has been associated with increased burden, depression, grief, a decreased sense of well-being and quality of life, and a weakening of social support. Little is known about the experience of caregiving in Dementia with Lewy Bodies (DLB). The present study examines differences in the caregiving experience of spouse versus adult child caregivers of individuals with DLB.Research design and methodsIn this cross-sectional analytic study of spouses (n = 255) and adult children (n = 160) caregivers of individuals with DLB, participants completed an online survey of burden, grief, depression, well-being, quality of life, and social support.ResultsAdult child caregivers were more likely to care for women (p < .001) and see the care recipient less often (p < .001) than spouses. Adult child caregivers reported lower quality of life (p < .001) and more caregiver burden (p < .009), but also greater social support (p < .001) than spouses. Between group analyses of caregiver type by disease severity demonstrated that spousal caregivers experience greater grief with advancing disease (p = .005), while adult child caregivers increase social support with advancing disease (p < .001).Discussion and implicationsSpouses and adult children experience DLB caregiving differently. This was explained by the younger age of the adult child caregiver, frequency of contact with the care recipient, and differences in the care recipient's characteristics, frequency of neuropsychiatric symptoms, and disease severity. DLB caregiver support for this population should target psychoeducation for complicated neuropsychiatric symptoms in the care recipient. Screening all DLB caregivers for burden, grief, and depression is suggested to identify those that may benefit most from intervention. Spouses specifically may benefit from interventions that target increasing social support, while adult child caregivers may benefit from interventions aimed at mitigating burden and improving quality of life

A Search for Binary Stars at Low Metallicity

We present initial results measuring the companion fraction of metal-poor stars ([Fe/H]$<-$2.0). We are employing the Lick Observatory planet-finding system to make high-precision Doppler observations of these objects. The binary fraction of metal-poor stars provides important constraints on star formation in the early Galaxy (Carney et al. 2003). Although it has been shown that a majority of solar metallicity stars are in binaries, it is not clear if this is the case for metal-poor stars. Is there a metallicity floor below which binary systems do not form or become rare? To test this we are determining binary fractions at metallicities below [Fe/H]$=-2.0$. Our measurments are not as precise as the planet finders', but we are still finding errors of only 50 to 300 m/s, depending on the signal-to-noise of a spectrum and stellar atmosphere of the star. At this precision we can be much more complete than previous studies in our search for stellar companions.Comment: To appear in conference proceedings,"First Stars III", eds. B. O'Shea, A. Heger & T. Abel. 3 pages, 5 figure

Biochemical Properties of a Decoy Oligodeoxynucleotide Inhibitor of STAT3 Transcription Factor.

Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 h in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials

Druggable Protein Interaction Sites Are More Predisposed to Surface Pocket Formation than the Rest of the Protein Surface

Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically “druggable” by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that “druggability” is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands; additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention.This work was supported by grants from the National Center for Research Resources (5P30RR030926) and the National Institute of General Medical Sciences (1R01GM099959 and 8P30GM103495) of the National Institutes of Health, and the Alfred P. Sloan Fellowship (JK)

Selectivity by Small-Molecule Inhibitors of Protein Interactions Can Be Driven by Protein Surface Fluctuations

Small-molecules that inhibit interactions between specific pairs of proteins have long represented a promising avenue for therapeutic intervention in a variety of settings. Structural studies have shown that in many cases, the inhibitor-bound protein adopts a conformation that is distinct from its unbound and its protein-bound conformations. This plasticity of the protein surface presents a major challenge in predicting which members of a protein family will be inhibited by a given ligand. Here, we use biased simulations of Bcl-2-family proteins to generate ensembles of low-energy conformations that contain surface pockets suitable for small molecule binding. We find that the resulting conformational ensembles include surface pockets that mimic those observed in inhibitor-bound crystal structures. Next, we find that the ensembles generated using different members of this protein family are overlapping but distinct, and that the activity of a given compound against a particular family member (ligand selectivity) can be predicted from whether the corresponding ensemble samples a complementary surface pocket. Finally, we find that each ensemble includes certain surface pockets that are not shared by any other family member: while no inhibitors have yet been identified to take advantage of these pockets, we expect that chemical scaffolds complementing these “distinct” pockets will prove highly selective for their targets. The opportunity to achieve target selectivity within a protein family by exploiting differences in surface fluctuations represents a new paradigm that may facilitate design of family-selective small-molecule inhibitors of protein-protein interactions.This work was supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health (R01GM099959), the National Science Foundation through XSEDE allocation MCB130049, and the Alfred P. Sloan Fellowship (JK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Employee Age as a Moderator of the Relationship Between Ambition and Work Role Affect

Past research has demonstrated a negative relationship between ambition, or the desire to get ahead, and job satisfaction. In the present paper, age was hypothesized to moderate the relationship between ambition and job satisfaction such that the relationship between ambition and satisfaction is more negative for older employees than for younger employees. Three studies, with three criterion variables (promotion satisfaction, extrinsic job satisfaction, overall job satisfaction), were used to test the hypothesis. Results indicated support for the hypothesized interaction. The discussion focuses on the implications of the results for organizational and individual career management strategies