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

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

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

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

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

Recalling Why Corporate Officers are Fiduciaries

For all the recent federal attention to regulating - and differentiating - corporate officer and director functions, a curious fact remains: state fiduciary duty law makes no distinction between the fiduciary duties of these two groups. Instead, courts and commentators routinely describe the duties of directors and officers together, and in identical terms. To lump officers and directors together as generic fiduciaries with no distinction being made between them, suggests - as patently is not the case - that their institutional function and legal roles within the corporation are the same. Such a view, consequently, undermines efforts more sharply to distinguish, not blur, the governance responsibilities of these two groups. Failure to differentiate the duties of officers, who daily manage corporate operations, from directors, who more remotely monitor corporate affairs, stems from a puzzling failure to address an even deeper issue in corporate law: What exactly is the theoretical and conceptual basis for the widespread claim that corporate officers owe fiduciary duties to a corporation and its stockholders? Hardly a week goes by without yet another Delaware decision addressing the subject of director duties. Yet, surprisingly, no Delaware decision ever has clearly articulated the subject of officer duties and judicial standards for reviewing their discharge. For persons occupying such central places of power in corporations, senior officers largely have succeeded in eluding the distinctive attention of state corporation law. The thesis of this article is that corporate officers are fiduciaries because they are agents. The argument is not that agency principles should be introduced formalistically or uncritically into corporate governance. Rather, the claim is that drawing on the fiduciary duties of agents for guidance in fashioning modern understandings of corporate officer duties - and differentiating those duties from those of directors - can provide much-needed structure to what otherwise threatens to be an ad hoc enterprise. There are at least three benefits of our thesis. First, by understanding officer duties and director-officer interaction in this way it can be seen that state law remains the primary source for establishing the basic framework of corporate governance relations, both through corporate statutes and through judge-made fiduciary duty law. With a more highly differentiated state law model of director-officer relations, recent efforts of Congress, the SEC, the NYSE and Nasdaq to impose new responsibilities on directors - in an effort to improve their vital role in monitoring corporate officers - can be seen as congruent with, rather than at odds with, the underlying state framework. The current emphasis on director independence and the special focus on various board committees - audit, nominating/governance and compensation - can be seen as an effort to develop mechanisms to aid the board both in detaching from management and in divvying up the board\u27s key monitoring functions. Moreover, efforts by Congress and the SEC to place additional and different functions on senior officers also can be seen as supplementing, rather than displacing, existing state law-based fiduciary duties of officers. As a second benefit, our thesis clarifies immensely why courts can and should more closely scrutinize officer conduct than they now review director performance - i.e., the fiduciary duties of agents are more demanding than those of directors, especially the duty of care, and officers rightly face a greater risk of personal liability for misconduct. Heightened review of officer performance is especially fitting given that many of the recent corporate scandals involved wrongdoing at the officer level, and given that state law has been eerily silent about why officers owe duties at all, much less holding them to account. It also is important in light of the fact that recent federal initiatives aimed at improving officer performance eventually will be translated into, and will heavily influence, state fiduciary duty analysis. At a theoretical level, the third payoff, our thesis has several implications. These include our belief that we are entering an era when, due to heavier corporate regulation, the entity conception of the firm will be strengthened, as positive law, including agency law, still builds on that understanding of corporate relations. This period follows a span of perhaps twenty years when a highly disaggregated conception of corporate relations - the nexus of contracts theory - has predominated. We also believe that in the policy arguments for and against strong fiduciary duties over the years, virtually no attention has been given to distinguishing whether what is fitting for outside directors in the fiduciary duty area - relatively slack duties - is also fitting for corporate officers. Moreover, although agency law suggests greater liability for officers than directors, widespread (and longstanding) failure to understand officers in those terms means corporate law cannot as confidently assume that existing liability outcomes for officers are optimal, as might be the case with rules governing directors. We believe that, from a policy perspective, the fiduciary duties and liability rules for officers should be analyzed separately from those for outside directors. Contemporary corporate law and fiduciary discourse do not do so, however, thereby hindering attention to this subject. In the terms recently used by Professors Black, Cheffins and Klaussner to describe the state of law governing outside directors, we believe the window of liability risk for inside directors - i.e., officers - is in fact wide open, but it is thought, wrongly, to be virtually shut