Exploring the topology of the plausible: Fs/QCA counterfactual analysis and the plausible fit of unobserved organizational configurations

The main aim of this contribution is to expand the dominant rationale of organizational design research by including solutions and possibilities not observed in reality. We believe that the counterfactual approach to configurations responds to an open call in organization theory and strategy to move the modelling of fit towards a more robust and theory-based specification. With this new approach we propose to rediscover the roots of organization design as a distinct normative discipline that ‘should stand approximately in relation to the basic social sciences as engineering stands with respect to physical sciences or medicine to the biological’. At a more general level, our view implies an expansion of the dominant meaning of the concept of ‘relevance’ in management research. While we agree with Gulati (2007: 780) that we as scholars should probe ‘more deeply into the problems and other issues that managers care about’, we also believe that relevance does not necessarily mean that researchers have to use an ex-post rationality by studying only empirically frequent phenomena. In contrast, we think that any management esearcher should bring with her or himself a fragment of the spirit of the great Greek philosopher Anaximander (c. 610–c. 546 BC), who foresaw the concept of the infinite universe without the support of any empirical observation and against the predominant wisdom of the time. Not by chance, Karl Popper (1998) onsidered Anaximander’s intuitions among the most vivid demonstrations of the power of human thought and logic

Dynamic Interchanging Native States of Lymphotactin Examined by SNAPP-MS

The human chemokine lymphotactin (Ltn) is a remarkable protein that interconverts between two unrelated native state structures in the condensed phase. It is possible to shift the equilibrium toward either conformation with selected sequence substitutions. Previous results have shown that a disulfide-stabilized variant preferentially adopts the canonical chemokine fold (Ltn10), while a single amino acid change (W55D) favors the novel Ltn40 dimeric structure. Selective noncovalent adduct protein probing (SNAPP) is a recently developed method for examining solution phase protein structure. Herein, it is demonstrated that SNAPP can easily recognize and distinguish between the Ltn10 and Ltn40 states of lymphotactin in aqueous solution. The effects of organic denaturants, acid, and disulfide bond reduction and blocking were also examined using SNAPP for the CC3, W55D, and wild type proteins. Only disulfide reduction was shown to significantly perturb the protein, and resulted in considerably decreased adduct formation consistent with loss of tertiary/secondary structure. Cold denaturation experiments demonstrated that wild-type Ltn is the most temperature sensitive of the three proteins. Examination of the higher charge states in all experiments, which are presumed to represent transition state structures between Ltn-10 and Ltn-40, reveals increased 18C6 attachment relative to the more folded structures. This observation is consistent with increased competitive intramolecular hydrogen bonding, which may guide the transition. Experiments examining the gas phase structures revealed that all three proteins can be structurally distinguished in the gas phase. In addition, the gas phase experiments enabled identification of preferred adduct binding sites

Methionine oxidation in α-synuclein inhibits its propensity for ordered secondary structure.

α-Synuclein (AS) is an intrinsically disordered protein highly expressed in dopaminergic neurons. Its amyloid aggregates are the major component of Lewy bodies, a hallmark of Parkinson's disease (PD). AS is particularly exposed to oxidation of its methionine residues, both in vivo and in vitro. Oxidative stress has been implicated in PD and oxidized α-synuclein has been shown to assemble into soluble, toxic oligomers, rather than amyloid fibrils. However, the structural effects of methionine oxidation are still poorly understood. In this work, oxidized AS was obtained by prolonged incubations with dopamine (DA) or epigallocatechin-3-gallate (EGCG), two inhibitors of AS aggregation, indicating that EGCG promotes the same final oxidation product as DA. The conformational transitions of the oxidized and non-oxidized protein were monitored by complementary biophysical techniques, including MS, ion mobility (IM), CD and FTIR spectroscopy assays. Although the two variants displayed very similar structures under conditions that stabilize highly disordered or highly ordered states, differences emerged in the intermediate points of transitions induced by organic solvents, such as trifluoroethanol (TFE) and methanol (MeOH), indicating a lower propensity of the oxidized protein for forming either α- or β-type secondary structure. Furthermore, oxidized AS displayed restricted secondary-structure transitions in response to dehydration and slightly amplified tertiary-structure transitions induced by ligand binding. This difference in susceptibility to induced folding could explain the loss of fibrillation potential observed for oxidized AS

Sp1 Is Essential for p16(INK4a) Expression in Human Diploid Fibroblasts during Senescence

BACKGROUND: p16 (INK4a) tumor suppressor protein has been widely proposed to mediate entrance of the cells into the senescent stage. Promoter of p16 (INK4a) gene contains at least five putative GC boxes, named GC-I to V, respectively. Our previous data showed that a potential Sp1 binding site, within the promoter region from −466 to −451, acts as a positive transcription regulatory element. These results led us to examine how Sp1 and/or Sp3 act on these GC boxes during aging in cultured human diploid fibroblasts. METHODOLOGY/PRINCIPAL FINDINGS: Mutagenesis studies revealed that GC-I, II and IV, especially GC-II, are essential for p16 (INK4a) gene expression in senescent cells. Electrophoretic mobility shift assays (EMSA) and ChIP assays demonstrated that both Sp1 and Sp3 bind to these elements and the binding activity is enhanced in senescent cells. Ectopic overexpression of Sp1, but not Sp3, induced the transcription of p16 (INK4a). Both Sp1 RNAi and Mithramycin, a DNA intercalating agent that interferes with Sp1 and Sp3 binding activities, reduced p16 (INK4a) gene expression. In addition, the enhanced binding of Sp1 to p16 (INK4a) promoter during cellular senescence appeared to be the result of increased Sp1 binding affinity, not an alteration in Sp1 protein level. CONCLUSIONS/SIGNIFICANCE: All these results suggest that GC- II is the key site for Sp1 binding and increase of Sp1 binding activity rather than protein levels contributes to the induction of p16 (INK4a) expression during cell aging

A Chemistry of Organization: Combinatory Structural Analysis and Design

This paper is a response to the call for models of organization design as a science revealing the inner composition of organization and specifying the laws to be respected when crafting it. It maintains that the needed science is a chemistry of organization, addressing the combination of 'organizational elements' playing a role analogous to that of chemical elements in composing a variety of substances. Drawing both on classic organization design theory and on configurational and complementarity-based approaches, the paper specifies a set of basic organizational elements and a set of combinatory laws regulating their effective combinations. Testable propositions are derived on the necessary and sufficient conditions that the composition of organizations should have respect for achieving high levels of efficiency and innovation. These propositions are tested empirically on a sample of firms, using an innovative application of Boolean algebra