While similar arguments can be made about other, nonlabor investments (e.g., Biddle et al. 2009), an examination of labor is of particular interest in this context for two primary reasons. First, labor is an important factor of production, with labor costs typically representing roughly two-thirds of economy-wide value added (Hamermesh 1993;Bernanke 2004). For example, the U.S. Census Bureau's Annual Survey of Manufacturers reports that payroll and employee benefits in the manufacturing sector totaled $784 billion for 2008, compared to $166 billion in capital expenditures. 3 Clearly, labor investments are economically significant. Second, while evidence from prior research suggests that accounting quality improves the efficiency of capital expenditures by reducing financing frictions, it is not obvious that this result extends to labor. The adjustment costs associated with labor tend to be relatively low compared to capital expenditures (Dixit and Pindyck 1994), and traditional economic models have often treated labor as a variable factor of production. To the extent that labor costs are variable, they are paid out of current revenues and do not require financing (and by extension do not face the financing frictions that highquality accounting mitigates). Thus, whether high-quality accounting improves the efficiency of investments in labor is an open question.Despite the economic importance and distinguishing features of labor, prior literature (reviewed in section 2) relates financial reporting quality primarily to capital expenditures, without examining the effects on labor. The lack of attention to labor in this setting is noteworthy, particularly given that human capital is increasingly viewed as one of the most important factors for a firm's competitive success (e.g., Pfeffer 1996). This study addresses that gap in the literature.Our examination requires measures of both labor investment efficiency and accounting quality. We use firms' net hiring (percentage change in the number of employees) to proxy for investment in labor, and we create an inverse measure of investment efficiency using the absolute deviation of actual net hiring from its expected level. For our primary analyses, the expected level of net hiring is based on the model of Pinnuck and Lillis (2007), which includes economic variables that explain normal hiring practices, such as sales growth, liquidity, leverage, and profitability. Thus, our measure of abnormal net hiring captures the amount of net hiring not attributable to underlying economic factors. In sensitivity tests, we use the industry median to estimate expected net hiring and also consider several modifications of the baseline Pinnuck and Lillis model, including adding controls for labor power and for other concurrent investments.Our empirical proxies for financial reporting quality are drawn from prior literature. Our primary measure is based on a cross-sectional version of the Dechow and Dichev (2002) model, as modified by McNichols (2002) andSchipper (2005). In sensitivity tests,...

Protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase; it forms diverse heterotrimeric holoenzymes that counteract kinase actions. Using a peptidome that tiles the disordered regions of the human proteome, we identified proteins containing [LMFI]xx[ILV]xEx motifs that serve as interaction sites for B′-family PP2A regulatory subunits and holoenzymes. The B′-binding motifs have important roles in substrate recognition and in competitive inhibition of substrate binding. With more than 100 novel ligands identified, we confirmed that the recently identified LxxIxEx B′α-binding motifs serve as common binding sites for B′ subunits with minor variations, and that S/T phosphorylation or D/E residues at positions 2, 7, 8 and 9 of the motifs reinforce interactions. Hundreds of proteins in the human proteome harbor intrinsic or phosphorylation-responsive B′-interaction motifs, and localize at distinct cellular organelles, such as midbody, predicting kinase-facilitated recruitment of PP2A-B′ holoenzymes for tight spatiotemporal control of phosphorylation at mitosis and cytokinesis. Moroever, Polo-like kinase 1-mediated phosphorylation of Cyk4/RACGAP1, a centralspindlin component at the midbody, facilitates binding of both RhoA guanine nucleotide exchange factor (epithelial cell transforming sequence 2 (Ect2)) and PP2A-B′ that in turn dephosphorylates Cyk4 and disrupts Ect2 binding. This feedback signaling loop precisely controls RhoA activation and specifies a restricted region for cleavage furrow ingression. Our results provide a framework for further investigation of diverse signaling circuits formed by PP2A-B′ holoenzymes in various cellular processes.

The aryl hydrocarbon receptor (AHR) belongs to the PAS (PER-ARNT-SIM) family transcription factors and mediates broad responses to numerous environmental pollutants and cellular metabolites, modulating diverse biological processes from adaptive metabolism, acute toxicity, to normal physiology of vascular and immune systems. The AHR forms a transcriptionally active heterodimer with ARNT (AHR nuclear translocator), which recognizes the dioxin response element (DRE) in the promoter of downstream genes. We determined the crystal structure of the mammalian AHR-ARNT heterodimer in complex with the DRE, in which ARNT curls around AHR into a highly intertwined asymmetric architecture, with extensive heterodimerization interfaces and AHR interdomain interactions. Specific recognition of the DRE is determined locally by the DNA-binding residues, which discriminates it from the closely related hypoxia response element (HRE), and is globally affected by the dimerization interfaces and interdomain interactions. Changes at the interdomain interactions caused either AHR constitutive nuclear localization or failure to translocate to nucleus, underlying an allosteric structural pathway for mediating ligand-induced exposure of nuclear localization signal. These observations, together with the global higher flexibility of the AHR PAS-A and its loosely packed structural elements, suggest a dynamic structural hierarchy for complex scenarios of AHR activation induced by its diverse ligands.he aryl hydrocarbon receptor (AHR) belongs to the PER-ARNT-SIM (PAS) family transcription factor that mediates broad responses to cellular and environmental cues. The AHR has been shown to be activated by diverse environmental toxicants and endogenous ligands, and play an important role in adaptive metabolism, dioxin toxicity, and normal vascular and immune development (1, 2), ever since it was identified four decades ago for mediating metabolic responses to aryl hydrocarbon toxicants (3, 4) and the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (5). The AHR was more recently found to mediate diverse cellular and physiological responses and likely respond to unknown endogenous AHR ligands (1, 2, 6-8). Developmentally, the AHR plays a role in the normal development and function of both the vascular and immune systems (9-12), and has close links to cancer, metabolic, immune, and cardiovascular diseases (13-18).Intense efforts in the past four decades have yielded important insights into the molecular processes governing AHR signaling. Newly synthesized AHR is located in cytosol and associated with the chaperones Hsp90 (19), P23 (20, 21), and AHR associated protein 9 (ARA9, also known as XAP2 or AIP) (22-24). Binding of ligands induces conformational changes in the AHR that lead to exposure of nuclear localization sequences (NLS) (25, 26). Following nuclear translocation, the AHR exchanges chaperones for a transcription partner, ARNT (1) and the AHR-ARNT heterodimer binds near the promoters of target genes at dioxin-response element (DRE...

SUMMARY Metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) are overexpressed and interact in diverse cancer types. The structural mechanism of their interaction remains unclear. Here we determined the high-resolution crystal structure of MTDH-SND1 complex, which reveals an 11-residue MTDH peptide motif occupying an extended protein groove between two SN domains (SN1/2), with two MTDH tryptophan residues nestled into two well-defined pockets in SND1. At the opposite side of the MTDH-SND1 binding interface, SND1 possesses long protruding arms and deep surface valleys that are prone to binding with other partners. Despite the simple binding mode, interactions at both tryptophan-binding pockets are important for MTDH and SND1’s roles in breast cancer and for SND1 stability under stress. Our study revealed a unique mode of interaction with SN domains that dictates cancer-promoting activity, and provided structural basis for mechanistic understanding of MTDH-SND1 mediated signaling and for exploring therapeutic targeting of this complex.

Tolerance, representing a permissible variation of a dimension in an engineering drawing, is synthesized by considering assembly stack-up conditions based on manufacturing cost minimization. A random variable and its standard deviation are associated with a dimension and its tolerance. This probabilistic approach makes it possible to perform trade-off between performance and tolerance rather than the worst case analysis as it is commonly practiced. Tolerance (stack-up) analysis, as an inner loop in the overall algorithm for tolerance synthesis, is performed by approximating the volume under the multivariate probability density function constrained by nonlinear stack-up conditions with a convex polytope. This approximation makes use of the notion of reliability index [10] in structural safety. Consequently, the probabilistic optimization problem for tolerance synthesis is simplified into a deterministic nonlinear programming problem. An algorithm is then developed and is proven to converge to the global optimum through an investigation of the monotonic relations among tolerance, the reliability index, and cost. Examples from the implementation of the algorithm are given.