Energy’s Role in the Extraversion (Dis)advantage: How Energy Ties and Task Conflict Help Clarify the Relationship Between Extraversion and Proactive Performance

While academic and practitioner literatures have proposed that extraverts are at an advantage in team-based work, it remains unclear exactly what that advantage might be, how extraverts attain such an advantage, and under which conditions. Theory highlighting the importance of energy in the coordination of team efforts helps to answer these questions. We propose that extraverted individuals are able to develop more energizing relationships with their teammates and as a result are seen as proactively contributing to their team. However, problems in coordination (i.e., team task conflict) can reverse this extraversion advantage. We studied 27 project-based teams at their formation, peak performance, and after disbandment. Results suggest that when team task conflict is low, extraverts energize their teammates and are viewed by others as proactively contributing to the team. However, when team task conflict is high, extraverts develop energizing relationships with fewer of their teammates and are not viewed as proactively contributing to the team. Our findings regarding energizing relationships and team task conflict clarify why extraversion is related to proactive performance and in what way, how, and when extraverts may be at a (dis)advantage in team-based work

Long-Range Coupling in an Allosteric Receptor Revealed by Mutant Cycle Analysis

The functional coupling of residues that are far apart in space is the quintessential property of allosteric proteins. For example, in Cys-loop receptors, the gating of an intrinsic ion channel is allosterically regulated by the binding of small molecule neurotransmitters 50–60 Å from the channel gate. Some residues near the binding site must have as their primary function the communication of the binding event to the gating region. These gating pathway residues are essential to function, but their identification and characterization can be challenging. This work introduces a simple strategy, derived from mutant cycle analysis, for identifying gating pathway residues using macroscopic measurements alone. In the exemplar Cys-loop receptor, the nicotinic acetylcholine receptor, a well-characterized reporter mutation (βL9′S) known to impact gating, was combined with mutations of target residues in the ligand-binding domain hypothesized or previously found to be functionally significant. A mutant cycle analysis of the macroscopic EC50 measurements can then provide insights into the role of the target residue. This new method, elucidating long-range functional coupling in allosteric receptors, can be applied to several reporter mutations in a wide variety of receptors to identify previously characterized and novel mutations that impact the gating pathway. We support our interpretation of macroscopic data with single-channel studies. Elucidating long-range functional coupling in allosteric receptors should be broadly applicable to determining functional roles of residues in allosteric receptors

Evidence for an Extended Hydrogen Bond Network in the Binding Site of the Nicotinic Receptor: Role of the Vicinal Disulfide of the α1 Subunit

The defining feature of the α subunits of the family of nicotinic acetylcholine receptors is a vicinal disulfide between Cys-192 and Cys-193. Although this structure has played a pivotal role in a number of pioneering studies of nicotinic receptors, its functional role in native receptors remains uncertain. Using mutant cycle analysis and unnatural residue mutagenesis, including backbone mutagenesis of the peptide bond of the vicinal disulfide, we have established the presence of a network of hydrogen bonds that extends from that peptide NH, across a β turn to another backbone hydrogen bond, and then across the subunit interface to the side chain of a functionally important Asp residue in the non-α subunit. We propose that the role of the vicinal disulfide is to distort the β turn and thereby properly position a backbone NH for intersubunit hydrogen bonding to the key Asp

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Relationships among Polycyclic Aromatic Hydrocarbon–DNA Adducts, Proximity to the World Trade Center, and Effects on Fetal Growth

Polycyclic aromatic hydrocarbons (PAHs) are toxic pollutants released by the World Trade Center (WTC) fires and various urban combustion sources. Benzo[a]pyrene (BaP) is a representative member of the class of PAHs. PAH–DNA adducts, or BaP–DNA adducts as their proxy, provide a measure of chemical-specific genetic damage that has been associated with increased risk of adverse birth outcomes and cancer. To learn whether PAHs from the WTC disaster increased levels of genetic damage in pregnant women and their newborns, we analyzed BaP–DNA adducts in maternal (n = 170) and umbilical cord blood (n = 203) obtained at delivery from nonsmoking women who were pregnant on 11 September 2001 and were enrolled at delivery at three downtown Manhattan hospitals. The mean adduct levels in cord and maternal blood were highest among newborns and mothers who resided within 1 mi of the WTC site during the month after 11 September, intermediate among those who worked but did not live within this area, and lowest in those who neither worked nor lived within 1 mi (reference group). Among newborns of mothers living within 1 mi of the WTC site during this period, levels of cord blood adducts were inversely correlated with linear distance from the WTC site (p = 0.02). To learn whether PAHs from the WTC disaster may have affected birth outcomes, we analyzed the relationship between these outcomes and DNA adducts in umbilical cord blood, excluding preterm births to reduce variability. There were no independent fetal growth effects of either PAH–DNA adducts or environmental tobacco smoke (ETS), but adducts in combination with in utero exposure to ETS were associated with decreased fetal growth. Specifically, a doubling of adducts among ETS-exposed subjects corresponded to an estimated average 276-g (8%) reduction in birth weight (p = 0.03) and a 1.3-cm (3%) reduction in head circumference (p = 0.04). The findings suggest that exposure to elevated levels of PAHs, indicated by PAH–DNA adducts in cord blood, may have contributed to reduced fetal growth in women exposed to the WTC event

Reframing Digital Humanities: Conversations with Digital Humanists

Defining digital humanities is a unique academic challenge. In this volume, Julian Chambliss, Professor of English at Michigan State University, explores the meaning, practice, and implication of digital humanities by talking to scholars deeply engaged with digital methods and the promise they hold for the humanities

The molecular basis of breast cancer pathological phenotypes

The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or RPPA subtype. Marked nuclear pleomorphism, necrosis, inflammation and high mitotic count were associated with Basal-like subtype and have similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed using the METABRIC dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of epithelial tubule formation was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2