While existing research has demonstrated that intrinsic motivation can increase task performance, jobs are composed of multiple tasks, and it remains to be seen how intrinsic motivation in one task ...affects performance on other tasks. Drawing on theories of psychological contrast, we hypothesize that high intrinsic motivation in one task reduces performance on less intrinsically motivating tasks. In a field study at a Korean department store, employees with the highest maximum intrinsic motivation in one task had lower average and minimum performance across their other tasks as well as more performance variance across their tasks. In a laboratory experiment in the United States, working on a highly intrinsically motivating initial task led participants to perform worse in a subsequent task if it was uninteresting, but not if it was interesting. This effect was mediated by boredom, but not by a range of other psychological processes. Across both studies, moderate intrinsic motivation in one task was associated with better performance in less interesting tasks than high intrinsic motivation, revealing a curvilinear cross-task effect of intrinsic motivation. Our research advances knowledge about the dark side of intrinsic motivation, the design of work, and the drivers of task performance.
The interplay between magnetic fields and interacting particles can lead to exotic phases of matter that exhibit topological order and high degrees of spatial entanglement. Although these phases were ...discovered in a solid-state setting, recent innovations in systems of ultracold neutral atoms-uncharged atoms that do not naturally experience a Lorentz force-allow the synthesis of artificial magnetic, or gauge, fields. This experimental platform holds promise for exploring exotic physics in fractional quantum Hall systems, owing to the microscopic control and precision that is achievable in cold-atom systems. However, so far these experiments have mostly explored the regime of weak interactions, which precludes access to correlated many-body states. Here, through microscopic atomic control and detection, we demonstrate the controlled incorporation of strong interactions into a two-body system with a chiral band structure. We observe and explain the way in which interparticle interactions induce chirality in the propagation dynamics of particles in a ladder-like, real-space lattice governed by the interacting Harper-Hofstadter model, which describes lattice-confined, coherently mobile particles in the presence of a magnetic field. We use a bottom-up strategy to prepare interacting chiral quantum states, thus circumventing the challenges of a top-down approach that begins with a many-body system, the size of which can hinder the preparation of controlled states. Our experimental platform combines all of the necessary components for investigating highly entangled topological states, and our observations provide a benchmark for future experiments in the fractional quantum Hall regime.
A surface wave dispersion data set of unprecedented size is used to obtain a variable‐resolution model of the radially anisotropic shear wave velocity structure of the upper mantle beneath North ...America and globally. Love and Rayleigh wave phase velocities for periods in the range 35–150 s constrain a three‐dimensional model of velocity variations on a length scale of a few hundred kilometers within the North American continent and a few thousand kilometers globally. The short‐ and long‐wavelength models are determined simultaneously. Long‐period surface wave phase velocities (200–350 s) are used to help constrain longer‐wavelength and transition zone structure. Laterally varying velocity sensitivity kernels are used to account for the dependence of the velocity sensitivity on lateral variations in crust and mantle velocity structure. The sensitivity kernels are updated in several iterations to avoid nonlinearities associated with the inverse problem for the determination of mantle structure. Variations in isotropic velocity in the uppermost several hundred kilometers of the mantle are found to correlate well with surface tectonic features. Within the North American craton, the locations of strongest radial anisotropy generally correlate with the locations of fastest isotropic velocity. Variations in radial anisotropy show a clear continent‐ocean signature. Strong anisotropy occurs at shallow depths (<100 km) under the continents, with a secondary peak found at a depth of ∼200 km. Maximum anisotropy under the oceans occurs at a depth of ∼125 km, with no secondary maximum. Combined interpretation of isotropic and anisotropic continent‐ocean differences suggests a different role for the low‐velocity zone under continental and oceanic regions.
Long-read sequencing and novel long-range assays have revolutionized de novo genome assembly by automating the reconstruction of reference-quality genomes. In particular, Hi-C sequencing is becoming ...an economical method for generating chromosome-scale scaffolds. Despite its increasing popularity, there are limited open-source tools available. Errors, particularly inversions and fusions across chromosomes, remain higher than alternate scaffolding technologies. We present a novel open-source Hi-C scaffolder that does not require an a priori estimate of chromosome number and minimizes errors by scaffolding with the assistance of an assembly graph. We demonstrate higher accuracy than the state-of-the-art methods across a variety of Hi-C library preparations and input assembly sizes. The Python and C++ code for our method is openly available at https://github.com/machinegun/SALSA.
Bacteriophages (phages) are critical players in the dynamics and function of microbial communities and drive processes as diverse as global biogeochemical cycles and human health. Phages tend to be ...predators finely tuned to attack specific hosts, even down to the strain level, which in turn defend themselves using an array of mechanisms. However, to date, efforts to rapidly and comprehensively identify bacterial host factors important in phage infection and resistance have yet to be fully realized. Here, we globally map the host genetic determinants involved in resistance to 14 phylogenetically diverse double-stranded DNA phages using two model Escherichia coli strains (K-12 and BL21) with known sequence divergence to demonstrate strain-specific differences. Using genome-wide loss-of-function and gain-of-function genetic technologies, we are able to confirm previously described phage receptors as well as uncover a number of previously unknown host factors that confer resistance to one or more of these phages. We uncover differences in resistance factors that strongly align with the susceptibility of K-12 and BL21 to specific phage. We also identify both phage-specific mechanisms, such as the unexpected role of cyclic-di-GMP in host sensitivity to phage N4, and more generic defenses, such as the overproduction of colanic acid capsular polysaccharide that defends against a wide array of phages. Our results indicate that host responses to phages can occur via diverse cellular mechanisms. Our systematic and high-throughput genetic workflow to characterize phage-host interaction determinants can be extended to diverse bacteria to generate datasets that allow predictive models of how phage-mediated selection will shape bacterial phenotype and evolution. The results of this study and future efforts to map the phage resistance landscape will lead to new insights into the coevolution of hosts and their phage, which can ultimately be used to design better phage therapeutic treatments and tools for precision microbiome engineering.
Diverse soil-resident bacteria can contribute to plant growth and health, but the molecular mechanisms enabling them to effectively colonize their plant hosts remain poorly understood. We used ...randomly barcoded transposon mutagenesis sequencing (RB-TnSeq) in Pseudomonas simiae, a model root-colonizing bacterium, to establish a genome-wide map of bacterial genes required for colonization of the Arabidopsis thaliana root system. We identified 115 genes (2% of all P. simiae genes) with functions that are required for maximal competitive colonization of the root system. Among the genes we identified were some with obvious colonization-related roles in motility and carbon metabolism, as well as 44 other genes that had no or vague functional predictions. Independent validation assays of individual genes confirmed colonization functions for 20 of 22 (91%) cases tested. To further characterize genes identified by our screen, we compared the functional contributions of P. simiae genes to growth in 90 distinct in vitro conditions by RB-TnSeq, highlighting specific metabolic functions associated with root colonization genes. Our analysis of bacterial genes by sequence-driven saturation mutagenesis revealed a genome-wide map of the genetic determinants of plant root colonization and offers a starting point for targeted improvement of the colonization capabilities of plant-beneficial microbes.
To extend research on the effects of networks for career outcomes, this paper examines how career processes shape network structure. I hypothesize that brokerage results from two distinct mechanisms: ...links with former coworkers and with friends of friends accumulated as careers unfold. Furthermore, I hypothesize that "organizational misfits"—people who followed career trajectories that are atypical in their organization—will have access to more valuable brokerage opportunities than those whose careers followed more conventional paths. I tested this hypothesis with career history data recorded longitudinally for 30,000 employees in a large information technology firm over six years and sequence-analyzed to measure individuallevel fit with typical career paths in the organization. Network position was measured using a unique data set of over 250 million electronic mail messages. Empirical results support the hypotheses that diverse, and especially atypical, careers have an effect on brokerage through mechanisms rooted in social capital, even when accounting for endogeneity between networks and mobility. In theorizing about misfit from prototypical patterns, this paper offers a new, theory-driven application of sequence-analytic methods as well as a novel measure of brokerage based on interactions across observable boundaries, a complement to the structural constraint measure based on interactions across holes in social structure.
Metabolic production of acetyl coenzyme A (acetyl-CoA) is linked to histone acetylation and gene regulation, but the precise mechanisms of this process are largely unknown. Here we show that the ...metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) directly regulates histone acetylation in neurons and spatial memory in mammals. In a neuronal cell culture model, ACSS2 increases in the nuclei of differentiating neurons and localizes to upregulated neuronal genes near sites of elevated histone acetylation. A decrease in ACSS2 lowers nuclear acetyl-CoA levels, histone acetylation, and responsive expression of the cohort of neuronal genes. In adult mice, attenuation of hippocampal ACSS2 expression impairs long-term spatial memory, a cognitive process that relies on histone acetylation. A decrease in ACSS2 in the hippocampus also leads to defective upregulation of memory-related neuronal genes that are pre-bound by ACSS2. These results reveal a connection between cellular metabolism, gene regulation, and neural plasticity and establish a link between acetyl-CoA generation 'on-site' at chromatin for histone acetylation and the transcription of key neuronal genes.
Advancements in molecular profiling and endocrine therapy (ET) have led to more focused clinical attention on precision medicine. These advances have expanded our understanding of breast cancer (BC) ...pathogenesis and hold promising implications for the future of therapy. The estrogen receptor‐α is a predominant endocrine regulatory protein in the breast and in estrogen‐induced BC. Successful targeting of proteins and genes within estrogen receptor (ER) nuclear and nonnuclear pathways remains a clinical goal. Several classes of antiestrogenic agents are available for patients with early, advanced, or metastatic BC, including selective ER modulators, aromatase inhibitors, and a selective ER degrader. Clinical development is focused upon characterizing the efficacy and tolerability of inhibitors that target the phosphatidylinositol 3 kinase (PI3K)/akt murine thymoma viral oncogene (AKT)/mammalian target of rapamycin inhibitor (mTOR) signaling pathway or the cyclin‐dependent kinase 4/6 (CDK4/6) cell cycle pathway in women with hormone receptor‐positive, human epidermal growth receptor 2‐negative BC who have demonstrated disease recurrence or progression. De novo and acquired resistance remain a major challenge for women with BC receiving antiestrogenic therapy. Therefore, sequential combination of targeted ET is preferred in these patients, and the ever‐increasing understanding of resistance mechanisms may better inform the selection of future therapy. This review describes the intricate roles of the PI3K/AKT/mTOR and CDK4/6 pathways in intracellular signaling and the use of endocrine and endocrine‐based combination therapy in BC.
Implications for Practice
The foundational strategy for treating hormone receptor‐positive, human epidermal growth receptor 2‐negative, advanced breast cancer includes the use of endocrine therapy either alone or in combination with targeted agents. The use of combination therapy aims to downregulate cell‐signaling pathways with the intent of minimizing cellular “crosstalk,” which can otherwise result in continued tumorigenesis or progression through redundant pathways. This review provides the clinician with the molecular rationale and clinical evidence for these treatments and refers to evidence‐based guidelines to inform the decision‐making process.
摘要
分子表达谱和内分泌疗法 (ET) 的进步使得精准医疗获得更为集中的临床关注。这些进步拓展了我们对乳腺癌 (BC) 发病机制的了解, 并预示未来疗法的良好前景。雌激素受体 α 是乳腺及雌激素诱导 BC 中的主要内分泌调节蛋白。对雌激素受体 (ER) 核途径和非核途径中的蛋白质和基因进行成功靶向仍是临床目标。早期、晚期和转移性 BC 患者现可使用多种抗雌激素药物, 包括选择性 ER 调节剂、芳香化酶抑制剂和选择性 ER 降解剂。临床开发专注于表征以磷脂酰肌醇 3 激酶 (PI3K)/akt 鼠胸腺瘤病毒致癌基因 (AKT)/哺乳动物雷帕霉素靶蛋白 (mTOR) 抑制剂信号传导通路或细胞周期依赖性激酶 4/6 (CDK4/6) 细胞周期通路为靶标的抑制剂在显现疾病复发或进展的激素受体阳性、人表皮生长受体 2 阴性 BC 女性中的疗效和耐受性。在接受抗雌激素治疗的 BC 女性中, 原发性及获得性耐药仍是主要挑战。因此, 靶向 ET 的序贯联合治疗是这些患者的首选, 对耐药性机制的理解不断增加可更好地指导未来疗法的选择。本综述介绍了 PI3K/AKT/mTOR 和 CDK4/6 通路在细胞内信号传导中的复杂作用以及内分泌和以内分泌为基础的联合疗法在 BC 中的使用。
对临床实践的启示：激素受体阳性、人表皮生长受体 2 阴性晚期乳腺癌的基本治疗策略包括单独使用内分泌疗法或与靶向药物联用。使用联合疗法旨在下调细胞信号传导通路, 目的最大程度地减少细胞“串扰”, 否则可能会通过冗余途径导致持续肿瘤发生或进展。本综述为临床医生提供了该类治疗的分子依据和临床证据, 并援引循证指南指导决策过程
This review describes the role of intracellular signaling pathways and the estrogen receptor in breast cancer, the role of anti‐estrogens in the treatment of HR1 advanced breast cancer, the development of resistance to anti‐estrogen therapy, and the use of endocrine and endocrine‐based combination therapy in breast cancer.
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