Models of mammalian regulatory networks controlling gene expression have been inferred from genomic data, yet have largely not been validated. We present an unbiased strategy to systematically perturb candidate regulators and monitor cellular transcriptional responses. We apply this approach to derive regulatory networks that control the transcriptional response of mouse primary dendritic cells (DCs) to pathogens. Our approach revealed the regulatory functions of 125 transcription factors, chromatin modifiers, and RNA binding proteins and constructed a network model consisting of two dozen core regulators and 76 fine-tuners that help explain how pathogen-sensing pathways achieve specificity. This study establishes a broadly-applicable, comprehensive and unbiased approach to reveal the wiring and functions of a regulatory network controlling a major transcriptional response in primary mammalian cells.

TitleThermal comfort, perceived air quality and cognitive performance when personally controlled air movement is used by tropically acclimatized persons AbstractIn a warm and humid climate, increasing the temperature setpoint offers considerable energy benefits with low first costs. Elevated air movement generated by a personally controlled fan can compensate for the negative effects caused by an increased temperature setpoint. Fifty-six tropically acclimatized persons in common Singaporean office attire (0.7 clo) were exposed for 90 minutes to each of five conditions: 23, 26, and 29 °C and in the latter two cases with and without occupant controlled air movement. Relative humidity was maintained at 60%. We tested thermal comfort, perceived air quality, sick building syndrome symptoms and cognitive performance. We found that thermal comfort, perceived air quality, and sick building syndrome symptoms are equal or better at 26 °C and 29 °C than at the common setpoint of 23°C if a personally controlled fan is available for use. The best cognitive performance (as indicated by task speed) was obtained at 26 °C; at 29 °C, the availability of an occupantcontrolled fan partially mitigated the negative effect of the elevated temperature. The typical Singaporean indoor air temperature setpoint of 23 °C yielded the lowest cognitive performance. An elevated setpoint in air-conditioned buildings augmented with personally controlled fans might yield benefits for reduced energy use and improved indoor environmental quality in tropical climates.Keywords Thermal comfort; Perceived air quality; Sick building syndrome; Cognitive performance; Air movement; Tropically acclimatized person Practical ImplicationsIncreasing the indoor temperature setpoint to values in the range 26-29 °C (79-84 °F) and simultaneously providing occupants with personally controlled fans could be a cost-effective, sustainable and energy-efficient option for providing thermal comfort in new and existing buildings in the tropics. We show that this strategy can be implemented without negative influence on the well-being of occupants, and with almost 100% thermal comfort satisfaction. Cognitive tests showed the lowest performance at 23 °C and the highest at 26 °C.

Objective The antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAVs) form a group of small‐vessel vasculitides with systemic involvement. Although the etiology of AAVs remains largely unknown, both genetic and environmental factors have been implicated. Recently, certain alleles in the HLA–DPB1 region on chromosome 6 were shown to be associated with proteinase 3 (PR3)–ANCA–positive AAV but not with myeloperoxidase (MPO)–ANCA–positive AAV. The aim of this study was to investigate whether different alleles in the HLA–DPB1 region have clinical and/or prognostic implications in AAV. Methods One hundred seventy‐four patients with a diagnosis of AAV were recruited at the Maastricht University Medical Centre between 2000 and 2009. Seventeen different HLA–DPB1 alleles were determined using the restriction fragment length polymorphism technique. A validation cohort of 170 AAV patients from the Vasculitis Centre of Luebeck/Bad Bramstedt was included. Results In the initial cohort, the distribution of HLA–DPB1 alleles was significantly different between PR3‐ANCA–positive compared with MPO‐ANCA–positive AAV patients, ANCA‐negative AAV patients, and healthy controls. Importantly, HLA–DPB1*04:01 was present in 90% of PR3‐ANCA–positive AAV patients compared with 63% of MPO‐ANCA–positive AAV patients, 58% of ANCA‐negative patients, and 63% of healthy controls. Patients homozygous for HLA–DPB1*04:01 had relapses more often compared with heterozygous patients and noncarrier patients. This association persisted after correction for ANCA subtype and diagnosis. In the validation cohort, patients homozygous for HLA–DPB1*04:01 and those heterozygous for HLA–DPB1*04:01 had relapses more often compared with noncarrier patients. When both patient cohorts were merged (n = 344), homozygous patients relapsed most often, followed by heterozygous patients and noncarrier patients. Conclusion Carriage of HLA–DPB1*04:01 in patients with AAV is significantly associated with an increased risk of relapse compared with HLA–DPB1*04:01–negative patients, irrespective of ANCA status or clinical AAV entity.

Measuring complete gene expression profiles for a large number of experiments is costly. We propose an approach in which a small subset of probes is selected based on a preliminary set of full expression profiles. In subsequent experiments, only the subset is measured, and the missing values are imputed. We develop several algorithms to simultaneously select probes and impute missing values, and demonstrate that these probe selection for imputation (PSI) algorithms can successfully reconstruct missing gene expression values in a wide variety of applications, as evaluated using multiple metrics of biological importance. We analyze the performance of PSI methods under varying conditions, provide guidelines for choosing the optimal method based on the experimental setting, and indicate how to estimate imputation accuracy. Finally, we apply our approach to a large-scale study of immune system variation.

The notion that human learning follows a smooth power law (PL) of diminishing gains is well-established in psychology. This characteristic is observed when multiple curves are averaged, potentially masking more complex dynamics underpinning the curves of individual learners. Here, we analyzed 25,280 individual learning curves, each comprising 500 measurements of cognitive performance taken from four cognitive tasks. A piecewise PL (PPL) model explained the individual learning curves significantly better than a single PL, controlling for model complexity. The PPL model allows for multiple PLs connected at different points in the learning process. We also explored the transition dynamics between PL curve component pieces. Performance in later pieces typically surpassed that in earlier pieces, after a brief drop in performance at the transition point. The transition rate was negatively associated with age, even after controlling for overall performance. Our results suggest at least two processes at work in individual learning curves: locally, a gradual, smooth improvement, with diminishing gains within a specific strategy, which is modeled well as a PL; and globally, a discrete sequence of strategy shifts, in which each strategy is better in the long term than the ones preceding it. The piecewise extension of the classic PL of practice has implications for both individual skill acquisition and theories of learning.