Sustainable performance : a comparison between the sports, corporate and arts industries

This study sought to recognise individual sustainability as a tangible and identifiable concept, by beginning to determine some of the contributing factors of individual sustainability of performance, or individual sustainability of competitive advantage. As no comprehensive research presently exists in relation to individual sustainability, the approach taken was to build on and extend current research, as well as addressing issues on individual sustainability of performance. An accepted theoretical framework (the resource based theory) was used to guide data collection, and both elite sustainable and elite non-sustainable performers participated. The primary focus of the research was to identify the processes, (individual and historical variables), that were characteristics of sustained performers at an elite level. So that this could be accomplished, a number of aims were proposed, including: To determine the relationship between sustained performance, levels of sustained performance and specific individual and historical variables; to identify whether differences exist as a function of gender; and to identify whether differences exist due to type of performance discipline. A multi-method approach was used, with 50 individuals completing a questionnaire, and 18 individuals participating further in an interview. Results indicated significant differences between sustainable and non-sustainable performers on a variety of variables. For example, sustainable performers demonstrated a significantly higher level of innate confidence as compared to non-sustainable performers. The concept of failure was also highlighted as being of singular importance. Criticality of gender, both generally, and in relation to sustainability was established, with differences also being revealed between industries. Specific variables such as gender, confidence and failure were found to be predictors of sustainability. The findings clearly indicated areas for future consideration in the research and development of the concept of individual sustainability

Dual gene activation and knockout screen reveals directional dependencies in genetic networks.

Understanding the direction of information flow is essential for characterizing how genetic networks affect phenotypes. However, methods to find genetic interactions largely fail to reveal directional dependencies. We combine two orthogonal Cas9 proteins from Streptococcus pyogenes and Staphylococcus aureus to carry out a dual screen in which one gene is activated while a second gene is deleted in the same cell. We analyze the quantitative effects of activation and knockout to calculate genetic interaction and directionality scores for each gene pair. Based on the results from over 100,000 perturbed gene pairs, we reconstruct a directional dependency network for human K562 leukemia cells and demonstrate how our approach allows the determination of directionality in activating genetic interactions. Our interaction network connects previously uncharacterized genes to well-studied pathways and identifies targets relevant for therapeutic intervention

Spawning Induction in the Carp: Past Experience and Future Prospects - A Review

Most fish in aquaculture either fail to breed in captivity or their spawning occurs sporadically and late in the season. This is mainly due to the lack of natural cues in captivity, which leads to dysfunction of the endocrine axis regulating oocyte maturation and ovulation. Hypophysation as a remedy for this situation in fish has been employed in aquaculture since the 1930s and is still widely practiced. However, using crude pituitary homogenates in local hatcheries has frequently ended in failures that were attributed to the incon- sistent potency of the injected material and the unknown ovarian stage of the recipient fish. Since the mid 1980s, hypophysation has improved through the introduction of a standardized dry carp pituitary extract in which the luteinizing hormone (LH) content and activity have been calibrated (cal- ibrated carp pituitary extract = CCPE). Induction of spawning, however, is successful mainly in female cohorts in which 65% or more of the oocytes in an ovarian biopsy have migrating germinal vesicles. Further, due to decreasing quantities of industry-processed common carp and the expan- sion of ornamental carp production (koi and goldfish), the growing demand for CCPE could not be met, and an alternative had to be found. A hypo- thalamic approach, introduced into Israeli aquaculture in 1993 (called Dagin), combines a superactive analog of sGnRH (10 μg/kg), with the water-soluble dopamine (D2) receptor antagonist, metoclopramide (20 mg/kg). The progress of oocyte maturation in ovarian biopsies has been studied in parallel with changes in levels of LH, estradiol, and the matura- tion-inducing steroid (MIS; 17α, 20β, dihydroxy-4-pregnene-3-one). The hormone profile indicated that the gradual increases in LH and MIS follow- ing a single administration of Dagin were similar to those in fish treated with priming and resolving doses of CCPE. This would explain why Dagin is effective even when only a single injection is given, saving labor and reduc- ing handling stress. CCPE and Dagin were tested in parallel on common carp in a commercial hatchery. The spawning ratio and embryo viability were similar, although the latency between injection and ovulation was con- siderably longer and more variable in Dagin-treated than in CCPE-treated carp. It is recommended to use CCPE at the beginning and end of the spawning season when the LH content in the pituitary is low, and Dagin in mid-season and in field spawning. Future prospects raise the possibility that by employing molecular tools, a recombinant carp LH will be produced that will have the regular and expected potency of the hypophyseal approach without the risk of spreading pathogens from donor fish to broodstock. Work along this line is currently in progress

The antibiotic bedaquiline activates host macrophage innate immune resistance to bacterial infection

Antibiotics are widely used in the treatment of bacterial infections. Although known for their microbicidal activity, antibiotics may also interfere with the host's immune system. Here, we analyzed the effects of bedaquiline (BDQ), an inhibitor of the mycobacterial ATP synthase, on human macrophages. Genome-wide gene expression analysis revealed that BDQ reprogramed cells into potent bactericidal phagocytes. We found that 579 and 1,495 genes were respectively differentially expressed in naive- and M. tuberculosis-infected macrophages incubated with the drug, with an over-representation of lysosome-associated genes. BDQ treatment triggered a variety of antimicrobial defense mechanisms, including phagosome-lysosome fusion, and autophagy. These effects were associated with activation of transcription factor EB, involved in the transcription of lysosomal genes, resulting in enhanced intracellular killing of different bacterial species that were naturally insensitive to BDQ. Thus, BDQ could be used as a host-directed therapy against a wide range of bacterial infections

PhysioZoo: The Open Digital Physiological Biomarkers Resource

PhysioZoo is a collaborative platform designed for the analysis of continuous physiological time series. The platform currently comprises four modules, each consisting of a library, a user interface, and a set of tutorials: (1) PhysioZoo HRV, dedicated to studying heart rate variability (HRV) in humans and other mammals; (2) PhysioZoo SPO2, which focuses on the analysis of digital oximetry biomarkers (OBM) using continuous oximetry (SpO2) measurements from humans; (3) PhysioZoo ECG, dedicated to the analysis of electrocardiogram (ECG) time series; (4) PhysioZoo PPG, designed to study photoplethysmography (PPG) time series. In this proceeding, we introduce the PhysioZoo platform as an open resource for digital physiological biomarkers engineering, facilitating streamlined analysis and data visualization of physiological time series while ensuring the reproducibility of published experiments. We welcome researchers to contribute new libraries for the analysis of various physiological time series, such as electroencephalography, blood pressure, and phonocardiography. You can access the resource at physiozoo.com. We encourage researchers to explore and utilize this platform to advance their studies in the field of continuous physiological time-series analysis.Comment: 4 pages, 2 figure, 50th Computing in Cardiology conference in Atlanta, Georgia, USA on 1st - 4th October 202

An essential function for the ATR-Activation-Domain (AAD) of TopBP1 in mouse development and cellular senescence

ATR activation is dependent on temporal and spatial interactions with partner proteins. In the budding yeast model, three proteins – Dpb11TopBP1, Ddc1Rad9 and Dna2 - all interact with and activate Mec1ATR. Each contains an ATR activation domain (ADD) that interacts directly with the Mec1ATR:Ddc2ATRIP complex. Any of the Dpb11TopBP1, Ddc1Rad9 or Dna2 ADDs is sufficient to activate Mec1ATR in vitro. All three can also independently activate Mec1ATR in vivo: the checkpoint is lost only when all three AADs are absent. In metazoans, only TopBP1 has been identified as a direct ATR activator. Depletion-replacement approaches suggest the TopBP1-AAD is both sufficient and necessary for ATR activation. The physiological function of the TopBP1 AAD is, however, unknown. We created a knock-in point mutation (W1147R) that ablates mouse TopBP1-AAD function. TopBP1-W1147R is early embryonic lethal. To analyse TopBP1-W1147R cellular function in vivo, we silenced the wild type TopBP1 allele in heterozygous MEFs. AAD inactivation impaired cell proliferation, promoted premature senescence and compromised Chk1 signalling following UV irradiation. We also show enforced TopBP1 dimerization promotes ATR-dependent Chk1 phosphorylation. Our data suggest that, unlike the yeast models, the TopBP1-AAD is the major activator of ATR, sustaining cell proliferation and embryonic development

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

The Escherichia coli transcriptome mostly consists of independently regulated modules

Underlying cellular responses is a transcriptional regulatory network (TRN) that modulates gene expression. A useful description of the TRN would decompose the transcriptome into targeted effects of individual transcriptional regulators. Here, we apply unsupervised machine learning to a diverse compendium of over 250 high-quality Escherichia coli RNA-seq datasets to identify 92 statistically independent signals that modulate the expression of specific gene sets. We show that 61 of these transcriptomic signals represent the effects of currently characterized transcriptional regulators. Condition-specific activation of signals is validated by exposure of E. coli to new environmental conditions. The resulting decomposition of the transcriptome provides: a mechanistic, systems-level, network-based explanation of responses to environmental and genetic perturbations; a guide to gene and regulator function discovery; and a basis for characterizing transcriptomic differences in multiple strains. Taken together, our results show that signal summation describes the composition of a model prokaryotic transcriptome

Lac repressor mediated DNA looping: Monte Carlo simulation of constrained DNA molecules complemented with current experimental results

Tethered particle motion (TPM) experiments can be used to detect time-resolved loop formation in a single DNA molecule by measuring changes in the length of a DNA tether. Interpretation of such experiments is greatly aided by computer simulations of DNA looping which allow one to analyze the structure of the looped DNA and estimate DNA-protein binding constants specific for the loop formation process. We here present a new Monte Carlo scheme for accurate simulation of DNA configurations subject to geometric constraints and apply this method to Lac repressor mediated DNA looping, comparing the simulation results with new experimental data obtained by the TPM technique. Our simulations, taking into account the details of attachment of DNA ends and fluctuations of the looped subsegment of the DNA, reveal the origin of the double-peaked distribution of RMS values observed by TPM experiments by showing that the average RMS value for anti-parallel loop types is smaller than that of parallel loop types. The simulations also reveal that the looping probabilities for the anti-parallel loop types are significantly higher than those of the parallel loop types, even for loops of length 600 and 900 base pairs, and that the correct proportion between the heights of the peaks in the distribution can only be attained when loops with flexible Lac repressor conformation are taken into account. Comparison of the in silico and in vitro results yields estimates for the dissociation constants characterizing the binding affinity between O1 and Oid DNA operators and the dimeric arms of the Lac repressor. © 2014 Biton et al