Split histidine kinases enable ultrasensitivity and bistability in two-component signaling networks

Bacteria sense and respond to their environment through signaling cascades generally referred to as two-component signaling networks. These networks comprise histidine kinases and their cognate response regulators. Histidine kinases have a number of biochemical activities: ATP binding, autophosphorylation, the ability to act as a phosphodonor for their response regulators, and in many cases the ability to catalyze the hydrolytic dephosphorylation of their response regulator. Here, we explore the functional role of “split kinases” where the ATP binding and phosphotransfer activities of a conventional histidine kinase are split onto two distinct proteins that form a complex. We find that this unusual configuration can enable ultrasensitivity and bistability in the signal-response relationship of the resulting system. These dynamics are displayed under a wide parameter range but only when specific biochemical requirements are met. We experimentally show that one of these requirements, namely segregation of the phosphatase activity predominantly onto the free form of one of the proteins making up the split kinase, is met in Rhodobacter sphaeroides. These findings indicate split kinases as a bacterial alternative for enabling ultrasensitivity and bistability in signaling networks. Genomic analyses reveal that up 1.7% of all identified histidine kinases have the potential to be split and bifunctional

Lighting as a Circadian Rhythm-Entraining and Alertness-Enhancing Stimulus in the Submarine Environment

The human brain can only accommodate a circadian rhythm that closely follows 24 hours. Thus, for a work schedule to meet the brain’s hard-wired requirement, it must employ a 24 hour-based program. However, the 6 hours on, 12 hours off (6/12) submarine watchstanding schedule creates an 18-hour “day” that Submariners must follow. Clearly, the 6/12 schedule categorically fails to meet the brain’s operational design, and no schedule other than one tuned to the brain’s 24 hour rhythm can optimize performance. Providing Submariners with a 24 hour-based watchstanding schedule—combined with effective circadian entrainment techniques using carefully-timed exposure to light—would allow crewmembers to work at the peak of their daily performance cycle and acquire more restorative sleep. In the submarine environment, where access to natural light is absent, electric lighting can play an important role in actively entraining—and closely maintaining—circadian regulation. Another area that is likely to have particular importance in the submarine environment is the potential effect of light to help restore or maintain alertness

Global Maps of Science based on the new Web-of-Science Categories

In August 2011, Thomson Reuters launched version 5 of the Science and Social Science Citation Index in the Web of Science (WoS). Among other things, the 222 ISI Subject Categories (SCs) for these two databases in version 4 of WoS were renamed and extended to 225 WoS Categories (WCs). A new set of 151 Subject Categories (SCs) was added, but at a higher level of aggregation. Since we previously used the ISI SCs as the baseline for a global map in Pajek (Rafols et al., 2010) and brought this facility online (at http://www.leydesdorff.net/overlaytoolkit), we recalibrated this map for the new WC categories using the Journal Citation Reports 2010. In the new installation, the base maps can also be made using VOSviewer (Van Eck & Waltman, 2010).Comment: Scientometrics, in pres

Genetic determinants of rates of cognitive decline in preclinical Alzheimer’s Disease

In 2015 the number of people worldwide living with Dementia was 46.8 million, with approximately 50-75% of these cases being clinically defined as Alzheimer’s disease (AD). Despite extensive efforts, clinical trials have so far failed to yield a treatment that successfully addresses the underlying cause of AD. This lack of treatment has been suggested, in part, to be a result of late stage of intervention in current clinical trial design. For this reason, greater focus has been placed on preclinical trials and in turn both the identification of individuals at-risk for AD and, amongst these, those that are expected to decline over the course of a trial. While brain imaging to determine Aβ- amyloid burden has utility in identifying individuals with preclinical AD, further work needs to be conducted to determine what influences rates of change during these early disease stages. Of particular focus is the rate of decline in cognitive performance, as it is the primary outcome measure of efficacy in clinical trials. A number of genetic variants have been associated with cognitive performance, however additional research needs to be conducted to accurately understand the influence that genetic variation has on cognition in preclinical AD. Aims Initially the aim of this thesis was to assess the combined genetic influence of established AD risk genetic variants on preclinical cognitive performance, specifically using AD-risk effect-size weighted polygenic risk scores (PRSs) (Chapter 2). It was then aimed to evaluate the effects on cognitive rates of change in preclinical AD of genes with a priori evidence for association with cognition, both individually (Chapter 3) and then when combined (Chapter 4). The results of the preceding chapters informed the final aim which was to determine a novel method of weighting individual variants in genes associated with AD-risk and/or cognition, for use in a genetic risk score that would improve the prediction of preclinical cognitive rates of change (Chapter 5). Methods All studies presented in this thesis utilised data from the highly characterised Australian Imaging, Biomarkers and Lifestyle Study of Aging (AIBL). The AIBL study is a longitudinal cohort study collecting data at 18-monthly intervals, currently consisting of 7.5 years of follow up. Individuals investigated in this thesis had been Positron Emission Tomography (PET) imaged to determine neocortical amyloid burden. Further, all individuals were classified as Αβhigh or Αβlow based on tracer specific cut offs. In addition, a subset of these samples underwent lumbar puncture for CSF collection at the study baseline, and Aβ42, total-tau and phospho-tau were quantified. Finally, based on the AIBL neuropsychological test battery, three cognitive composites previously developed were calculated for all participants. The cognitive composites investigated were; verbal episodic memory, a statistically driven global cognition composite, and the Pre-Alzheimer’s Cognitive Composite. The AD-risk weighted PRS (Chapter 2) consisted of 22 genetic variants associated with AD classification, and was calculated by weighting individual variants based on their previously published associations with risk for AD. A statistically derived Cognitive Genetic Risk Profile (Cog-GRP), specifically driven by verbal episodic memory, was developed using a decision tree analysis (Chapter 4). Finally, a 27 genetic variant cognition weighted PRS (cwPRS), was developed and tested in a preclinical AD sample (Chapter 5). For the cwPRS, effect sizes for decline in a verbal episodic memory were determined individually for all variants in a reference sample. The resulting effect sizes were then used to calculate the cwPRS for each participant in a test sample (Chapter 5). For both the AD-risk weighted PRS (Chapter 2) and the cwPRS (Chapter 5), PRS calculations were conducted with both the inclusion and exclusion of the major genetic risk factor for, Apolipoprotein E (APOE). In all studies, linear mixed models were used to investigate associations between genetic factors, independent or in combination, and longitudinal rates of cognitive performance. Results In CN older adults the AD-risk weighted PRS, both including and excluding APOE, was positively correlated with brain and blood biomarkers, specifically; brain Aβ burden, CSF total-tau and phospho-tau (Chapter 2). When investigating cognitive performance, specifically in CN Αβhigh participants, significant associations with baseline and longitudinal cognition were only observed in the AD-risk weighted PRS with APOE (Chapter 2). When investigating gene variants previously reported to influence cognition, in CN Αβhigh participants, no independent associations were observed for any variant (Chapter 3). However, in the same sample, after interaction with APOE e4, significant associations were observed for variants in the Kidney Brain Expressed Protein (KIBRA) and Spondin-1 (SPON1) genes (Chapter 3). The combination of variants investigated in Chapter 3, with additional variants, resulted in the development of the Cog-GRP (Chapter 4). The Cog-GRP was able to delineate four groups: APOE ε4+ Risk, APOE ε4+ Resilient, APOE ε4- Risk, APOE ε4- Resilient, with the ε4+ Risk group reporting significantly faster decline in cognition than all other groups (Chapter 4). Finally, a PRS encompassing a combination of AD-risk genes (Chapter 2) and cognitive-risk genes (Chapters 3 and 4), weighted by episodic memory (cwPRS), was reported to be associated with preclinical longitudinal cognitive performance (Chapter 5). Further, these associations were observed irrespective of the presence or absence of APOE in the calculation of the cwPRS (Chapter 5). Conclusions The work presented in this thesis provides an in depth investigation of genetic influences in preclinical AD, particularly on cognitive performance. Importantly, it supports the hypothesis that there is are differences between the genetic architectures of AD-risk and AD progression. The results presented here support the use of combinatory approaches when investigating genetic influence. Finally, reported here is a novel method for PRS weighting, with the ability to predict preclinical cognitive performance in the presence and absence of APOE. Further investigation is required in cohorts with comparable data to the AIBL study, to validate the methods explored in this thesis, allowing for their eventual use in a clinical setting

Long-term material compatibility testing system

System includes procedure for hermetically sealing solid materials and fluids in glass ampoule and use of temperature-controlled facility containing sample holder, which permits sample containers to be retrieved safely and conveniently. Solid material and fluid are sealed within chemically-clean glass ampoule according to highly detailed procedure

Restrictions and Stability of Time-Delayed Dynamical Networks

This paper deals with the global stability of time-delayed dynamical networks. We show that for a time-delayed dynamical network with non-distributed delays the network and the corresponding non-delayed network are both either globally stable or unstable. We demonstrate that this may not be the case if the network's delays are distributed. The main tool in our analysis is a new procedure of dynamical network restrictions. This procedure is useful in that it allows for improved estimates of a dynamical network's global stability. Moreover, it is a computationally simpler and much more effective means of analyzing the stability of dynamical networks than the procedure of isospectral network expansions introduced in [Isospectral graph transformations, spectral equivalence, and global stability of dynamical networks. Nonlinearity, 25 (2012) 211-254]. The effectiveness of our approach is illustrated by applications to various classes of Cohen-Grossberg neural networks.Comment: 32 pages, 9 figure

The Use of Online Panel Data in Management Research: A Review and Recommendations

Management scholars have long depended on convenience samples to conduct research involving human participants. However, the past decade has seen an emergence of a new convenience sample: online panels and online panel participants. The data these participants provide—online panel data (OPD)—has been embraced by many management scholars owing to the numerous benefits it provides over “traditional” convenience samples. Despite those advantages, OPD has not been warmly received by all. Currently, there is a divide in the field over the appropriateness of OPD in management scholarship. Our review takes aim at the divide with the goal of providing a common understanding of OPD and its utility and providing recommendations regarding when and how to use OPD and how and where to publish it. To accomplish these goals, we inventoried and reviewed OPD use across 13 management journals spanning 2006 to 2017. Our search resulted in 804 OPD-based studies across 439 articles. Notably, our search also identified 26 online panel platforms (“brokers”) used to connect researchers with online panel participants. Importantly, we offer specific guidance to authors, reviewers, and editors, having implications for both micro and macro management scholars

Suicide and self-harm in Britain: researching risk and resilience using UK surveys

Aim The main aim of this study was to raise awareness of surveys that could be used to inform self-harm and suicide prevention work. We asked: What UK survey datasets are available for research? What aspects of people’s lives are associated with self-harm and attempted suicide? How do statistical findings resonate with people’s lived experience? What implications do they see? Findings Survey analyses revealed that risk factors for self-harm are wide ranging and include: Mental health Physical health and health behaviours Social relationships Stressful events Employment and financial circumstances Identity and demographics Many different factors are independently associated with self-harm. There is a dose relationship, with more exposure to a factor linked with increased risk. Risks are cumulative that is, exposure to multiple factors is associated with greater risk. Through facilitated consultation, men with lived experience, bereaved family members, and practitioners identified recommendations for responding to suicidal distress in men. These related to the following three main areas: 1. Recognising need: who is ‘ill enough’? Permission - men said that they often did not know they were entitled to help Ask - people who outwardly appear to be functioning may not be Persistence - ask and offer help more than once. 2. Facilitating access: right words, time and place What is available - support is needed with ongoing stress as well as for crises Find the words - men wanted examples of how to ask for help Allow time - employers expect recovery to be swift, some men felt rushed to come off medications or were discharged from services they still needed. 3. Adjusting delivery: equal engagement Power - some were uncomfortable with service dynamics, preferring peer support Every service contact counts - negative contacts had particular impact Safe spaces - may be different for men and women. Methods There were three strands of work: Secondary analysis of nine survey series, spanning more than twenty years Linkage of 144,000 survey participants to information on whether they were alive in 2013 and whether they had taken their own life Facilitated consultation, through depth interviews with people with lived experience

A Theory of Errors in Quantum Measurement

It is common to model random errors in a classical measurement by the normal (Gaussian) distribution, because of the central limit theorem. In the quantum theory, the analogous hypothesis is that the matrix elements of the error in an observable are distributed normally. We obtain the probability distribution this implies for the outcome of a measurement, exactly for the case of 2x2 matrices and in the steepest descent approximation in general. Due to the phenomenon of `level repulsion', the probability distributions obtained are quite different from the Gaussian.Comment: Based on talk at "Spacetime and Fundamental Interactions: Quantum Aspects" A conference to honor A. P. Balachandran's 65th Birthda