The Enigma of Tubulin Detyrosination - Functional Evidence from Plants

Detyrosination of alpha-tubulin seems to be conserved over all eukaryotes. However, its biological function in plants has remained obscure. In order to get insight into the physiological function of tubulin detyrosination, I was phenotyping an overexpressor rice mutant, which is shifting the cycle towards the tyrosinated form. In a second approach an in vitro system was established in order to analyze what happens to microtubule polymerization if these conditions are changed outside a cell

Accountability in Public Administration Education: Assessing the Martin School

Accountability is required for programs to maintain accreditation and is essential to the overall success of graduate programs like the Martin School. To show that it is meeting the stated goals, the Martin School has put tracking measures in place to gauge the success of the Master of Public Administration (MPA) program. These measures include pre and post skills assessments and an alumni survey among others. Analysis of the results is used to determine where goals are being met as well as areas where improvement is possible, and make necessary and appropriate adjustments. The pre-test is given at orientation and the post-test is given during the capstone course. Students are asked to rate their skill level in several areas, then asked to do the same at the end of the program. These tools can be used to determine how helpful students have found the curriculum in giving them the skills necessary for success in the workforce. Another mechanism for assessment is the alumni survey. The instrument asks alumni a number of questions regarding their experience at the Martin School and how this education has or has not helped in their professional lives. The data from this survey may be useful in determining weaknesses graduates see in the program in terms of professional development. The final method for assessing the program is through a Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis which is conducted during the capstone course. Students are asked to critically evaluate the MPA program and complete the SWOT matrix. Responses are combined and examined by the Martin School. This paper primarily deals with analysis of the data obtained by the skills assessment and alumni survey, but also examines the assessment tools themselves. Recommendations have been made regarding possible adjustments to the program and changes to the assessment tools. Several general statements can be made from the data collected. First, the data shows that the Martin School has been successful in increasing the confidence level of its students in all of the 19 areas currently measured. Second, the data from the alumni survey shows a general satisfaction with the education provided by the Martin School. Finally, the information gathered through the SWOT analysis mirrors, in large part, the results obtained from the alumni survey. With respect to the assessment tools, the combination of surveys of various stakeholders, including alumni and internship supervisors, SWOT analysis and the pre/post testing appears to be gathering the information desired by the Martin School. While the language on some of the tools could be improved and the tools could be changed to better align with one another, drastic changes are not needed

Applying a framework for assessing the health system challenges to scaling up mHealth in South Africa

Background: Mobile phone technology has demonstrated the potential to improve health service delivery, but there is little guidance to inform decisions about acquiring and implementing mHealth technology at scale in health systems. Using the case of community-based health services (CBS) in South Africa, we apply a framework to appraise the opportunities and challenges to effective implementation of mHealth at scale in health systems. Methods: A qualitative study reviewed the benefits and challenges of mHealth in community-based services in South Africa, through a combination of key informant interviews, site visits to local projects and document reviews. Using a framework adapted from three approaches to reviewing sustainable information and communication technology (ICT), the lessons from local experience and elsewhere formed the basis of a wider consideration of scale up challenges in South Africa. Results: Four key system dimensions were identified and assessed: government stewardship and the organisational, technological and financial systems. In South Africa, the opportunities for successful implementation of mHealth include the high prevalence of mobile phones, a supportive policy environment for eHealth, successful use of mHealth for CBS in a number of projects and a well-developed ICT industry. However there are weaknesses in other key health systems areas such as organisational culture and capacity for using health information for management, and the poor availability and use of ICT in primary health care. The technological challenges include the complexity of ensuring interoperability and integration of information systems and securing privacy of information. Finally, there are the challenges of sustainable financing required for large scale use of mobile phone technology in resource limited settings. Conclusion: Against a background of a health system with a weak ICT environment and limited implementation capacity, it remains uncertain that the potential benefits of mHealth for CBS would be retained with immediate large-scale implementation. Applying a health systems framework facilitated a systematic appraisal of potential challenges to scaling up mHealth for CBS in South Africa and may be useful for policy and practice decision-making in other low- and middle-income settings.Web of Scienc

Pareto-Optimal Algorithms for Learning in Games

We study the problem of characterizing optimal learning algorithms for playing repeated games against an adversary with unknown payoffs. In this problem, the first player (called the learner) commits to a learning algorithm against a second player (called the optimizer), and the optimizer best-responds by choosing the optimal dynamic strategy for their (unknown but well-defined) payoff. Classic learning algorithms (such as no-regret algorithms) provide some counterfactual guarantees for the learner, but might perform much more poorly than other learning algorithms against particular optimizer payoffs. In this paper, we introduce the notion of asymptotically Pareto-optimal learning algorithms. Intuitively, if a learning algorithm is Pareto-optimal, then there is no other algorithm which performs asymptotically at least as well against all optimizers and performs strictly better (by at least $\Omega(T)$) against some optimizer. We show that well-known no-regret algorithms such as Multiplicative Weights and Follow The Regularized Leader are Pareto-dominated. However, while no-regret is not enough to ensure Pareto-optimality, we show that a strictly stronger property, no-swap-regret, is a sufficient condition for Pareto-optimality. Proving these results requires us to address various technical challenges specific to repeated play, including the fact that there is no simple characterization of how optimizers who are rational in the long-term best-respond against a learning algorithm over multiple rounds of play. To address this, we introduce the idea of the asymptotic menu of a learning algorithm: the convex closure of all correlated distributions over strategy profiles that are asymptotically implementable by an adversary. We show that all no-swap-regret algorithms share the same asymptotic menu, implying that all no-swap-regret algorithms are ``strategically equivalent''

Gender differences in frailty transition and its prediction in community-dwelling old adults

Frailty is very common in old age and often associated with adverse events. Transitioning between frailty states is possible in both directions (improvement and worsening) offering targets for interventions. Frailty is more prevalent in women, but little is known about the impact of gender on frailty transition. The aim of this study is to identify gender differences for frailty transition in older adults and to develop gender-stratified prognostic prediction models for frailty transition. We performed a longitudinal analyses of the Berlin Initiative (cohort) Study with a frailty follow-up of 2.1 years. Description of frailty transition using the frailty phenotype and development of prognostic prediction models using multivariable logistic regressions for transition (improvement or worsening) stratified by gender following the TRIPOD statement were performed. In total, the study population consisted of 1158 community-dwelling adults with a mean age of 84.4 years and of whom 55% were women. Out of 1158 participants 225 (19%) were robust, 532 (46%) prefrail and 401 (35%) frail. After 2.1 (IQR 2.0-2.3) years, half of the participants had transitioned between frailty states. Men worsened more often and those who were already frail died more often than women. Gender-stratified prediction models for frailty transition demonstrated that some predictors (age, self-rated health, cognitive impairment, baseline frailty status) were included in all models. While stroke, diabetes mellitus, smoking and glomerular filtration rate were unique predictors in the models for females, osteoarthritis, hospitalization and education were predictors in the models for males. There are gender differences in frailty transition rates, patterns and prediction. This supports the importance of considering gender when addressing frailty and targeting interventions in old age

Suppression of tubulin detyrosination by parthenolide recruits the plant-specific kinesin KCH to cortical microtubules

Detyrosination of α-tubulin seems to be conserved in all eukaryotes. However, its biological function in plants has remained obscure. A conserved C-terminal tyrosine is removed by a still unidentified tubulin–tyrosine carboxypeptidase (TTC) and can be religated by a tubulin–tyrosine ligase (TTL). To obtain insight into the still elusive biological function of this detyrosination–tyrosination cycle, the effects of the TTC inhibitor parthenolide were analysed in BY-2 tobacco cells. Parthenolide caused a depletion of detyrosinated α-tubulin, whereas the level of tyrosinated tubulin was elevated. This biochemical effect was accompanied by growth inhibition in cycling BY-2 cells and alteration of microtubule-dependent events that define division and expansion geometry such as cell plate alignment or axial expansion. Furthermore, parthenolide triggered an apoplastic alkalinization indicative of activation of defence-related calcium influx channels. At the same time, parthenolide promoted the association of the plant-specific kinesin KCH with cortical microtubules. These observations are integrated into a working model, where detyrosination acts as signal to modulate the binding of kinesin motors involved in structural and sensory functions of the microtubular cytoskeleton

Wolf 1130: A Nearby Triple System Containing a Cool, Ultramassive White Dwarf

Following the discovery of the T8 subdwarf WISEJ200520.38+542433.9 (Wolf 1130C), with common proper motion to a binary (Wolf 1130AB) consisting of an M subdwarf and a white dwarf, we set out to learn more about the old binary in the system. We find that the A and B components of Wolf 1130 are tidally locked, which is revealed by the coherence of more than a year of V band photometry phase folded to the derived orbital period of 0.4967 days. Forty new high-resolution, near-infrared spectra obtained with the Immersion Grating Infrared Spectrometer (IGRINS) provide radial velocities and a projected rotational velocity (v sin i) of 14.7 +/- 0.7 km/s for the M subdwarf. In tandem with a Gaia parallax-derived radius and verified tidal-locking, we calculate an inclination of i=29 +/- 2 degrees. From the single-lined orbital solution and the inclination we derive an absolute mass for the unseen primary (1.24+0.19-0.15 Msun). Its non-detection between 0.2 and 2.5 microns implies that it is an old (>3.7 Gyr) and cool (Teff<7000K) ONe white dwarf. This is the first ultramassive white dwarf within 25pc. The evolution of Wolf 1130AB into a cataclysmic variable is inevitable, making it a potential Type Ia supernova progenitor. The formation of a triple system with a primary mass >100 times the tertiary mass and the survival of the system through the common-envelope phase, where ~80% of the system mass was lost, is remarkable. Our analysis of Wolf 1130 allows us to infer its formation and evolutionary history, which has unique implications for understanding low-mass star and brown dwarf formation around intermediate mass stars.Comment: 37 pages, 9 Figures, 5 Table

Open access-enabled evaluation of epigenetic age acceleration in colorectal cancer and development of a classifier with diagnostic potential

Aberrant DNA methylation (DNAm) is known to be associated with the aetiology of cancer, including colorectal cancer (CRC). In the past, the availability of open access data has been the main driver of innovative method development and research training. However, this is increasingly being eroded by the move to controlled access, particularly of medical data, including cancer DNAm data. To rejuvenate this valuable tradition, we leveraged DNAm data from 1,845 samples (535 CRC tumours, 522 normal colon tissues adjacent to tumours, 72 colorectal adenomas, and 716 normal colon tissues from healthy individuals) from 14 open access studies deposited in NCBI GEO and ArrayExpress. We calculated each sample's epigenetic age (EA) using eleven epigenetic clock models and derived the corresponding epigenetic age acceleration (EAA). For EA, we observed that most first- and second-generation epigenetic clocks reflect the chronological age in normal tissues adjacent to tumours and healthy individuals [e.g., Horvath (r = 0.77 and 0.79), Zhang elastic net (EN) (r = 0.70 and 0.73)] unlike the epigenetic mitotic clocks (EpiTOC, HypoClock, MiAge) (r < 0.3). For EAA, we used PhenoAge, Wu, and the above mitotic clocks and found them to have distinct distributions in different tissue types, particularly between normal colon tissues adjacent to tumours and cancerous tumours, as well as between normal colon tissues adjacent to tumours and normal colon tissue from healthy individuals. Finally, we harnessed these associations to develop a classifier using elastic net regression (with lasso and ridge regularisations) that predicts CRC diagnosis based on a patient's sex and EAAs calculated from histologically normal controls (i.e., normal colon tissues adjacent to tumours and normal colon tissue from healthy individuals). The classifier demonstrated good diagnostic potential with ROC-AUC = 0.886, which suggests that an EAA-based classifier trained on relevant data could become a tool to support diagnostic/prognostic decisions in CRC for clinical professionals. Our study also reemphasises the importance of open access clinical data for method development and training of young scientists. Obtaining the required approvals for controlled access data would not have been possible in the timeframe of this study