Cellular feedback dynamics and multilevel regulation driven by the hippo pathway

The Hippo pathway is a dynamic cellular signalling nexus that regulates differentiation and controls cell proliferation and death. If the Hippo pathway is not precisely regulated, the functionality of the upstream kinase module is impaired, which increases nuclear localisation and activity of the central effectors, the transcriptional co-regulators YAP and TAZ. Pathological YAP and TAZ hyperactivity consequently cause cancer, fibrosis and developmental defects. The Hippo pathway controls an array of fundamental cellular processes, including adhesion, migration, mitosis, polarity and secretion of a range of biologically active components. Recent studies highlight that spatio-temporal regulation of Hippo pathway components are central to precisely controlling its context-dependent dynamic activity. Several levels of feedback are integrated into the Hippo pathway, which is further synergized with interactors outside of the pathway that directly regulate specific Hippo pathway components. Likewise, Hippo core kinases also ‘moonlight’ by phosphorylating multiple substrates beyond the Hippo pathway and thereby integrates further flexibility and robustness in the cellular decision-making process. This topic is still in its infancy but promises to reveal new fundamental insights into the cellular regulation of this therapeutically important pathway. We here highlight recent advances emphasising feedback dynamics and multilevel regulation of the Hippo pathway with a focus on mitosis and cell migration, as well as discuss potential productive future research avenues that might reveal novel insights into the overall dynamics of the pathway

Mass Spectra Prediction with Structural Motif-based Graph Neural Networks

Mass spectra, which are agglomerations of ionized fragments from targeted molecules, play a crucial role across various fields for the identification of molecular structures. A prevalent analysis method involves spectral library searches,where unknown spectra are cross-referenced with a database. The effectiveness of such search-based approaches, however, is restricted by the scope of the existing mass spectra database, underscoring the need to expand the database via mass spectra prediction. In this research, we propose the Motif-based Mass Spectrum Prediction Network (MoMS-Net), a system that predicts mass spectra using the information derived from structural motifs and the implementation of Graph Neural Networks (GNNs). We have tested our model across diverse mass spectra and have observed its superiority over other existing models. MoMS-Net considers substructure at the graph level, which facilitates the incorporation of long-range dependencies while using less memory compared to the graph transformer model.Comment: 19 pages, 3figure

A study on the regulatory mechanism of DSCR1 expression

Department of Biological SciencesCommon features or prominent complications of Down Syndrome (DS) patients who have part of chromosome 21 as trisome made researchers interested in studying the DS related proteins. DSCR1 (Down Syndrome Critical Region 1) was found as the one of the critical proteins which markedly affects DS patient???s abnormality. A number of studies have been carried out to reveal the cellular functions of DSCR1, focusing on its duality of functions (beneficial or detrimental) in diverse conditions when this protein is either up-regulated or down-regulated. Although there have been some efforts in the past to interrogate the regulatory mechanisms of DSCR1 expression, our overall understanding of this mechanism remains fragmentary. In this study, we aimed to understand the regulatory mechanisms of DSCR1 expression, which might be utilized to develop therapeutic strategies for various disease conditions including leukemia, heart defects, and Alzheimer???s diseases. Here, we found that RALY isoform 2 protein may play a potential role in the regulation of DSCR1 expression as a suppressor in the endothelial cell. This study definitely requires further research for better understanding of detailed regulatory mechanisms and molecular players implicated in this process. However, our data still provides insight into potential strategy of DSCR1 regulation for gene therapy for DS.ope

Essays in applied microeconomics

The first chapter examines whether funding for public schools affects parents' decision to send their children to private schools in the US. In the wake of the Great Recession, funding for public K-12 education fell precipitously and stayed low for several years. Exploiting the fact that states with greater reliance on state appropriations and states with no income tax experienced larger cuts, I instrument for local public school funding. I find that students exposed to a $1,000 (9.0 percent) decrease in per-pupil funding are more likely to enroll in private schools by 0.48 to 0.59 percentage points (4.5 to 5.6 percent). I show further that the effect is strongest among high socioeconomic status students living in disadvantaged areas. These findings suggest that reductions in public school resources lead to greater inequality in education and negatively change student composition in public schools through school choice. In the second chapter, I investigate the effect of Facility-Based Childbirth Policy (FBCP) to promote facility-based child delivery (FBD) and prenatal care in Rwanda. To identify the causal effect on childhood mortality rates, I utilize the geographical variation of FBD in the baseline period and the timing of the policy in a difference-in-difference framework. The reform has a substantial effect on infant (under one year) and child (under five years) mortality, with reductions of 12 and 25 deaths per 1,000 live births, respectively. However, the overall reduction in newborn (seven days) neonatal (30 days) mortality is not statistically significant despite a large increase in FBD. I also show that other policy interventions like performance-based financing schemes can strengthen the treatment effect on newborn and neonatal mortality, implying the importance of multiple approaches to reduce mortality rates. The third chapter explores whether the increase in service outsourcing to India has reduced the employment of the occupations with greater exposure to Indian service imports. To account for endogeneity, I instrument for the growth of the US's service import from India, exploiting the change in Indian import in European countries. The occupation-level analysis produces a mixed result. An increase in service imports reduces the total employment from 2000 to 2006; however, the effect attenuates in the later period of 2006 to 2016. The change is skill-biased: the reduction in employment is smaller for college-educated workers in the first period, and the sign reverses later.Economic

Is the Role of Work Engagement Essential to Employee Performance or ‘Nice to Have’?

The current study aimed to scrutinize roles of work engagement as a mediator in the relationships between job and personal resources and employees’ outcomes, namely job performance and turnover intention, specifically focusing on testing the essentiality of work engagement. A total of 571 complete responses from full-time employees in Korean organizations were utilized for data analysis with structural equation modeling (SEM). This study analyzed two research models through the competing model approach: One model (Model 1) specified that job and personal resources directly influence job performance and turnover intention and also indirectly influence job performance and turnover intention through work engagement, whereas the other model (Model 2) specified that job and personal resources only indirectly influence turnover intention and job performance through work engagement. The results of the competing models demonstrated that overall, Model 2 adequately fit better than Model 1. The results also showed that the direct effects of job and personal resources on work engagement, as well as the direct effects of work engagement on job performance and turnover intention were statistically significant. In addition, the results of the study revealed statistically significant mediating effects of work engagement, not only on the relationship between job and personal resources and job performance, but also on the relationship between job and personal resources and turnover intention. Based on the results, theoretical and practical implications for human resource management, limitations, and recommendations for further research are discussed

The relationship between work engagement and work–life balance in organizations: a review of the empirical research

Employers increasingly attempt to create the right environments where employees experience work–life balance. At the same time, organizations concerned with their organizational-level outcomes encourage improving employee work engagement. The question becomes, how do employee work–life balance and work engagement relate to one another? A similar question concerns human resource development (HRD) practitioners who seek to help both employees with balancing their work and life and employers with their organizational goals. A body of literature has examined the relationship between work–life balance and work engagement, which we review in this article. We identify and synthesize the findings of 37 articles empirically investigating the relationship between work–life balance and work engagement. The findings showed the various antecedents, mediators, and moderators that depict the relationships between work engagement and work–life balance. Furthermore, we provide insight into HRD scholarship regarding how to clarify the direction of causality between two concepts, which has been largely left inconclusive. Finally, our article proposes insightful directions for future research and practice in the field of HRD

Using Raman Spectroscopy to Study Fouling Mechanisms in Reverse Osmosis Desalination

Despite an increased focus on alternative approaches, the dominant technology for desalination remains reverse osmosis (RO). However, like all membrane-based separation processes, RO suffers from membrane fouling, resulting in higher operating costs and energy consumption. Inorganic fouling, usually known as scaling, is a common form of fouling observed in RO-based membrane desalination of high-salinity seawaters and brackish waters. The presence of a variety of inorganics in brackish and seawater feeds, along with high spatial dependence of the concentration polarization-driven scale-formation process, necessitates a high spatial resolution, sensitive, and real-time fouling detection scheme with chemical identification of the foulants. This is crucial for devising an efficient scale removal and prevention strategy. Without real-time local scaling and chemical metrics, scale-control processes can rely on trial-and-error iterations, which can waste valuable resources in the form of energy and capital.Raman spectroscopy is a nondestructive, in situ (local), real-time methodology based on inelastic light-matter interactions. Raman spectra can provide the chemical fingerprint of the fouling species with spatial resolution (on order of microns) and a rapid temporal response (on the order of seconds). To demonstrate the capability of this technique, I designed and built a bench-scale flat sheet RO system capable of performing multi-day crossflow experiments. The custom flow cell of the RO system featured optical access to the membrane, interfacing with a Raman microscope. Chapters 1 defines the scope of the work and describes the organization of the dissertation. Chapters 2 and 3 present important technical background on reverse osmosis desalination and Raman spectroscopy. In Chapter 4, real-time Raman detection and monitoring was applied to the deposition and removal of gypsum scale. This study showed that Raman spectroscopy could provide crucial real-time chemical composition and spatial distribution information during membrane cleaning, which can inform more effective antiscaling and cleaning strategies. In Chapter 5, a new RO system and in-house Raman system were designed and assembled to enable the study of lateral scaling progression of calcium carbonate (i.e., scaling as a function of axial position) during longer scaling experiments. The limitations of the prior RO flow cell, namely nonuniform channel height and small, fixed optical window were resolved. The time evolution of the downstream and upstream calcium carbonate Raman signal was evaluated with respect to computed values of local concentration at the membrane surface, revealing a statistically significant dependence (p&lt;0.001). The real-time Raman data were bolstered by results of post-mortem analysis (scanning electron microscopy, gravimetric measurements, laser interferometry), which additionally revealed that the employed technique was capable of detecting crystals with characteristic lengths &lt;50 &mu;m. Chapter 6 addressed real-time Raman detection of two-component scaling using calcium sulfate and calcium carbonate as model scalants (components). First, the limitations of a single-point sampling strategy were demonstrated using the RO flow cell and system presented in Chapter 4. The average dimensions of the two scaling components and the Raman laser beam spot size were identified as important Raman sampling parameters. Flux decline as low as 0.4% and 0.5% was observed at the time of gypsum and calcium carbonate Raman detection, respectively. This supported the Raman sensor&rsquo;s early detection capability and utility as a real-time decision-making tool during plant operation. Additionally, the spatial distribution of the crystals was quantified using a normalized formulation of Ripley&rsquo;s K function. Results indicated that crystal distribution pattern was a critical design driver in the optimization of Raman sampling strategy. Chapter 7 summarizes the conclusions of the dissertation work and with recommendations for future work.</p