Time-varying effect in the competing risks based on restricted mean time lost

Patients with breast cancer tend to die from other diseases, so for studies that focus on breast cancer, a competing risks model is more appropriate. Considering subdistribution hazard ratio, which is used often, limited to model assumptions and clinical interpretation, we aimed to quantify the effects of prognostic factors by an absolute indicator, the difference in restricted mean time lost (RMTL), which is more intuitive. Additionally, prognostic factors may have dynamic effects (time-varying effects) in long-term follow-up. However, existing competing risks regression models only provide a static view of covariate effects, leading to a distorted assessment of the prognostic factor. To address this issue, we proposed a dynamic effect RMTL regression that can explore the between-group cumulative difference in mean life lost over a period of time and obtain the real-time effect by the speed of accumulation, as well as personalized predictions on a time scale. Through Monte Carlo simulation, we validated the dynamic effects estimated by the proposed regression having low bias and a coverage rate of around 95%. Applying this model to an elderly early-stage breast cancer cohort, we found that most factors had different patterns of dynamic effects, revealing meaningful physiological mechanisms underlying diseases. Moreover, from the perspective of prediction, the mean C-index in external validation reached 0.78. Dynamic effect RMTL regression can analyze both dynamic cumulative effects and real-time effects of covariates, providing a more comprehensive prognosis and better prediction when competing risks exist

Interannual Variability in Methane and Nitrous Oxide Concentrations and Sea-Air Fluxes Across the North American Arctic Ocean (2015–2019)

Between 2015 and 2018, we collected approximately 2,000 water column measurements of methane (CH4) and nitrous oxide (N2O) concentrations in the North American Arctic Ocean during summer and early fall. We also obtained 25 measurements of CH4 and N2O concentrations in rivers along the Northwest Passage and Ellesmere Island in midsummer 2017–2019. Our results show that N2O is generated in the highly productive Bering and Chukchi Seas and transported northeastward, producing a persistent subsurface N2O peak in the Beaufort Sea. The Chukchi and Beaufort Sea sediments are a significant source of CH4 to the water column. These sedimentary sources and associated water column consumption display significant spatial gradients and interannual variability. CH4 isotope data demonstrate the importance of CH4 oxidation across the study region. We find that rivers are not a significant source of CH4 or N2O to the Arctic Ocean at the time of year sampled. The estimated annual sea-air flux across the study region (2.3 million km2) had a median (first quartile, third quartile) of 0.009 (0.002, 0.023) Tg CH4 y−1 and −0.003 (−0.013, 0.010) Tg N y−1. These results suggest that the North American Arctic Ocean currently plays a negligible role in global CH4 and N2O budgets. Our expansive data set, with observations at many repeat stations, provides a synopsis of present-day Arctic CH4 and N2O distributions and their range of variability, as well as a benchmark against which future climatedependent changes can be evaluated

The Paf1 complex transcriptionally regulates the mitochondrial-anchored protein Atg32 leading to activation of mitophagy

Mitophagy is a critical process that safeguards mitochondrial quality control in order to maintain proper cellular homeostasis. Although the mitochondrial-anchored receptor Atg32-mediated cargo-recognition system has been well characterized to be essential for this process, the signaling pathway modulating its expression as a contribution of governing the mitophagy process remains largely unknown. Here, bioinformatics analyses of epigenetic or transcriptional regulators modulating gene expression allow us to identify the Paf1 complex (the polymerase-associated factor 1 complex, Paf1C,) as a transcriptional repressor of ATG genes. We show that Paf1C suppresses glucose starvation-induced autophagy, but does not affect nitrogen starvation- or rapamycin-induced autophagy. Moreover, we show that Paf1C specifically regulates mitophagy through modulating ATG32 expression. Deletion of the genes encoding two core subunits of Paf1C, Paf1 and Ctr9, increases ATG32 and ATG11 expression and facilitates mitophagy activity. Although Paf1C is required for many histone modifications and gene activation, we show that Paf1C regulates mitophagy independent of its positive regulatory role in other processes. More importantly, we also demonstrate the mitophagic role of PAF1C in mammals. Overall, we conclude that Paf1C maintains mitophagy at a low level through binding the promoter of the ATG32 gene in glucose-rich conditions. Dissociation of Paf1C from ATG32 leads to the increased expression of this gene, and mitophagy induction upon glucose starvation. Thus, we uncover a new role of Paf1C in modulating the mitophagy process at the transcriptional level

Novel Magnetic-Sensing Modalities with Nitrogen-Vacancy Centers in Diamond

In modern-day quantum metrology, quantum sensors are widely employed to detect weak magnetic fields or nanoscale signals. Quantum devices, exploiting quantum coherence, are inevitably connected to physical constants and can achieve accuracy, repeatability, and precision approaching fundamental limits. As a result, these sensors have shown utility in a wide range of research domains spanning both science and technology. A rapidly emerging quantum sensing platform employs atomic-scale defects in crystals. In particular, magnetometry using nitrogen-vacancy (NV) color centers in diamond has garnered increasing interest. NV systems possess a combination of remarkable properties, optical addressability, long coherence times, and biocompatibility. Sensors based on NV centers excel in spatial resolution and magnetic sensitivity. These diamond-based sensors promise comparable combination of high spatial resolution and magnetic sensitivity without cryogenic operation. The above properties of NV magnetometers promise increasingly integrated quantum measurement technology, as a result, they have been extensively developed with various protocols and find use in numerous applications spanning materials characterization, nuclear magnetic resonance (NMR), condensed matter physics, paleomagnetism, neuroscience and living systems biology, and industrial vector magnetometry. In this chapter, NV centers are explored for magnetic sensing in a number of contexts. In general, we introduce novel regimes for magnetic-field probes with NV ensembles. Specifically, NV centers are developed for sensitive magnetometers for applications where microwaves (MWs) are prohibitively invasive and operations need to be carried out under zero ambient magnetic field. The primary goal of our discussion is to improve the utility of these NV center-based magnetometers

Contrasting distributions and cycling of reduced sulfur compounds in saline and estuarine waters of the coastal NE subarctic Pacific

The trace gas dimethylsulfide (DMS) is considered to be one of the most important sulfur compounds in the marine environment. Research on this volatile sulfur compound has been stimulated by its potential role in regulating regional and global climate, and its importance, along with the related sulfur compounds, dimethylsulfoniopropionate (DMSP) and dimethylsulfoxide (DMSO), as carbon and sulfur sources for microbes in the marine environment. The northeast subarctic Pacific (NESAP) is one of the global DMS hotspots, with significant spatial and temporal variability in DMS production. The difference in nutrient supply between coastal and offshore waters in this region drives significant variability in phytoplankton community structure, primary productivity, and thus sulfur cycling. The goal of this thesis is to characterize the patterns of sulfur cycling in two hydrographically distinct regimes in the NESAP, and to provide insights into the relative contribution of various DMS production pathways. Chapter 2 presents new measurements of DMS, DMSP and DMSO (DMS/P/O) concentrations and turnover rate constants made in the coastal NESAP, as well as ancillary hydrographic and satellite data that help explain the underlying factors influencing DMS/P/O distributions and cycling. A strong linear relationship was demonstrated between DMS and DMSO concentrations, confirming similar ratios found in previous studies. Turnover rate constants for net DMS production from DMSO were comparable to those for DMSP, indicating DMSO reduction as an important pathway for marine DMS production. Similar rate constants for DMSP cleavage and DMSO reduction between the two regimes were found, although the lower average of kDMSPcleav in the continental shelf waters may indicate higher bacterial sulfur demand in the more productive shelf waters. Our findings provide insights into marine sulfur dynamics in adjacent but contrasting marine waters, and highlight the significant contribution of DMSO to DMS production. This result suggests a need for improved understanding of marine DMSO cycling. In addition to the main research presented in the body of this thesis, the Appendices present supplementary tests of various DMSP preservation methods, and a detailed protocol for DMSO reduction by the TiCl3 method. These methodological details will be useful for future sulfur studies.Science, Faculty ofEarth, Ocean and Atmospheric Sciences, Department ofGraduat

Inter-annual and spatial variability of methane and nitrous oxide distributions across the North American Arctic Ocean

Science, Faculty ofChemistry, Department ofUnreviewedUndergraduat

The Chinese version of the Maltreatment and Abuse Chronology of Exposure (MACE) scale: Psychometric properties in a sample of young adults

There are several effective self-report instruments used by Chinese researchers to retrospectively assess exposure to childhood maltreatment. However, these measures do not assess the timing of exposure, restricting efforts to identify periods of development when childhood maltreatment maximally increases vulnerability to psychopathology. In the current study we created a Chinese version of the Maltreatment and Abuse Chronology of Exposure (MACE) scale, which assesses multiplicity (number of types of maltreatment experienced) and severity of maltreatment as well as when it occurred during childhood and adolescence. Rasch modeling was used for scale development in a sample of 812 undergraduate students. Item reduction analysis of the original 75 items used to develop the 52-item MACE produced a 58-item Chinese version. The new scale showed the same factor structure as the original MACE, good three-week test-retest reliability, and good convergent validity with the Childhood Trauma Questionnaire (CTQ) and the revised Adverse Childhood Experiences Questionnaire (ACEQ-R). Variance decomposition analyses found that compared to the CTQ and ACE, the MACE Severity and Multiplicity scores explained higher variance in self-reported depression and anxiety symptom ratings on the Depression Anxiety Stress Scales (DASS). The results of the present study confirmed that the Chinese version of the MACE has sound psychometric properties in the Chinese cultural context. This new instrument will be a valuable tool for Chinese researchers to study retrospective reports of the type and timing of exposure to maltreatment

A1180V of Cardiac Sodium Channel Gene (SCN5A): Is It a Risk Factor for Dilated Cardiomyopathy or Just a Common Variant in Han Chinese?

Our previous study of a Chinese family with dilated cardiomyopathy (DCM) suggested that A1180V of the cardiac sodium channel gene (SCN5A) was associated with the disease within this family. According to data deposited in dbSNP, however, A1180V has been found in some small samples of the Asian population. In this study, we followed up the affected pedigree and expanded the investigation of the prevalence of A1180V in 460 unrelated healthy Han Chinese. Besides, we searched and analyzed it in other database as well. During the follow-up period, 1 A1180V carrier’s condition deteriorated alot, and another 4 carriers progressed to DCM or atrioventricular block (AVB). We also found that the A1180V was absent among the 460 individuals (0%, 0/460), and the carrier frequency of A1180V among Chinese was about 0.51% obtained from the 1000 genome project. In conclusion, our finding suggests that A1180V is a potential risk factor for DCM, and it is extremely rare among Healthy Han Chinese