Unraveling the allosteric inhibition mechanism of PARP-1 CAT and the D766/770A mutation effects via Gaussian accelerated molecular dynamics and Markov state model.

PARP-1 (Poly (ADP-ribose) polymerase 1) is a nuclear enzyme and plays a key role in many cellular functions, such as DNA repair, modulation of chromatin structure, and recombination. Developing the PARP-1 inhibitors has emerged as an effective therapeutic strategy for a growing list of cancers. The catalytic structural domain (CAT) of PARP-1 upon binding the inhibitor allosterically regulates the conformational changes of helix domain (HD), affecting its identification with the damaged DNA. The typical type I (EB47) and III (veliparib) inhibitors were able to lengthening or shortening the retention time of this enzyme on DNA damage and thus regulating the cytotoxicity. Nonetheless, the basis underlying allosteric inhibition is unclear, which limits the development of novel PARP-1 inhibitors. Here, to investigate the distinct allosteric changes of EB47 and veliparib against PARP-1 CAT, each complex was simulated via classical and Gaussian accelerated molecular dynamics (cMD and GaMD). To study the reverse allosteric basis and mutation effects, the complexes PARP-1 with UKTT15 and PARP-1 D766/770A mutant with EB47 were also simulated. Importantly, the markov state models were built to identify the transition pathways of crucial substates of allosteric communication and the induction basis of PARP-1 reverse allostery. The conformational change differences of PARP-1 CAT regulated by allosteric inhibitors were concerned with to their interaction at the active site. Energy calculations suggested the energy advantage of EB47 in inhibiting the wild-type PARP-1, compared with D766/770A PARP-1. Secondary structure results showed the change of two key loops (αB-αD and αE-αF) in different systems. This work reported the basis of PARP-1 allostery from both thermodynamic and kinetic views, providing the guidance for the discovery and design of more innovative PARP-1 allosteric inhibitors.

Childhood abuse as a mediator of the relationship between early family socio-economic status and geriatric depression: A population-based study in China.

Previous studies have suggested that childhood socioeconomic status (SES) is linked to geriatric depressive symptoms in many developed countries. However, the potential pathways of the relationship between childhood SES and geriatric depressive symptoms need to be further explored. This study aimed to assess the mediating effect of being abused during childhood on the association between childhood SES and geriatric depressive symptoms, using evidence from a longitudinal study in China. The study cohort included 8137 individuals. Childhood abuse was defined as experiences related to parental violence, sibling abuse, school violence, community violence, and parental quarrel. Results indicated poor childhood SES was associated significantly with geriatric depressive symptoms. The indirect effect of poor childhood SES to high geriatric depressive risk through community violence, sibling abuse, school violence, and parental quarrel were 0.02, 0.01, 0.02, and 0.01, respectively. Our findings shed new light on the literature regarding the impact of childhood SES on elderly depressive symptoms. Furthermore, childhood SES demonstrated a significant correlation with geriatric depressive symptoms through bullying behaviors. The findings highlight the need to promote both childhood social welfare and psychological well-being within the elderly population.

Developing a National-Scale Exposure Index for Combined Environmental Hazards and Social Stressors and Applications to the Environmental Influences on Child Health Outcomes (ECHO) Cohort.

Tools for assessing multiple exposures across several domains (e.g., physical, chemical, and social) are of growing importance in social and environmental epidemiology because of their value in uncovering disparities and their impact on health outcomes. Here we describe work done within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study to build a combined exposure index. Our index considered both environmental hazards and social stressors simultaneously with national coverage for a 10-year period. Our goal was to build this index and demonstrate its utility for assessing differences in exposure for pregnancies enrolled in the ECHO-wide Cohort Study. Our unitless combined exposure index, which collapses census-tract level data into a single relative measure of exposure ranging from 0-1 (where higher values indicate higher exposure to hazards), includes indicators for major air pollutants and air toxics, features of the built environment, traffic exposures, and social determinants of health (e.g., lower educational attainment) drawn from existing data sources. We observed temporal and geographic variations in index values, with exposures being highest among participants living in the West and Northeast regions. Pregnant people who identified as Black or Hispanic (of any race) were at higher risk of living in a "high" exposure census tract (defined as an index value above 0.5) relative to those who identified as White or non-Hispanic. Index values were also higher for pregnant people with lower educational attainment. Several recommendations follow from our work, including that environmental and social stressor datasets with higher spatial and temporal resolutions are needed to ensure index-based tools fully capture the total environmental context.

Comparing the cost-effectiveness of sintilimab + pemetrexed plus platinum and pemetrexed plus platinum alone as a first-line therapy for Chinese patients with nonsquamous non-small cell lung cancer.

Background: Pemetrexed plus platinum alone is the conventional first-line therapy for locally advanced metastatic nonsquamous non-small cell lung cancer (NSCLC) without targetable genetic aberrations. The ORIENT-11 trial revealed that sintilimab + pemetrexed plus platinum could yield more survival benefits for patients with nonsquamous NSCLC. The present study aimed to assess the cost-effectiveness of sintilimab + pemetrexed plus platinum vs. that of pemetrexed plus platinum alone as the first-line therapy for patients with nonsquamous NSCLC to inform clinically rational drug use and provide a basis for medical decision-making. Methods: A partitioned survival model was created to evaluate the cost-effectiveness of two groups from the perspective of the healthcare system in China. The clinical data for adverse event probabilities and extrapolating long-term survival originally collected in a phase III clinical trial (ORIENT-11) were retrieved. Local public databases and literature were used to acquire data on utility and cost. The heemod package in R software was used to calculate the life years (LYs), quality-adjusted LYs (QALYs), and total costs in each group to generate the incremental cost-effectiveness ratio (ICER) in the base case and to conduct deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA). Results: Our base case analysis (BCA) revealed that sintilimab combined with pemetrexed plus platinum provided an increase of 0.86 in QALYs with an increasing cost of United State dollar (USD) $4,317.84 relative to pemetrexed plus platinum in Chinese patients with nonsquamous NSCLC who were negative for targetable genetic variations, which induced an ICER of USD $5,020.74/QALY. The ICER value was lower than the set threshold value. The results exhibited strong robustness in the sensitivity analysis. In DSA, the parameter for the overall survival (OS) curve in chemotherapy and the cost of best supportive care were the main factors that impacted the result of the ICER. The PSA indicated that sintilimab and chemotherapy combination therapy was cost-effective. Conclusions: This study suggests that the combination of sintilimab + pemetrexed plus platinum is cost-effective as a first-line therapy in Chinese patients with nonsquamous NSCLC who are negative for targetable genetic variations from the perspective of the healthcare system.

Assessment and sources identification of microplastics, PAHs and OCPs in the Luoyuan Bay, China: Based on multi-statistical analysis.

Luoyuan Bay is a mariculture influenced water body located in southeastern China. Multi-statistical techniques were applied to 21 sampling locations in the bay to identify the sources of microplastics and other pollutants in the sediment. In microplastics detection, fragment was the most abundant shape (~36%), and rayon was the dominant polymer (~59%). The size of more than 48% of total microplastics observed was less than 200 µm. The study showed that the upper part of Luoyuan Bay was dominated by microplastic pollution, while the lower part of the bay was dominated by persistent organic pollutants (PAHs, OCPs). Mariculture is one of the main sources of pollution in Luoyuan Bay. Apart from mariculture, there were additional sources such as industry, land reclamation, port, and so on; industry and land reclamation were the leading sources of microplastics, while port, industry, and mariculture were the primary sources of PAHs and OCPs.

Fate, source and mass budget of sedimentary microplastics in the Bohai Sea and the Yellow Sea.

As reservoirs for pollutants transported via the Yangtze and Yellow Rivers, the Bohai Sea (BS) and Yellow Sea (YS) play an important role in transporting microplastics (MPs) to the Pacific Ocean. The fate, sources and mass budget of MPs in the BS and the YS were investigated by Pearson correlation, principal component analysis-multilinear regression analysis (PCA-MRLA) and a mass balance model to sedimentary MPs data. Average MP abundances were 137 and 119 items kg-1 in the Bohai and Yellow Seas, respectively. MPs <1000 µm exhibited similar distribution patterns to total organic carbon and fine-grained sediments, while MPs >1000 µm were confined in the BS and exhibited a strong positive correlation with chlorophyll-a and polyethylene terephthalate, suggesting that larger MPs might deposit faster due to biofouling or when comprised of high density polymers. PCA-MLRA analysis indicated land-based inputs (packing materials, textile material and daily commodities) were dominant in the BS, while maritime activities (fishing and mariculture) were the main source of MPs in the YS. The mass balance model revealed that the total MP input and output to the BS and the YS was 3396.92 t yr-1 and 3814.81 t yr-1, respectively. The major input pathway of MPs to the BS and the YS were river discharge and air deposition, respectively. Notably, 94% of MPs in the BS and the YS were deposited to sediments. This study revealed that BS and YS sediments play an important role in preventing MPs from being further transported to the Pacific Ocean, thus more attention should be paid to local ecological risk assessment.

Cost-effectiveness of pembrolizumab versus docetaxel as second-line treatment of non-small cell lung cancer in China.

BACKGROUND: Pharmacoeconomic information for pembrolizumab as a second-line lung cancer treatment is insufficient in China, so we aimed to assess its cost-effectiveness versus docetaxel as a second-line treatment for patients with non-small cell lung cancer (NSCLC) in China. METHODS: A partitioned survival model was developed to assess the cost-effectiveness of pembrolizumab versus docetaxel in the treatment of NSCLC patients. A phase III clinical trial (KEYNOTE-010) was used as the clinical data. Long-term survival data were extrapolated based on the clinical study data. Lifetime cost and utility were calculated with a discount set at 3%. One-way deterministic sensitivity analyses and probabilistic sensitivity analysis were used to test the robustness of incremental cost-effectiveness ratios (ICER). RESULTS: In the base-case scenario, the ICERs were $107,846/quality-adjusted life year (QALY) and $448,414/QALY for pembrolizumab (2 and 10 mg/kg) groups, respectively. Both ICER values were 3-fold higher than the threshold of China's per-capita GDP in 2019 ($30,055.01). One-way deterministic sensitivity analyses showed that the price of pembrolizumab is the main factor affecting the result of ICER. Median ICERs were $108,658/QALY ($107,005/QALY-$110,089/QALY) for the pembrolizumab 2 mg/kg group and $451,590/QALY ($443,685/QALY-$457,496/QALY) for the pembrolizumab 10 mg/kg group using the current price in China. For patients receiving regimens with 2 mg/kg pembrolizumab, the probabilities will be exceeding 95% when the price of pembrolizumab decreases by 25% in a high-income region (willing to pay setting as $71,406/QALY). CONCLUSIONS: The results suggest that for it to become a second-line treatment of NSCLC in China, a reduction in the cost of pembrolizumab is needed.

Linkage Analysis between Finance and Environmental Protection Sectors in China: An Approach to Evaluating Green Finance.

Given the growing awareness of sustainable development, the environmental protection industry has attracted much attention. Green finance has developed rapidly in policymaking and practices. This study provides a framework for evaluating green finance via linkage analysis based on input-output theory. Measurements on industrial linkages are calculated in China in two provinces from 2002 to 2018, which study the relationship between finance and environmental protection sectors. The results show that the environmental protection sector (EPS) in China has gradually developed from a sector with weak backward and strong forward linkages to a sector with strong backward and weak forward linkages from 2002 to 2015; however, in 2017 and 2018, the EPS returned to a sector with weak backward and strong forward linkages. At the provincial level, the EPS used to be a key sector with strong backward and forward linkages. The connection between the finance sector and the EPS rose first, then declined in the country and the Zhejiang province; Guangdong had a similar evolution in the former period, but it had a rising trend in the latest year. The findings provide insights for further promoting the support from the finance sector to the environmental protection activities.

Recommendations to the Society for Epidemiologic Research for Further Promoting Diversity and Inclusion at the Annual Meeting and Beyond.

Increasing diverse engagement in the Society for Epidemiologic Research (SER) will positively impact the field of epidemiology. As the largest and longest-running epidemiologic society in North America, SER has long been a pioneer in promoting diversity and inclusion. A recent survey of SER members, however, showed there is still room for improving diversity, inclusion, representation, and participation in the Society. In this commentary, as members of both the SER and the Johns Hopkins Bloomberg School of Public Health Department of Epidemiology's Inclusion, Diversity, Equity, Anti-Racism, and Science (Epi IDEAS) Working Group, we recommend 4 goals for the SER Annual Meeting and beyond: 1) convene epidemiologic researchers with diverse backgrounds and ideas; 2) promote an inclusive environment at the SER Annual Meeting; 3) develop, compile, and disseminate best practices to honor diversity in epidemiologic research; and 4) increase prioritization of health disparities research and methods. We also suggest strategies for achieving these goals so that SER can better include, support, and elevate members from historically disadvantaged groups. While our recommendations are tailored specifically to SER, the greater epidemiologic and academic communities could benefit from adopting these goals and strategies within their professional societies and conferences.

Quantitative Assessment of Invasion of High-Grade Gliomas Using Diffusion Tensor Magnetic Resonance Imaging.

OBJECTIVE: To determine heterogeneity of high-grade glioma (HGG) and its surrounding area and explore quantitative analysis of invasion of HGG using diffusion tensor imaging. METHODS: This study included 14 patients with HGG and preoperative magnetic resonance imaging and diffusion tensor imaging examinations. Three regions of interest were placed. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of these regions of interest were measured, and specimens from the 3 regions of interest were obtained under navigation guidance. Postoperative examinations of specimens were carried out. Correlations between ADC and FA values and tumor cell density were evaluated. RESULTS: Median survival was 36.7 months. As distance from the tumor increased, the number of tumor cells significantly decreased. Regarding levels of matrix metalloproteinase-9 and Ki-67, only the differences between tumor and distances of 1 cm and 2 cm away from the tumor were statistically significant. For analysis of the relationship between tumor cell density and ADC and FA values, the discriminant formulas were as follows: G1 = -13.678 + 14984.791 (X) + 14443.847 (Y) (tumor cell density ≥10%); G2 = -11.649 + 14443.847 (X) + 33.285 (Y) (tumor cell density <10%). CONCLUSIONS: We verified the heterogeneity of HGG and its surrounding area and found that patients with extensive resection may have longer survival. We also found a few formulas using FA and ADC values to predict tumor cell density.

In vivo assessment of postnatal murine ocular development by ultrasound biomicroscopy.

PURPOSE: Ultrasound biomicroscopy (UBM) can noninvasively provide anatomical information about mouse ocular structures. We present the quantitation of postnatal murine eye development using UBM. MATERIALS AND METHODS: The eyes from CD-1 mice were examined at 1, 2, 4, 6, and 8 weeks of postnatal development using 40 MHz UBM. Patterns of ocular tissue growth including the lens, globe, and anterior chamber were calculated. RESULTS: Postnatal CD-1 lens and globe volumes are consistent with an exponential decay of growth during the first 8 postnatal weeks. Anterior chamber depth increases most sharply in the first 2 postnatal weeks but continues to increase up to the 8th postnatal week. Anterior segment angle was observed to increase from 1 to 4 weeks. CONCLUSIONS: UBM can be used to obtain in vivo quantitative measurements of postnatal murine ocular structures. Our ability to obtain ocular anatomical information will facilitate future assessments of mouse models of human disease.