Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection.

Leishmania major are intramacrophage parasites whose eradication requires the induction of T helper 1 (Th1) effector cells capable of activating macrophages to a microbicidal state. Interleukin 12 (IL-12) has been recently identified as a macrophage-derived cytokine capable of mediating Th1 effector cell development, and of markedly enhancing interferon gamma (IFN-gamma) production by T cells and natural killer cells. Infection of macrophages in vitro by promastigotes of L. major caused no induction of IL-12 p40 transcripts, whereas stimulation using heat-killed Listeria or bacterial lipopolysaccharide induced readily detectable IL-12 mRNA. Using a competitor construct to quantitate a number of transcripts, a kinetic analysis of cytokine induction during the first few days of infection by L. major was performed. All strains of mice examined, including susceptible BALB/c and resistant C57BL/6, B10.D2, and C3H/HeN, had the appearance of a CD4+ population in the draining lymph nodes that contained transcripts for IL-2, IL-4, and IFN-gamma (and in some cases, IL-10) that peaked 4 d after infection. In resistant mice, the transcripts for IL-2, IL-4, and IL-10 were subsequently downregulated, whereas in susceptible BALB/c mice, these transcripts were only slightly decreased, and IL-4 continued to be reexpressed at high levels. IL-12 transcripts were first detected in vivo by 7 d after infection, consistent with induction by intracellular amastigotes. Challenge of macrophages in vitro confirmed that amastigotes, in contrast to promastigotes, induced IL-12 p40 mRNA. Reexamination of the cytokine mRNA at 4 d revealed expression of IL-13 in all strains analyzed, suggesting that IL-2 and IL-13 may mediate the IL-12-independent production of IFN-gamma during the first days after infection. Leishmania have evolved to avoid inducing IL-12 from host macrophages during transmission from the insect vector, and cause a striking induction of mRNAs for IL-2, IL-4, IL-10, and IL-13 in CD4+ T cells. Each of these activities may favor survival of the organism

Evaluating the current evidence to support therapeutic mammoplasty or breast-conserving surgery as an alternative to mastectomy in the treatment of multifocal and multicentric breast cancers

The oncological safety of treating multiple ipsilateral breast cancers (MIBCs) with types of breast conserving surgery (BCS) compared to mastectomy remains uncertain. This is predicated on the absence of any randomised controlled trials or high-quality protocol defined prospective cohort studies. A single recently published systematic review by the first author, reports its summarised results in this review. Fundamentally the important question is the evaluation of clinical safety following BCS compared to mastectomy for treating MIBC, which is reported in only six studies. Consequently, current evidence doesn’t support the latest St Gallen consensus suggesting the possibility of using BCS to treat all MIBC. There is minimal comparative outcomes data on multicentric (MC) cancers compared to multifocal (MF) cancers comparing BCS or mastectomy. There is also poor evidence of clinical outcomes following therapeutic mammoplasty (TM) for MIBC compared to mastectomy. The potential recommendation of two potential radiotherapy boosts to separate lumpectomy sites following BCS for MC cancers remains a novel treatment concept whose feasibility will be evaluated in the forthcoming NIHR funded randomised feasibility trial called MIAMI. This is a world first attempt to assess the feasibility of a randomised trial design alongside the on-going Alliance registry study (ACOSOG, American College of Surgeons Oncology Group Z11102) in the USA, in which there is no comparative evaluation of mastectomy outcomes. The MIAMI trial aims to assess the clinical safety of multiple lumpectomies combined with TM compared to the standard of mastectomy in MIBC stratified by MF or MC cancers. There is limited evidence on the impacts of inter-tumoral heterogeneity relating to breast cancer subtypes in relation to individualised treatments and recommendations for types of breast surgery. Recent studies have highlighted the potential contributions of stromal epigenetic changes that are currently poorly understood regarding their contributions to either clinical unifocal or MF cancers

The Construction of AN Assessment Index System of Law-based Governance of A City in China

Constructing an assessment index system of law-based governance of a city provides a data basis and an empirical basis for China’s urban construction of the rule of law and highlights its characteristics in the era of big data. A thorough understanding of the theory of the rule of law is required in order to establish this index system. The establishment of the index system needs to be based on a deep understanding of the theory of the rule of law. In particular, it is important to understand the relationship between the core content of the rule of law and the law-based governance of a city, and then to determine the connotation of law-based governance of a city. This serves as the starting point for constructing the index system. At the same time, it is necessary to have a solid grasp of the index theory, adhere to the method of index setting, break down the concept of law-based governance of a city into different levels of indicators according to the types and attributes of the indicators and continue to visualize and operationalize them until the content can be measured. As a whole, this forms a complete assessment index system. Of course, the content of the index system is not fixed and needs to be constantly tested and adjusted in practice. © 2022, University of Tyumen. All rights reserved.State Structure of Russia and China: Comparative Legal ResearchCouncil on grants of the President of the Russian Federation, (MK-6113.2021.2)Shanghai Municipal People's Government, (19SHJD013, 2020-Z-B01)This article is funded by the Decision Consulting Research Project of the Shanghai Municipal People’s Government (the project number is 2020-Z-B01) and by the 2019 China National Institute for SCO International Exchange and Judicial Cooperation Training Base Research Fund Project (the project number is 19SHJD013) (Z. Li) as well as by a grant from the President of the Russian Federation for young scientists No. MK-6113.2021.2 on the topic“The State Structure of Russia and China: Comparative Legal Research” (N. Symaniuk)

Handbook of Well-Being

It is a pleasure to bring to you the eHandbook of Subjective Well-Being, the science of when and why people experience and evaluate their lives in positive ways, including aspects such as positive feelings, life satisfaction, and optimism. There are chapters in this eHandbook on the philosophy and history of well-being, as well as reviews of empirical research on the ways to assess well-being, the circumstances that predict it, the outcomes that it produces, the societal policies that enhance it, and many other social, biological, and cultural processes that help us understand why some people are happy and satisfied with their lives, while others are not. There are also chapters on theories of well-being, such as the baseline or set-point models. We believe that Open publication is the wave of the future (Jhangiani & Biswas-Diener, 2017). Therefore, we are presenting the handbook in an electronic format so that it is widely available to everyone around the world. The handbook is entirely open and free – anyone can read and use it without cost. This is important to us as we desire to lower knowledge barriers for individuals and communities, especially because it provides access to students, educators, and scholars who do not have substantial financial resources. We are not certain if this is the first free and open handbook in the behavioral sciences, but hopefully it will not be the last. In the past the prohibitive price of many handbooks have made them available only to scholars or institutions in wealthy nations, and this is unfortunate. We believe scientific scholarship should be available to all. The field of subjective well-being has grown at rapid pace over the last several decades, and many discoveries have been made. When Ed Diener began his research within the field in 1981 there were about 130 studies published that year on the topic, as shown using a Google Scholar search on “subjective well-being.” Eighteen years later when Shigehiro Oishi earned his Ph.D. in 2000 there were 1,640 publications that year on the topic, and when Louis Tay was awarded a Ph.D. in 2011 there were 10,400 publications about subjective well-being. Finally, in 2016 there were 18,300 publications – in that single year alone! In other words, during the time that Diener has been studying the topic, scholarship on subjective well-being has grown over 100-fold! It is not merely the number of published studies that has grown, but there have been enormous leaps forward in our understanding. In the 1980s, there were questions about the reliability and validity of subjective well-being assessments, and the components that underlie it. One notable advance is our understanding and measurement of well-being. We now know a great deal about the validity of self-report measures, as well as the core evaluative and affective components that make up subjective well-being. Further, scholars have a much greater understanding of the processes by which people report their subjective well-being, and various biases or artifacts that may influence these reports. In 1982 many studies were focused on demographic factors such as income, sex, and age that were correlated with subjective well-being. By 2016 we understood much more about temperament and other internal factors that influence happiness, as well as some of the outcomes in behavior that subjective well-being helps produce (e.g., income, performance, physical health, longevity). In the 1980s, researchers assumed that people adapt to almost any life event, and that different life events only have a short-term effect on subjective well-being. A number of large-scale longitudinal studies later showed that that is not the case. By now we know what kinds of life events affect our subjective well-being, how much, and for roughly how long. In the 1980s researchers believed that economic growth would not increase the happiness of a given nation. Now we know when economic growth tends to increase the happiness of a given nation. Additionally, we know much more about the biology of subjective well-being, and an enormous amount more about culture and well-being, a field that was almost nonexistent in 1982. With the advent of positive psychology, we are also beginning to examine practices and interventions that can raise subjective well-being. Given the broad interest in subjective well-being in multiple fields like psychology, economics, political science, and sociology, there have been important developments made toward understanding how societies differ in well-being. This understanding led to the development of national accounts of well-being – societies using well-being measures to help inform policy deliberations. This advance changes the focus of governments away from a narrow emphasis on economic development to a broader view which sees government policies as designed to raise human well-being. We were fortunate to have so many leading scholars of subjective well-being and related topics contribute to this volume. We might be slightly biased but most of the chapters in this eHandbook are truly superb. Not only do they provide a broad coverage of a large number of areas, but many of the chapters present new ways of thinking about these areas. Below is a brief overview of each of the sections in this volume: In Section 1 we begin the volume with chapters on philosophical, historical, and religious thinking on well-being through the ages. Next, we cover the methods and measures used in the scientific study of well-being. Section 2 is devoted to theories of well-being such as the top-down theory, activity theory, goal theory, self-determination theory, and evolutionary theory. Section 3 covers the personality, genetics, hormones, and neuroscience of well-being. Then, demographic factors such as age, gender, race, religion, and marital status are discussed. Section 4 is devoted to how domains of life – such as work, finance, close relationships, and leisure – are related to overall subjective well-being. Section 5 covers the various outcomes of subjective well-being, ranging from work outcomes, to cognitive outcomes, to health, and finally relationship outcomes. Section 6 covers interventions to increase subjective well-being. Finally, Section 7 is devoted to cultural, geographical, and historical variations in subjective well-being. This eHandbook presents the most up-to-date and comprehensive understanding of subjective well-being – and it is freely available to all! The editors would like to extend their thanks to several individuals who have been critical to the success of the handbook. First, our gratitude is immense toward Chris Wiese, Keya Biswas-Diener, and Danielle Geerling, who organized and kept the entire venture on track. Their hard work and organizational skills were wonderful, and the book would not have been possible without them. Second, we extend our thanks to the Diener Education Fund, a charitable organization devoted to education that in part made this project possible. In particular we express deep gratitude to Mary Alice and Frank Diener. Not only did their help make this eHandbook possible, but their lives stood as shining examples of the way to pursue well-being!https://digitalcommons.unomaha.edu/psychfacbooks/1008/thumbnail.jp

Charm-Quark Production in Deep-Inelastic Neutrino Scattering at Next-to-Next-to-Leading Order in QCD

We present a fully differential next-to-next-to-leading order calculation of charm-quark production in charged-current deep-inelastic scattering, with full charm-quark mass dependence. The next-to-next-to-leading order corrections in perturbative quantum chromodynamics are found to be comparable in size to the next-to-leading order corrections in certain kinematic regions. We compare our predictions with data on dimuon production in (anti)neutrino scattering from a heavy nucleus. Our results can be used to improve the extraction of the parton distribution function of a strange quark in the nucleon.National Natural Science Foundation (China) (Grant No. 11375013)National Natural Science Foundation (China) (Grant No. 11135003)United States. Dept. of Energy (Contract No. DE-AC02-06CH11357)United States. Dept. of Energy. Office of Nuclear Physics (U.S. DOE Contract No. DE-SC0011090

Developing a Nomogram for Predicting Colorectal Cancer and Its Precancerous Lesions Based on Data from Three Non-Invasive Screening Tools, APCS, FIT, and sDNA

Yuan Ze,1 Hui-Ming Tu,2 Yuan-Yuan Zhao,1 Lin Zhang3,4 1Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, People’s Republic of China; 2Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, 214122, People’s Republic of China; 3Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, 230026, People’s Republic of China; 4School of Population Medicine and Public Health, Peking Union Medical College/Chinese Academy of Medical Sciences, Beijing, 100053, People’s Republic of ChinaCorrespondence: Hui-Ming Tu, Department of Gastroenterology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Binhu District, Wuxi, 214122, People’s Republic of China, Tel +86-13861753621, Email [email protected] Yuan-Yuan Zhao, Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan, 250021, People’s Republic of China, Tel +86-13589097201, Email [email protected]: This study aimed to develop and validate a nomogram for predicting positive colonoscopy results using the data from non-invasive screening strategies.Methods: The volunteers participated in primary colorectal cancer (CRC) screenings using Asia-Pacific colorectal screening (APCS) scoring, faecal immunochemical testing (FIT) and stool deoxyribonucleic acid (sDNA) testing and underwent a colonoscopy. The positive colonoscopy results included CRC, advanced adenoma (AA), high-grade intraepithelial neoplasia (HGIN), and low-grade intraepithelial neoplasia (LGIN). The enrolled participants were randomly selected for training and validation sets in a 7:3 ratio. A model for predicting positive colonoscopy results was virtualized by the nomogram using logistic regression analysis.Results: Among the 179 enrolled participants, 125 were assigned to training set, while 54 were assigned to validation set. After multivariable logistic regression was done, APCS score, FIT result, and sDNA result were all identified as the predictors for positive colonoscopy results. A model that incorporated the above independent predictors was developed and presented as a nomogram. The C-index of the nomogram in the validation set was 0.768 (95% CI, 0.644– 0.891). The calibration curve demonstrated a good agreement between prediction and observation. The decision curve analysis (DCA) curve showed that the model achieved a net benefit across all threshold probabilities. The AUC of the prediction model for predicting positive colonoscopy results was much higher than that of the FIT + sDNA test scheme.Conclusion: The nomogram for predicting positive colonoscopy results was successfully developed based on 3 non-invasive screening tools (APCS scoring, FIT and sDNA test).Keywords: nomogram, colorectal cancer, primary screening, faecal immunochemical testing, stool deoxyribonucleic aci

Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene

The vascular hypothesis of Alzheimer's disease (AD) has proposed the involvement of brain hypoperfusion in AD pathogenesis, where cognitive decline and dysfunction result from dwindling cerebral blood flow (CBF). Based on the vascular hypothesis of Alzheimer's disease, we focused on exploring how genetic factors influence AD pathogenesis via the cerebrovascular system. To investigate the role of CBF endophenotypes in AD pathogenesis, we performed a targeted genetic analysis of 258 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort to examine associations between 4033 single-nucleotide polymorphisms of 24 AD genes and CBF measures in 4 brain regions. A novel association with CBF measure in the left angular gyrus was identified in an INPP5D single-nucleotide polymorphism (i.e., rs61068452; p = 1.48E-7; corrected p = 2.39E-3). The gene-based analysis discovered both INPP5D and CD2AP associated with the left angular gyrus CBF. Further analyses on nonoverlapping samples revealed that rs61068452-G was associated with lower CSF t-tau/Aβ1–42 ratio. Our findings suggest a protective role of rs61068452-G in an AD-relevant cerebrovascular endophenotype, which has the potential to provide novel insights for better mechanistic understanding of AD