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

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

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

Causality in Non-Commutative Quantum Field Theories

We study causality in non-commutative quantum field theory with a space-space non-commutativity. We employ the S-operator approach of Bogoliubov-Shirkov(BS). We generalize the BS criterion of causality to the noncommutative theory. The criterion to test causality leads to a nonzero difference between T*-product and T-product as a condition of causality violation for a spacelike separation. We discuss two examples; one in a scalar theory and one in the Yukawa theory. In particular, in the context of a non-commutative Yukawa theory, with the interaction Lagrangian $\bar{\psi}(x)\star\psi(x)\star\phi(x)$, is observed to be causality violating even in case of space-space noncommutativity for which \theta^{0i}=0. \Comment: 18 pages, LaTeX; A few changes in sections 3.2,3.3 and

Association of PON2 Gene Polymorphisms (Ser311Cys and Ala148Gly) With the Risk of Developing Type 2 Diabetes Mellitus in the Chinese Population

Background: The association between paraoxonase 2 (PON2) gene polymorphisms and type 2 diabetes mellitus (T2DM) has been extensively investigated in the Chinese population with conflicting results. In this study, we systematically evaluated the association between PON2 Ser311Cys and Ala148Gly polymorphisms and T2DM risk by pooling all relevant studies.Methods: We searched PubMed, Embase, CNKI, and Wanfang databases for the studies. The strength of association was determined by the allelic, homozygous, heterozygous, recessive, and dominant genetic models and measured as odds ratio (OR) and 95% confidence interval (CI), under fixed- or random-effect models.Results: There was no significant association between PON2 Ser311Cys polymorphism and T2DM under any of the genetic models: allelic (OR = 1.06, 95% CI = 0.77–1.45; P = 0.721), heterozygous (OR = 1.13, 95% CI = 0.87–1.45; P = 0.362), dominant (OR = 1.10, 95% CI = 0.80–1.51; P = 0.562), recessive (OR = 0.87, 95% CI = 0.48–1.58; P = 0.648), homozygous (OR = 0.94, 95% CI = 0.47–1.89; P = 0.865). Similarly, no significant association was found in PON2 Arg148Gly polymorphism under any of the models: allelic (OR = 1.17, 95% CI = 0.91–1.50; P = 0.218), heterozygous (OR = 1.28, 95% CI = 0.94–1.74; P = 0.117), dominant (OR = 1.25, 95% CI = 0.93–1.67; P = 0.142), recessive (OR = 0.99, 95% CI = 0.52–1.88; P = 0.973), homozygous (OR = 1.08, 95% CI = 0.57–2.07; P = 0.808).Conclusions: The PON2 Ser311Cys and Ala148Gly polymorphisms were not associated with the risk of developing T2DM in the Chinese population