抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Chronic obstructive pulmonary disease (COPD) remains a major public health problem. It is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide, according to a study published by the World Bank/World Health Organization. Yet, COPD remains relatively unknown or ignored by the public as well as public health and government officials. In 1998, in an effort to bring more attention to COPD, its management, and its prevention, a committed group of scientists encouraged the U.S. National Heart, Lung, and Blood Institute and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Among the important objectives of GOLD are to increase awareness of COPD and to help the millions of people who suffer from this disease and die prematurely of it or its complications. The first step in the GOLD program was to prepare a consensus report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, published in 2001. The present, newly revised document follows the same format as the original consensus report, but has been updated to reflect the many publications on COPD that have appeared. GOLD national leaders, a network of international experts, have initiated investigations of the causes and prevalence of COPD in their countries, and developed innovative approaches for the dissemination and implementation of COPD management guidelines. We appreciate the enormous amount of work the GOLD national leaders have done on behalf of their patients with COPD. Despite the achievements in the 5 years since the GOLD report was originally published, considerable additional work is ahead of us if we are to control this major public health problem. The GOLD initiative will continue to bring COPD to the attention of governments, public health officials, health care workers, and the general public, but a concerted effort by all involved in health care will be necessary.

https://www.who.int/respiratory/copd/GOLD_WR_06.pdf

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.

XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

Efforts to understand and mitigate the health effects of particulate matter (PM) air pollution have a rich and interesting history. This review focuses on six substantial lines of research that have been pursued since 1997 that have helped elucidate our understanding about the effects of PM on human health. There has been substantial progress in the evaluation of PM health effects at different time-scales of exposure and in the exploration of the shape of the concentration-response function. There has also been emerging evidence of PM-related cardiovascular health effects and growing knowledge regarding interconnected general pathophysiological pathways that link PM exposure with cardiopulmonary morbidity and mortality. Despite important gaps in scientific knowledge and continued reasons for some skepticism, a comprehensive evaluation of the research findings provides persuasive evidence that exposure to fine particulate air pollution has adverse effects on cardiopulmonary health. Although much of this research has been motivated by environmental public health policy, these results have important scientific, medical, and public health implications that are broader than debates over legally mandated air quality standards.

/pdf/health-effects-of-fine-particulate-air-pollution-lines-that-s831sp8jap.pdf

Health effects of fine particulate air pollution: lines that connect

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

29 – Sex, Gender, and Chronic Obstructive Pulmonary Disease

The interplay among microRNAs (miRNAs) plays an important role in the developments of complex human diseases. Co-expression networks can characterize the interactions among miRNAs. Differential correlation network is a powerful tool to investigate the differences of co-expression networks between cases and controls. To construct a differential correlation network, the Fisher9s Z-transformation test is usually used. However, the Fisher9s Z-transformation test requires the normality assumption, the violation of which would result in inflated Type I error rate. Several bootstrapping-based improvements for Fisher9s Z test have been proposed. However, these methods are too computationally intensive to be used to construct differential correlation networks for high-throughput genomic data. In this article, we proposed six novel robust equal-correlation tests that are computationally efficient. The systematic simulation studies and a real microRNA data analysis showed that one of the six proposed tests (ST5) overall performed better than other methods.

/pdf/new-statistical-methods-for-constructing-robust-differential-3taeau9qmv.pdf

New Statistical Methods for Constructing Robust Differential Correlation Networks

Scanning the genome for the sequence patterns defined by Position Weight Matrices (PWM) is commonly used to estimate transcription factor (TF) binding “motif” locations. However, the PWM-based scores assigned to these inferred locations are associated with only modest accuracy when benchmarked against in vivo TF binding. One reason for this limited performance may be because PWMs do not incorporate information regarding the epigenetic context necessary for TF binding. To investigate this, we developed a framework to score inferred TF binding locations using CpG methylation data. We intersected motif locations identified using PWMs with methylation information captured in both whole genome bisulfite sequencing and Illumina EPIC array data for six cell lines, scored motif locations based on these data, and compared with experimental data characterizing TF binding (ChIP-seq). We found that, for most TFs, binding is better predicted using methylation-based scoring compared to standard PWM scores. In addition, our analysis shows that, while most TFs do not bind to methylated promoter regions, there are several exceptions to this rule, indicating that the role of methylation in TF binding may be cell-type and context specific. Finally, we also illustrate that our approach can be generalized to infer TF binding when methylation information is only proximally available, i.e. measured for nearby CpGs that do not directly overlap with a motif location. Overall, our approach provides a framework for inferring context specific TF binding using methylation data, a crucial initial step for understanding the impact of methylation on gene regulatory processes.

Using methylation data to improve transcription factor binding prediction

Significant sex differences are observed in colon cancer, and understanding these differences is essential to advance disease prevention, diagnosis, and treatment. Males have a higher risk of developing colon cancer and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood. We used both transcript-based and gene regulatory network methods to analyze RNA-Seq data from The Cancer Genome Atlas for 445 patients with colon cancer. We compared gene expression between tumors in men and women and found no significant sex differences except for sex-chromosome genes. We then inferred patient-specific gene regulatory networks, and found significant regulatory differences between males and females, with drug and xenobiotics metabolism via cytochrome P450 pathways more strongly targeted in females. This finding was validated in a dataset that included 1,193 patients from five independent studies. While targeting of the drug metabolism pathway did not change the overall survival for males treated with adjuvant chemotherapy, females with greater targeting had an increase in 10-year overall survival probability, with 89% (95% CI: 78%-100%) survival compared to 61% (95% CI: 45%-82%) for women with lower targeting, respectively (p=0.034). Our network analysis uncovered patterns of transcriptional regulation that differentiate male and female colon cancer. Most importantly, targeting of the drug metabolism pathway was predictive of survival in women who received adjuvant chemotherapy. This network-based approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases.

https://www.biorxiv.org/content/biorxiv/early/2018/03/07/277186.full.pdf

Gene regulatory network analysis identifies sex-linked differences in colon cancer drug metabolism processes

Inflammatory Protein Biomarkers in COPD Subjects with and without Alpha-1 Antitrypsin Deficiency

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