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Human alveolar macrophages are critical components of the innate immune system. Cigarette smoking-induced changes in alveolar macrophage gene expression are linked to reduced resistance to pulmonary infections and to the development of emphysema/COPD. We hypothesized that microRNAs (miRNAs) could control, in part, the unique messenger RNA (mRNA) expression profiles found in alveolar macrophages of cigarette smokers. Activation of macrophages with different stimuli in vitro leads to a diverse range of M1 (inflammatory) and M2 (anti-inflammatory) polarized phenotypes that are thought to mimic activated macrophages in distinct tissue environments. Microarray mRNA data indicated that smoking promoted an \"inverse\" M1 mRNA expression program, defined by decreased expression of M1-induced transcripts and increased expression of M1-repressed transcripts with few changes in M2-regulated transcripts. RT-PCR arrays identified altered expression of many miRNAs in alveolar macrophages of smokers and a decrease in global miRNA abundance. Stratification of human subjects suggested that the magnitude of the global decrease in miRNA abundance was associated with smoking history. We found that many of the miRNAs with reduced expression in alveolar macrophages of smokers were predicted to target mRNAs upregulated in alveolar macrophages of smokers. For example, miR-452 is predicted to target the transcript encoding MMP12, an important effector of smoking-related diseases. Experimental antagonism of miR-452 in differentiated monocytic cells resulted in increased expression of MMP12. The comprehensive mRNA and miRNA expression profiles described here provide insight into gene expression regulation that may underlie the adverse effects cigarette smoking has on alveolar macrophages.

Hearing loss affects approximately one-third of adults 61 to 70 years of age and more than 80 percent of those older than 85 years. Men usually experience greater hearing loss and have earlier onset compared with women. The most common type is age-related hearing loss; however, many conditions can interfere with the conduction of sound vibrations to the inner ear and their conversion to electrical impulses for conduction to the brain. Screening for hearing loss is recommended in adults older than 50 to 60 years. Office screening tests include the whispered voice test and audioscopy. Older patients who admit to having difficulty hearing may be referred directly for audiometry. The history can identify risk factors for hearing loss, especially noise exposure and use of ototoxic medications. Examination of the auditory canal and tympanic membrane can identify causes of conductive hearing loss. Audiometric testing is required to confirm hearing loss. Adults presenting with idiopathic sudden sensorineural hearing loss should be referred for urgent assessment. Management of hearing loss is based on addressing underlying causes, especially obstructions (including cerumen) and ototoxic medications. Residual hearing should be optimized by use of hearing aids, assistive listening devices, and rehabilitation programs. Surgical implants are indicated for selected patients. Major barriers to improved hearing in older adults include lack of recognition of hearing loss; perception that hearing loss is a normal part of aging or is not amenable to treatment; and patient nonadherence with hearing aids because of stigma, cost, inconvenience, disappointing initial results, or other factors. ( Am Fam Physician. 2012;85(12):1150-1156. Copyright © 2012 American Academy of Family Physicians.)

Suspected non-Alzheimer disease pathophysiology (SNAP) is a biomarker-based concept that applies to individuals with normal levels of amyloid-β biomarkers in the brain, but in whom biomarkers of neurodegeneration are abnormal. Clinically normal and mildly impaired individuals with SNAP are at increased risk of poor clinical and cognitive outcomes. In this Perspectives article, Clifford Jack and colleagues describe the available data on SNAP and address topical controversies in the field. Suspected non-Alzheimer disease pathophysiology (SNAP) is a biomarker-based concept that applies to individuals with normal levels of amyloid-β biomarkers in the brain, but in whom biomarkers of neurodegeneration are abnormal. The term SNAP has been applied to clinically normal individuals (who do not meet criteria for either mild cognitive impairment or dementia) and to individuals with mild cognitive impairment, but is applicable to any amyloid-negative, neurodegeneration-positive individual regardless of clinical status, except when the pathology underlying neurodegeneration can be reliably inferred from the clinical presentation. SNAP is present in ∼23% of clinically normal individuals aged >65 years and in ∼25% of mildly cognitively impaired individuals. APOE* ε 4 is underrepresented in individuals with SNAP compared with amyloid-positive individuals. Clinically normal and mildly impaired individuals with SNAP have worse clinical and/or cognitive outcomes than individuals with normal levels of neurodegeneration and amyloid-β biomarkers. In this Perspectives article, we describe the available data on SNAP and address topical controversies in the field.

Marine stickleback fish have colonized and adapted to thousands of streams and lakes formed since the last ice age, providing an exceptional opportunity to characterize genomic mechanisms underlying repeated ecological adaptation in nature. Here we develop a high-quality reference genome assembly for threespine sticklebacks. By sequencing the genomes of twenty additional individuals from a global set of marine and freshwater populations, we identify a genome-wide set of loci that are consistently associated with marine–freshwater divergence. Our results indicate that reuse of globally shared standing genetic variation, including chromosomal inversions, has an important role in repeated evolution of distinct marine and freshwater sticklebacks, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. Both coding and regulatory changes occur in the set of loci underlying marine–freshwater evolution, but regulatory changes appear to predominate in this well known example of repeated adaptive evolution in nature. A reference genome sequence for threespine sticklebacks, and re-sequencing of 20 additional world-wide populations, reveals loci used repeatedly during vertebrate evolution; multiple chromosome inversions contribute to marine-freshwater divergence, and regulatory variants predominate over coding variants in this classic example of adaptive evolution in natural environments. The genomics of stickleback speciation Threespine sticklebacks have become a powerful model for studying the molecular basis of adaptive evolution. This paper presents a high-quality reference genome sequence, along with genomes of 20 further individuals from a global set of marine and freshwater populations. Genomic analysis reveals that reuse of globally shared standing genetic variation plays an important part in repeated evolution of distinct stickleback populations, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. The data are consistent with an important role for regulatory changes during parallel evolution of marine and freshwater sticklebacks.

In this Series paper, we review trends since the 2005 Lancet Series on Neonatal Survival to inform acceleration of progress for newborn health post-2015. On the basis of multicountry analyses and multi-stakeholder consultations, we propose national targets for 2035 of no more than 10 stillbirths per 1000 total births, and no more than 10 neonatal deaths per 1000 livebirths, compatible with the under-5 mortality targets of no more than 20 per 1000 livebirths. We also give targets for 2030. Reduction of neonatal mortality has been slower than that for maternal and child (1–59 months) mortality, slowest in the highest burden countries, especially in Africa, and reduction is even slower for stillbirth rates. Birth is the time of highest risk, when more than 40% of maternal deaths (total about 290 000) and stillbirths or neonatal deaths (5·5 million) occur every year. These deaths happen rapidly, needing a rapid response by health-care workers. The 2·9 million annual neonatal deaths worldwide are attributable to three main causes: infections (0·6 million), intrapartum conditions (0·7 million), and preterm birth complications (1·0 million). Boys have a higher biological risk of neonatal death, but girls often have a higher social risk. Small size at birth—due to preterm birth or small-for-gestational-age (SGA), or both—is the biggest risk factor for more than 80% of neonatal deaths and increases risk of post-neonatal mortality, growth failure, and adult-onset non-communicable diseases. South Asia has the highest SGA rates and sub-Saharan Africa has the highest preterm birth rates. Babies who are term SGA low birthweight (10·4 million in these regions) are at risk of stunting and adult-onset metabolic conditions. 15 million preterm births, especially of those younger than 32 weeks' gestation, are at the highest risk of neonatal death, with ongoing post-neonatal mortality risk, and important risk of long-term neurodevelopmental impairment, stunting, and non-communicable conditions. 4 million neonates annually have other life-threatening or disabling conditions including intrapartum-related brain injury, severe bacterial infections, or pathological jaundice. Half of the world's newborn babies do not get a birth certificate, and most neonatal deaths and almost all stillbirths have no death certificate. To count deaths is crucial to change them. Failure to improve birth outcomes by 2035 will result in an estimated 116 million deaths, 99 million survivors with disability or lost development potential, and millions of adults at increased risk of non-communicable diseases after low birthweight. In the post-2015 era, improvements in child survival, development, and human capital depend on ensuring a healthy start for every newborn baby—the citizens and workforce of the future.

Most cellular processes are carried out by multiprotein complexes. The identification and analysis of their components provides insight into how the ensemble of expressed proteins (proteome) is organized into functional units. We used tandem-affinity purification (TAP) and mass spectrometry in a large-scale approach to characterize multiprotein complexes in Saccharomyces cerevisiae. We processed 1,739 genes, including 1,143 human orthologues of relevance to human biology, and purified 589 protein assemblies. Bioinformatic analysis of these assemblies defined 232 distinct multiprotein complexes and proposed new cellular roles for 344 proteins, including 231 proteins with no previous functional annotation. Comparison of yeast and human complexes showed that conservation across species extends from single proteins to their molecular environment. Our analysis provides an outline of the eukaryotic proteome as a network of protein complexes at a level of organization beyond binary interactions. This higher-order map contains fundamental biological information and offers the context for a more reasoned and informed approach to drug discovery.

Advancements in methods, technology, and our understanding of the pathobiology of lung injury have created the need to update the definition of experimental acute lung injury (ALI). We queried 50 participants with expertise in ALI and acute respiratory distress syndrome using a Delphi method composed of a series of electronic surveys and a virtual workshop. We propose that ALI presents as a “multidimensional entity” characterized by four “domains” that reflect the key pathophysiologic features and underlying biology of human acute respiratory distress syndrome. These domains are 1) histological evidence of tissue injury, 2) alteration of the alveolar–capillary barrier, 3) presence of an inflammatory response, and 4) physiologic dysfunction. For each domain, we present “relevant measurements,” defined as those proposed by at least 30% of respondents. We propose that experimental ALI encompasses a continuum of models ranging from those focusing on gaining specific mechanistic insights to those primarily concerned with preclinical testing of novel therapeutics or interventions. We suggest that mechanistic studies may justifiably focus on a single domain of lung injury, but models must document alterations of at least three of the four domains to qualify as “experimental ALI.” Finally, we propose that a time criterion defining “acute” in ALI remains relevant, but the actual time may vary based on the specific model and the aspect of injury being modeled. The continuum concept of ALI increases the flexibility and applicability of the definition to multiple models while increasing the likelihood of translating preclinical findings to critically ill patients.

Though clinically similar, Ebola virus disease and Marburg virus disease are caused by different viruses. Of the 30 documented outbreaks of these diseases in sub-Saharan Africa, eight were major outbreaks ([greater than or equal to]200 cases; five caused by Zaire ebolavirus [EBOV], two by Sudan ebolavirus [SUDV], and one by Marburg virus [MARV]). Our purpose is to develop a multivalent vaccine regimen protecting against each of these filoviruses. This first-in-human study assessed the safety and immunogenicity of several multivalent two-dose vaccine regimens that contain Ad26.Filo and MVA-BN-Filo. Ad26.Filo combines three vaccines encoding the glycoprotein (GP) of EBOV, SUDV, and MARV. MVA-BN-Filo is a multivalent vector encoding EBOV, SUDV, and MARV GPs, and Taï Forest nucleoprotein. This Phase 1, randomized, double-blind, placebo-controlled study enrolled healthy adults (18-50 years) into four groups, randomized 5:1 (active:placebo), to assess different Ad26.Filo and MVA-BN-Filo vaccine directionality and administration intervals. The primary endpoint was safety; immune responses against EBOV, SUDV, and MARV GPs were also assessed. Seventy-two participants were randomized, and 60 (83.3%) completed the study. All regimens were well tolerated with no deaths or vaccine-related serious adverse events (AEs). The most frequently reported solicited local AE was injection site pain/tenderness. Solicited systemic AEs most frequently reported were headache, fatigue, chills, and myalgia; most solicited AEs were Grade 1-2. Solicited/unsolicited AE profiles were similar between regimens. Twenty-one days post-dose 2, 100% of participants on active regimen responded to vaccination and exhibited binding antibodies against EBOV, SUDV, and MARV GPs; neutralizing antibody responses were robust against EBOV (85.7-100%), but lower against SUDV (35.7-100%) and MARV (0-57.1%) GPs. An Ad26.Filo booster induced a rapid further increase in humoral responses. This study demonstrates that heterologous two-dose vaccine regimens with Ad26.Filo and MVA-BN-Filo are well tolerated and immunogenic in healthy adults.

Guillain-Barré syndrome consists of a group of neuropathic conditions characterized by progressive weakness and diminished or absent myotatic reflexes. The estimated annual incidence in the United States is 1.65 to 1.79 per 100,000 persons. Guillain-Barré syndrome is believed to result from an aberrant immune response that attacks nerve tissue. This response may be triggered by surgery, immunizations, or infections. The most common form of the disease, acute inflammatory demyelinating polyradiculoneuropathy, presents as progressive motor weakness, usually beginning in the legs and advancing proximally. Symptoms typically peak within four weeks, then plateau before resolving. More than one-half of patients experience severe pain, and about two-thirds have autonomic symptoms, such as cardiac arrhythmias, blood pressure instability, or urinary retention. Advancing symptoms may compromise respiration and vital functions. Diagnosis is based on clinical features, cerebrospinal fluid testing, and nerve conduction studies. Cerebrospinal fluid testing shows increased protein levels but a normal white blood cell count. Nerve conduction studies show a slowing, or possible blockage, of conduction. Patients should be hospitalized for multidisciplinary supportive care and disease-modifying therapy. Supportive therapy includes controlling pain with nonsteroidal anti-inflammatory drugs, carbamazepine, or gabapentin; monitoring for respiratory and autonomic complications; and preventing venous thrombosis, skin breakdown, and deconditioning. Plasma exchange therapy has been shown to improve short-term and long-term outcomes, and intravenous immune globulin has been shown to hasten recovery in adults and children. Other therapies, including corticosteroids, have not demonstrated benefit. About 3 percent of patients with Guillain-Barré syndrome die. Neurologic problems persist in up to 20 percent of patients with the disease, and one-half of these patients are severely disabled.