RNA-binding proteins in regulation of alternative cleavage and polyadenylation.

Almost all eukaryotic pre-mRNAs are processed at the 3' end by the cleavage and polyadenylation (C/P) reaction, which preludes termination of transcription and gives rise to the poly(A) tail of mature mRNA. Genomic studies in recent years have indicated that most eukaryotic mRNA genes have multiple cleavage and polyadenylation sites (pAs), leading to alternative cleavage and polyadenylation (APA) products. APA isoforms generally differ in their 3' untranslated regions (3' UTRs), but can also have different coding sequences (CDSs).

The Simplified Acute Physiology Score III Is Superior to the Simplified Acute Physiology Score II and Acute Physiology and Chronic Health Evaluation II in Predicting Surgical and ICU Mortality in the "Oldest Old".

Elderly patients in the USA account for 26-50% of all intensive care unit (ICU) admissions. The applicability of validated ICU scoring systems to predict outcomes in the "Oldest Old" is poorly documented. We evaluated the utility of three commonly used ICU scoring systems (SAPS II, SAPS III, and APACHE II) to predict clinical outcomes in patients > 90 years.

Accurate mapping of cleavage and polyadenylation sites by 3' region extraction and deep sequencing.

Deep sequencing of RNA (RNA-seq) is becoming a standard method to study gene expression. While RNA-seq reads cover most regions of an mRNA sequence, they are often depleted in the 3' end region, making them less amenable for mapping the cleavage and polyadenylation site (pA). A major problem in identification of pA is mispriming at internal A-rich regions and oligo(A) tails when an oligo(dT) primer is used for reverse transcription or sequencing.

Growth-inhibitory activity of natural and synthetic isothiocyanates against representative human microbial pathogens.

Aims: The aim of this study was to test the growth inhibition activity of isothiocyanates (ITCs), defence compounds of plants, against common human microbial pathogens.

Methods And Results: In this study, we have tested the growth-inhibitory activity of a diverse collection of new and previously known representative ITCs of various structural classes against pathogenic bacteria, fungi and moulds by a serial dilution method. Generally, the compounds were more active against Gram-positive bacteria and fungi exhibiting species-specific bacteriostatic or bactericidal effect.

Posterior spinal fusion in children with flaccid neuromuscular scoliosis: the role of noninvasive positive pressure ventilatory support.

Background: Noninvasive intermittent positive pressure ventilatory assistance/support (NIV) can permit long-term survival for patients with no autonomous ability to breathe. Its role was explored in the perioperative management of children with flaccid neuromuscular scoliosis.

Methods: Vital capacity (VC), peak cough flow, and the extent of ventilator dependence were documented before and after surgical correction of scoliosis for children with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) with VCs as low as 2%.

Molecular immunologic correlates of spontaneous latency in a rabbit model of pulmonary tuberculosis.

Background: Infection of humans with Mycobacterium tuberculosis (Mtb) results in latent tuberculosis infection (LTBI) in 90-95% of immune competent individuals, with no symptoms of active disease. The World Health Organization estimates that 1.5 billion people have LTBI, which can reactivate in the setting of waning host immunity, posing a threat to global TB control.

Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib.

Diabetes mellitus (DM) and hypercholesterolemia (HC) have emerged as major risk factors for Alzheimer's disease, highlighting the importance of vascular health to normal brain functioning. Our previous study showed that DM and HC favor the development of advanced coronary atherosclerosis in a porcine model, and that treatment with darapladib, an inhibitor of lipoprotein-associated phospholipase A2, blocks atherosclerosis progression and improves animal alertness and activity levels. In the present study, we examined the effects of DM and HC on the permeability of the blood-brain barrier (BBB) using immunoglobulin G (IgG) as a biomarker.

Antidepressant-selective gynecomastia.

Objective: To describe what we believe is the first reported case of synergistic gynecomastia during treatment of depressive and anxiety disorders when sertraline was added to a stable medication regimen including duloxetine, rosuvastatin, and amlodipine.

Case Summary: A 67-year-old male with major depression, dysthymia, obsessive-compulsive disorder, social anxiety, hypertension, diabetes, and hyperlipidemia presented with new-onset gynecomastia and breast tenderness. Mammography revealed bilateral gynecomastia (fibroglandular tissue posterior to the nipples bilaterally) without suspicious mass, calcification, or other abnormalities.

Analysis of alternative cleavage and polyadenylation by 3' region extraction and deep sequencing.

Alternative cleavage and polyadenylation (APA) generates diverse mRNA isoforms. We developed 3' region extraction and deep sequencing (3'READS) to address mispriming issues that commonly plague poly(A) site (pA) identification, and we used the method to comprehensively map pAs in the mouse genome. Thorough annotation of gene 3' ends revealed over 5,000 previously overlooked pAs (∼8% of total) flanked by A-rich sequences, underscoring the necessity of using an accurate tool for pA mapping.

Nicotine intake and smoking topography in smokers with bipolar disorder.

Objectives: Cigarette smoking behavior in bipolar disorder (BPD), including the effects of mood-stabilizing medications, has not been well characterized.

Methods: We compared serum nicotine, nicotine metabolite levels, and smoking topography in 75 smokers with BPD to 86 control smokers (CON). For some comparisons, an additional control group of 75 smokers with schizophrenia (SCZ) were included.

Exposures to volatile organic compounds (VOCs) and associated health risks of socio-economically disadvantaged population in a "hot spot" in Camden, New Jersey.

To address disparities in health risks associated with ambient air pollution for racial/ethnic minority groups, this study characterized personal and ambient concentrations of volatile organic compounds (VOCs) in a suspected hot spot of air pollution - the Village of Waterfront South (WFS), and an urban reference community - the Copewood/Davis Streets (CDS) neighborhood in Camden, New Jersey. Both are minority-dominant, impoverished communities. We collected 24-h integrated personal air samples from 54 WFS residents and 53 CDS residents, with one sample on a weekday and one on a weekend day during the summer and winter seasons of 2004-2006.

Associations between quantitative measures of fungi in home floor dust and lung function among older adults with chronic respiratory disease: a pilot study.

Objective: Many fungi may cause allergic reactions and increase asthma symptoms prevalence and severity. One susceptible, vulnerable population subgroup of increasing size in industrialized countries and of public health concern who spends the majority of their time at home is older adults. Older adults diagnosed with chronic obstructive pulmonary disease (COPD) are at risk of exposure to fungi.

Chronic pulmonary cavitary tuberculosis in rabbits: a failed host immune response.

The molecular determinants of the immune response to Mycobacterium tuberculosis HN878 infection in a rabbit model of pulmonary cavitary tuberculosis were studied. Aerosol infection of rabbits resulted in a highly differentially expressed global transcriptome in the lungs at 2 weeks, which dropped at 4 weeks and then gradually increased. While IFNγ was progressively upregulated throughout the infection, several other genes in the IFNγ network were not.

Management of cartilage defects in the shoulder.

Articular cartilage lesions of the glenohumeral joint are an especially difficult clinical problem to manage, particularly in the younger, more active patient. Left untreated, these lesions may progress in the long-term, leading to further pain and disability. While shoulder arthroplasty remains a viable option in older patients with glenohumeral arthritis, concerns over component longevity and loosening in younger patients make it less attractive in that age group.

Neuronal PAD4 expression and protein citrullination: possible role in production of autoantibodies associated with neurodegenerative disease.

Peptidyl arginine deiminases (PADs) catalyze a post-translational protein modification reaction called citrullination, where arginine is converted to citrulline. This modification has been linked to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA). More recently, several studies have suggested that Alzheimer's disease (AD), a devastating neurodegenerative disorder, may have an autoimmune component.

Internucleosomal interactions mediated by histone tails allow distant communication in chromatin.

Action across long distances on chromatin is a hallmark of eukaryotic transcriptional regulation. Although chromatin structure per se can support long-range interactions, the mechanisms of efficient communication between widely spaced DNA modules in chromatin remain a mystery. The molecular simulations described herein suggest that transient binary internucleosomal interactions can mediate distant communication in chromatin.

Effectiveness of structured discharge process in reducing hospital readmission of adult patients with community acquired pneumonia: A systematic review.

Background: Hospital readmission soon after discharge is common and costly. To date, published studies of effectiveness of structured discharge process addressing reduction of hospital readmission have focused on patients with chronic conditions and complex needs, but not in adult patients with community acquired pneumonia.

Objectives: To examine and synthesise the best available evidence related to effectiveness of structured discharge process in reducing hospital readmission of adult patients with community acquired pneumonia.

Hemobilia Secondary to Transjugular Intrahepatic Portosystemic Shunt Procedure: A Case Report.

A 59 year-old woman with liver cirrhosis due to hepatitis C, complicated by refractory hepatic hydrothorax was treated with a TIPS (transjugular intrahepatic portosystemic shunt) procedure. The procedure was complicated by substantial gastrointestinal hemorrhage. EGD (esophagogastroduodenoscopy) was performed and revealed hemobilia.

Disrupted membrane structure and intracellular Ca²⁺ signaling in adult skeletal muscle with acute knockdown of Bin1.

Efficient intracellular Ca²⁺ ([Ca²⁺]i) homeostasis in skeletal muscle requires intact triad junctional complexes comprised of t-tubule invaginations of plasma membrane and terminal cisternae of sarcoplasmic reticulum. Bin1 consists of a specialized BAR domain that is associated with t-tubule development in skeletal muscle and involved in tethering the dihydropyridine receptors (DHPR) to the t-tubule. Here, we show that Bin1 is important for Ca²⁺ homeostasis in adult skeletal muscle.

Computational design of thermostabilizing D-amino acid substitutions.

Judicious incorporation of D-amino acids in engineered proteins confers many advantages such as preventing degradation by endogenous proteases and promoting novel structures and functions not accessible to homochiral polypeptides. Glycine to D-alanine substitutions at the carboxy termini can stabilize α-helices by reducing conformational entropy. Beyond alanine, we propose additional side chain effects on the degree of stabilization conferred by D-amino acid substitutions.

Phosphodiesterase-4 inhibition alters gene expression and improves isoniazid-mediated clearance of Mycobacterium tuberculosis in rabbit lungs.

Tuberculosis (TB) treatment is hampered by the long duration of antibiotic therapy required to achieve cure. This indolent response has been partly attributed to the ability of subpopulations of less metabolically active Mycobacterium tuberculosis (Mtb) to withstand killing by current anti-TB drugs. We have used immune modulation with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, that reduces tumor necrosis factor alpha (TNF-α) production by increasing intracellular cAMP in macrophages, to examine the crosstalk between host and pathogen in rabbits with pulmonary TB during treatment with isoniazid (INH).