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1.  A spatial covariance 123I-5IA-85380 SPECT study of α4β2 nicotinic receptors in Alzheimer's disease 
Neurobiology of Aging  2016;47:83-90.
Alzheimer's disease (AD) is characterized by widespread degeneration of cholinergic neurons, particularly in the basal forebrain. However, the pattern of these deficits and relationship with known brain networks is unknown. In this study, we sought to clarify this and used 123I-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (1235IA-85380) single photon emission computed tomography to investigate spatial covariance of α4β2 nicotinic acetylcholine receptors in AD and healthy controls. Thirteen AD and 16 controls underwent 1235IA-85380 and regional cerebral blood flow (99mTc-exametazime) single photon emission computed tomography scanning. We applied voxel principal component (PC) analysis, generating series of principal component images representing common intercorrelated voxels across subjects. Linear regression generated specific α4β2 and regional cerebral blood flow covariance patterns that differentiated AD from controls. The α4β2 pattern showed relative decreased uptake in numerous brain regions implicating several networks including default mode, salience, and Papez hubs. Thus, as well as basal forebrain and brainstem cholinergic system dysfunction, cholinergic deficits mediated through nicotinic acetylcholine receptors could be evident within key networks in AD. These findings may be important for the pathophysiology of AD and its associated cognitive and behavioral phenotypes.
PMCID: PMC5082764  PMID: 27565302
Alzheimer's disease; Cholinergic; Acetylcholine; Nicotinic; Spatial covariance; SPECT
2.  Obesity associated with increased brain age from midlife 
Neurobiology of Aging  2016;47:63-70.
Common mechanisms in aging and obesity are hypothesized to increase susceptibility to neurodegeneration, however, direct evidence in support of this hypothesis is lacking. We therefore performed a cross-sectional analysis of magnetic resonance image-based brain structure on a population-based cohort of healthy adults. Study participants were originally part of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) and included 527 individuals aged 20–87 years. Cortical reconstruction techniques were used to generate measures of whole-brain cerebral white-matter volume, cortical thickness, and surface area. Results indicated that cerebral white-matter volume in overweight and obese individuals was associated with a greater degree of atrophy, with maximal effects in middle-age corresponding to an estimated increase of brain age of 10 years. There were no similar body mass index-related changes in cortical parameters. This study suggests that at a population level, obesity may increase the risk of neurodegeneration.
PMCID: PMC5082766  PMID: 27562529
Obesity; White-matter volume; Structural MRI; Population-based
3.  Auditory perception in the aging brain: the role of inhibition and facilitation in early processing 
Neurobiology of Aging  2016;47:23-34.
Aging affects the interplay between peripheral and cortical auditory processing. Previous studies have demonstrated that older adults are less able to regulate afferent sensory information and are more sensitive to distracting information. Using auditory event-related potentials we investigated the role of cortical inhibition on auditory and audiovisual processing in younger and older adults. Across puretone, auditory and audiovisual speech paradigms older adults showed a consistent pattern of inhibitory deficits, manifested as increased P50 and/or N1 amplitudes and an absent or significantly reduced N2. Older adults were still able to use congruent visual articulatory information to aid auditory processing but appeared to require greater neural effort to resolve conflicts generated by incongruent visual information. In combination, the results provide support for the Inhibitory Deficit Hypothesis of aging. They extend previous findings into the audiovisual domain and highlight older adults' ability to benefit from congruent visual information during speech processing.
PMCID: PMC5082767  PMID: 27522518
Aging; Auditory event-related potentials; Inhibition; Speech; Audio-visual; N2; P3a
4.  Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis 
Neurobiology of Aging  2016;47:218.e1-218.e9.
Genetic factors have been suggested to be involved in the pathogenesis of sporadic inclusion body myositis (sIBM). Sequestosome 1 (SQSTM1) and valosin-containing protein (VCP) are 2 key genes associated with several neurodegenerative disorders but have yet to be thoroughly investigated in sIBM. A candidate gene analysis was conducted using whole-exome sequencing data from 181 sIBM patients, and whole-transcriptome expression analysis was performed in patients with genetic variants of interest. We identified 6 rare missense variants in the SQSTM1 and VCP in 7 sIBM patients (4.0%). Two variants, the SQSTM1 p.G194R and the VCP p.R159C, were significantly overrepresented in this sIBM cohort compared with controls. Five of these variants had been previously reported in patients with degenerative diseases. The messenger RNA levels of major histocompatibility complex genes were upregulated, this elevation being more pronounced in SQSTM1 patient group. We report for the first time potentially pathogenic SQSTM1 variants and expand the spectrum of VCP variants in sIBM. These data suggest that defects in neurodegenerative pathways may confer genetic susceptibility to sIBM and reinforce the mechanistic overlap in these neurodegenerative disorders.
PMCID: PMC5082791  PMID: 27594680
Sporadic inclusion body myositis; sIBM; SQSTM1; VCP; Genetic risk factor
5.  Randomized Trial of Mediastinal Lymph Node Sampling Versus Complete Lymphadenectomy During Pulmonary Resection in the Patient with N0 or N1 (Less Than Hilar) Non-Small Cell Carcinoma: Results of the ACOSOG Z0030 Trial 
To determine if mediastinal lymph node dissection (MLND) improves survival compared to mediastinal lymph node sampling (MLNS) in patients undergoing resection for N0 or non-hilar N1, T1 or T2 non-small cell lung cancer (NSCLC).
Patients with NSCLC underwent sampling of 2R, 4R, 7 and 10R for right sided tumors, and 5, 6, 7 and 10L for left sided tumors. If all were negative for malignancy, patients were randomized to no further lymph node sampling (MLNS) or complete MLND.
Of 1,111 patients randomized, 1,023 (498 MLNS, 525 MLND) were eligible/evaluable. There were no significant differences between the two groups in terms of demographics, ECOG status, histology, location of the cancer, type or extent of resection, or pathological stage. Occult N2 disease was found in 21 patients in the MLND group. At median follow-up of 6.5 years, 435 (43%) patients have died; (MLNS: 217 (44%);MLND:218 (42%)). The median survival for MLNS is8.1 years, and 8.5 years for MLND (p=0.25). The 5-year disease free survival rate was 69% (95% CI: 64%-74%) in the MLNS group versus 68%(95% CI: 64%-73%) years in the MLND group (p=0.92). There was no difference for local (p=0.52), regional (p=0.10), or distant (p=0.76) recurrence between the two groups.
If systematic, thorough presection sampling of the mediastinal and hilar lymph nodes is negative, MLND does not improve survival in patients with early stage NSCLC but these results are not generalizable to patients staged radiographically or those with higher stage tumors.
PMCID: PMC5082844  PMID: 21335122
Lung Cancer; lymph nodes; mediastinum; staging; randomized controlled trial
6.  Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study 
The Lancet. Respiratory medicine  2014;2(11):891-901.
Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10–20% of patients. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD.
We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40–85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3·0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomisation (block size of four), with an interactive voice or web-response system, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. Study site personnel included in study assessments, participants, and data analysts, were masked to treatment allocation. The primary endpoint was the annualised rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint George’s Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardised format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. We did a prespecified subgroup analysis by baseline blood eosinophil count. Analyses were by intention to treat and per-protocol. This trial is registered with, number NCT01227278.
We randomly assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus included 82 patients. Benralizumab did not reduce the annualised rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0·95 (0·68–1·29; n=40) versus 0·92 (0·67–1·25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was −0·06 L (SD 0·24) with placebo, and 0·13 L (0·41) with benralizumab (p=0·014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per µL or more or 300 cells per µL or more. Incidence of treatment-emergent adverse events was similar between the two groups, with the most common events being respiratory disorders (31 [62%] of 50 patients given placebo vs 32 [63%] of 51 given benralizumab) and infections (28 [56%] vs 27 [53%]). A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related.
Compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, the results of prespecified subgroup analysis support further investigation of benralizumab in patients with COPD and eosinophilia.
PMCID: PMC5082845  PMID: 25208464
7.  Knowledge and Perceptions of Overweight Employees about Lifestyle-Related Health Benefit Changes 
North Carolina medical journal  2011;72(3):183-190.
We investigated overweight state employees’ perceptions about health insurance benefit changes designed to reduce the scope of health benefits for employees who were obese or smoked.
Prior to implementation of health benefit plan changes, 658 overweight [body mass index (BMI) ≥25 kg/m2] state employees enrolled in a weight loss intervention study were asked about their attitudes and beliefs of the new benefit plan changes.
Thirty-one percent of employees with a BMI≥40 kg/ m2 were unaware that their current BMI would place them in a higher risk benefit plan. More than half reported that the new benefit change would motivate them to make behavioral changes, but less than half felt confident in making changes. Respondents with a BMI≥40 kg/m2 were more likely to oppose the new changes focused on BMI categories compared to respondents in lower BMI categories (P<0.0001). Current smokers were more likely to oppose the new benefit change focused on tobacco use than former smokers and non-smokers (P<0.01).
Participants represented a sample of employees enrolled in a weight loss study, limiting generalizability to the larger population of state employees.
Benefit plan changes that require employees who are obese or smoke to pay more for health care may motivate some, but not all, individuals to change their behaviors. Since confidence to lose weight was lowest among those in the highest weight categories, health plan benefit modifications may be required to achieve desired health behavior changes.
PMCID: PMC5082972  PMID: 21901911
Workplace health promotion; Health benefits; Smoking; Obesity; Policy change
8.  Mortality Among Persons With Obsessive-Compulsive Disorder in Denmark 
JAMA psychiatry  2016;73(3):268-274.
Several mental disorders have consistently been found to be associated with decreased life expectancy, but little is known about whether this is also the case for obsessive-compulsive disorder (OCD).
To determine whether persons who receive a diagnosis of OCD are at increased risk of death.
Using data from Danish registers, we conducted a nationwide prospective cohort study with 30 million person-years of follow-up. The data were collected from Danish longitudinal registers. A total of 3 million people born between 1955 and 2006 were followed up from January 1, 2002, through December 31, 2011. During this period, 27 236 people died. The data were analyzed primarily in June 2015.
We estimated mortality rate ratios (MRRs), adjusted for calendar year, age, sex, maternal and paternal age, place of residence at birth, and somatic comorbidities, to compare persons with OCT with persons without OCD.
Of 10 155 persons with OCD (5935 women and 4220 men with a mean [SD] age of 29.1 [11.3] years who contributed a total of 54 937 person-years of observation), 110 (1.1%) died during the average follow-up of 9.7 years. The risk of death by natural or unnatural causes was significantly higher among persons with OCD (MRR, 1.68 [95% CI, 1.31–2.12] for natural causes; MRR, 2.61 [95% CI, 1.91–3.47] for unnatural causes) than among the general population. After the exclusion of persons with comorbid anxiety disorders, depression, or substance use disorders, OCD was still associated with increased mortality risk (MRR, 1.88 [95% CI, 1.27–2.67]).
The presence of OCD was associated with a significantly increased mortality risk. Comorbid anxiety disorders, depression, or substance use disorders further increased the risk. However, after adjusting for these and somatic comorbidities, we found that the mortality risk remained significantly increased among persons with OCD.
PMCID: PMC5082974  PMID: 26818216
9.  Patterns of Nonrandom Mating Within and Across 11 Major Psychiatric Disorders 
JAMA psychiatry  2016;73(4):354-361.
Psychiatric disorders are heritable, polygenic traits, which often share risk alleles and for which nonrandom mating has been suggested. However, despite the potential etiological implications, the scale of nonrandom mating within and across major psychiatric conditions remains unclear.
To quantify the nature and extent of nonrandom mating within and across a broad range of psychiatric conditions at the population level.
Population-based cohort using Swedish population registers. Participants were all Swedish residents with a psychiatric diagnosis of interest (attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, bipolar disorder, major depression, generalized anxiety disorder, agoraphobia, social phobia, obsessive-compulsive disorder, anorexia, or substance abuse), along with their mates. Individuals with select nonpsychiatric disorders (Crohn’s disease, type 1 and type 2 diabetes mellitus, multiple sclerosis, or rheumatoid arthritis) were included for comparison. General population samples were also derived and matched 1:5 with each case proband. Inpatient and outpatient diagnostic data were derived from the Swedish National Patient Register (1973-2009), with analyses conducted between June 2014 and May 2015.
Correlation in the diagnostic status of mates both within and across disorders. Conditional logistic regression was used to quantify the odds of each diagnosis in the mates of cases relative to matched population controls.
Across cohorts, data corresponded to 707 263 unique case individuals, with women constituting 45.7% of the full population. Positive correlations in diagnostic status were evident between mates. Within-disorder correlations were marginally higher (range, 0.11-0.48) than cross-disorder correlations (range, 0.01-0.42). Relative to matched populations, the odds of psychiatric case probands having an affected mate were significantly elevated. Differences in the magnitude of observed relationships were apparent by disorder (odds ratio range, 0.8-11.4). The number of comorbidities in a case proband was associated with the proportion of affected mates. These relationships were not apparent or weaker in magnitude among nonpsychiatric conditions (correlation range, −0.03 to 0.17).
Nonrandom mating is evident in psychiatric populations both within specific disorders and across the spectrum of psychiatric conditions. This phenomenon may hold important implications for how we understand the familial transmission of these disorders and for psychiatric genetic research.
PMCID: PMC5082975  PMID: 26913486
10.  Geographic Variability in Potentially Discretionary Red Blood Cell Transfusions After Coronary Artery Bypass Grafting Surgery 
We assessed regional differences in potentially discretionary [<3 units of red blood cell (RBC)] transfusions across 56 medical centers and 11,200 patients undergoing isolated non-emergent coronary artery bypass (CABG) surgery. Regional variation in overall RBC rates remained after risk adjustment, perhaps due to differences in regional practice environments.
A number of established regional quality improvement collaboratives have partnered to assess and improve care across their regions under the umbrella of the “Cardiac Surgery Quality IMPROVEment (IMPROVE) Network”. The first effort of the IMPROVE Network has been to assess regional differences in potentially discretionary [<3 units of red blood cell (RBC)] transfusions.
We examined 11,200 patients undergoing isolated non-emergent coronary artery bypass (CABG) surgery across 56 medical centers in four IMPROVE Network regions between January 2008 and June 2012. Each center submitted the most recent 200 patients who received 0, 1, or 2 units of RBC transfusion during the index admission. Patient and disease characteristics, intra-operative practices, and percentage of cases receiving RBC transfusions were collected. Region-specific transfusion rates were calculated, after adjusting for pre- and intra-operative factors among region-specific centers.
There were small, but significant, differences in patient case mix across regions. RBC transfusions of 1 or 2 units occurred among 25.2% (2,826/11,200) of CABG procedures. Significant variation in use and number of RBCs existed across regions [None: 74.8% (min:max 70.0%, 84.1%), 1 unit: 9.7% (5.1%, 11.8%), 2 units: 15.5% (9.1%, 18.2%)], p<0.001. Variation in overall transfusion rates remained after adjustment (9.1% – 31.7%, p<0.001).
Delivery of small volumes of RBC transfusions was common, yet varied across geographic regions. These data suggest that differences in regional practice environments, including transfusion triggers and anemia management, may contribute to variability in RBC transfusion rates.
PMCID: PMC5082980  PMID: 25227699
Transfusion; Coronary artery bypass grafts; CABG
12.  Connectivity in Autism: A review of MRI connectivity studies 
Harvard review of psychiatry  2015;23(4):223-244.
Autism Spectrum Disorder (ASD) affects 1 in 50 children between the ages of 6–17 years as per a 2012 CDC survey of parents. The etiology of ASD is not precisely known. ASD is an umbrella term, which includes low (IQ<70) to high functioning (IQ>70) individuals. A better understanding of the disorder, and how it manifests in an individual subject can lead to more effective intervention plans to fulfill the individual’s treatment needs.
Magnetic resonance imaging (MRI) is a non-invasive investigational tool that can help study the ways in which the brain develops and/or deviates from the typical developmental trajectory. MRI offers insights into the structure, function, and metabolism of the brain. In this article, we review published studies on brain connectivity changes in ASD using either resting state functional MRI or diffusion tensor imaging.
The general findings of decreases in white matter integrity and long-range neural coherence are prevalent in ASD literature. However, there is somewhat less of a consensus in the detailed localization of these findings. There are even fewer studies linking these connectivity alterations with the behavioral phenotype of the disorder. Nevertheless, with the help of data sharing and large-scale analytic efforts, the field is advancing towards several convergent themes. These include reduced functional coherence of long-range intra-hemispheric cortico-cortical default mode circuitry, impaired inter-hemispheric regulation, and an associated, perhaps compensatory, increase in local and short-range cortico-subcortical coherence.
PMCID: PMC5083037  PMID: 26146755
autism; diffusion tensor imaging; resting state MRI; connectivity; behavioral correlation
13.  Dnmt1 regulates the myogenic lineage specification of muscle stem cells 
Scientific Reports  2016;6:35355.
DNA methylation is an important epigenetic mark that regulates gene expression. Dnmt1 plays an important role in maintaining DNA methylation patterns on daughter DNA strands. Studies have shed light into the functional role of Dnmt1 regulation in the hematopoietic and epidermal systems. Here we show that Dnmt1 is required for myogenesis. Loss of Dnmt1 results in reduced expression of myogenic genes and defects in myogenic differentiation. We have utilized a conditional knockout mouse approach to examine the functional consequences of Dnmt1 depletion specifically in the developing muscle. These mice were born runted, with smaller body weights, and reduced ability to form myotubes in vitro. We show that expression of Id-1, a negative regulator of myogenesis, is enhanced in Dnmt1-deficient cultures, leading to enhanced transdifferentiation of myoblasts toward the osteogenic lineage. Thus, these studies demonstrate that Dnmt1 influences cellular identity and determines lineage fidelity.
PMCID: PMC5082760  PMID: 27752090
14.  Genome-wide diversity and gene expression profiling of Babesia microti isolates identify polymorphic genes that mediate host-pathogen interactions 
Scientific Reports  2016;6:35284.
Babesia microti, a tick-transmitted, intraerythrocytic protozoan parasite circulating mainly among small mammals, is the primary cause of human babesiosis. While most cases are transmitted by Ixodes ticks, the disease may also be transmitted through blood transfusion and perinatally. A comprehensive analysis of genome composition, genetic diversity, and gene expression profiling of seven B. microti isolates revealed that genetic variation in isolates from the Northeast United States is almost exclusively associated with genes encoding the surface proteome and secretome of the parasite. Furthermore, we found that polymorphism is restricted to a small number of genes, which are highly expressed during infection. In order to identify pathogen-encoded factors involved in host-parasite interactions, we screened a proteome array comprised of 174 B. microti proteins, including several predicted members of the parasite secretome. Using this immuno-proteomic approach we identified several novel antigens that trigger strong host immune responses during the onset of infection. The genomic and immunological data presented herein provide the first insights into the determinants of B. microti interaction with its mammalian hosts and their relevance for understanding the selective pressures acting on parasite evolution.
PMCID: PMC5082761  PMID: 27752055
15.  Altered T cell phenotypes associated with clinical relapse of multiple sclerosis patients receiving fingolimod therapy 
Scientific Reports  2016;6:35314.
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease. Fingolimod, a highly effective disease-modifying drug for MS, retains CCR7+ central memory T cells in which autoaggressive T cells putatively exist, in secondary lymphoid organs, although relapse may still occur in some patients. Here, we analyzed the T cell phenotypes of fingolimod-treated, fingolimod-untreated patients, and healthy subjects. The frequency of CD56+ T cells and granzyme B-, perforin-, and Fas ligand-positive T cells significantly increased during fingolimod treatment. Each T cell subpopulation further increased during relapse. Interestingly, T cells from fingolimod-treated patients exhibited interferon-γ biased production, and more myelin basic protein-reactive cells was noted in CD56+ than in CD56− T cells. It is likely that the altered T cell phenotypes play a role in MS relapse in fingolimod-treated patients. Further clinical studies are necessary to investigate whether altered T cell phenotypes are a biomarker for relapse under fingolimod therapy.
PMCID: PMC5082790  PMID: 27752051
16.  Perirhinal cortex lesions that impair object recognition memory spare landmark discriminations 
Behavioural Brain Research  2016;313:255-259.
•Loss of perirhinal cortex spares mirror-imaged landmark discriminations.•Perirhinal cortex lesions do not disrupt latent spatial learning.•Further underlines dissociation between perirhinal and hippocampal function.
Rats with lesions in the perirhinal cortex and their control group learnt to discriminate between mirror-imaged visual landmarks to find a submerged platform in a watermaze. Rats initially learnt this discrimination passively, in that they were repeatedly placed on the platform in one corner of a square watermaze with walls of different appearance, prior to swimming to that same location for the first time in a subsequent probe trial. Perirhinal cortex lesions spared this passively learnt ability, despite the common visual elements shared by the guiding landmarks. These results challenge models of perirhinal function that emphasise its role in solving discriminations between stimuli with ambiguous or overlapping features, while underlining how this cortical region is often not required for spatial processes that involve the hippocampus.
PMCID: PMC4998350  PMID: 27449200
Hippocampus; Navigation; Parahippocampal cortex
17.  Boosting vaccine efficacy the natural (killer) way 
Trends in immunology  2015;36(9):536-546.
Coordination of the innate and adaptive immune systems is paramount to the development of protective humoral and cellular immunity following vaccination. Natural killer (NK) cells are front-line soldiers of the innate immune system, and recent studies have revealed functions for NK cells in long-lived immune memory and the regulation of adaptive immune responses. These findings suggest that NK cells may play important roles in the development of efficacious vaccines, as well as, in some contexts, failed immunizations. Here we review the current understanding of the immunomodulatory and memory differentiation capabilities of NK cells. We examine the context-dependency of the mechanisms and the nature NK cell-mediated modulation of the immune response, and discuss how these insights may impact immunization strategies and the development of next-generation vaccines.
PMCID: PMC4567442  PMID: 26272882
Natural killer cells; vaccination; immune regulation
18.  John (Jack) M. Pellock, MD: 1943–2016 
Epilepsy Currents  2016;16(5):335-336.
PMCID: PMC5083060
19.  Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors 
eLife  null;5:e17111.
Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction.
PMCID: PMC4996650  PMID: 27557444
Ras-ERK signalling; MEK inhibitor; cell-penetrating peptide; cocaine place preference; cocaine self-administration; Mouse
20.  The Dark Side of Dissemination: Traditional and Open Access Versus Predatory Journals 
Nursing Education Perspectives  2016;37(5):275-277.
The purpose of the article is to alert faculty about predatory online journals, review characteristics of three broad categories of journals, and provide suggestions for faculty evaluation of journals before submission of scholarship for publication.
The availability of online journals in recent years has rapidly increased the number of journals available for publication of faculty scholarship. However, not all online journals meet the same standards as traditional journals.
The article is not a report for a research study.
Currently, there are three broad categories of journals for faculty scholarship publication: traditional, open access scholarly, and predatory open access journals.
Faculty authors need to carefully evaluate the journal characteristics and publisher business practices before submitting a manuscript for publication to prevent inadvertent submission to a predatory open access journal.
PMCID: PMC4998130  PMID: 27740559
Academic Publishing; Online Journals; Open Access; Predatory Journals; Scholarly Publication
21.  Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice 
eLife  null;5:e16351.
The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.
eLife digest
Old age is the single greatest risk factor for many diseases including heart disease, arthritis, cancer and dementia. By delaying the biological aging process, it may be possible to reduce the impact of age-related diseases, which could have great benefits for society and the quality of life of individuals. A drug called rapamycin, which is currently used to prevent organ rejection in transplant recipients, is a leading candidate for targeting aging. Rapamycin increases lifespan in several types of animals and delays the onset of many age-related conditions in mice.
Nearly all of the aging-related studies in mice have used the same dose of rapamycin given throughout the lives of the animals. Lifelong treatment with rapamycin wouldn’t be practical in humans and is likely to result in undesirable side effects. For example, the high doses of rapamycin used in transplant patients cause side effects including poor wound healing, elevated blood cholesterol levels, and mouth ulcers. Before rapamycin can be used to promote healthy aging in humans, researchers must better understand at what point in life the drug is most effective, and what dose to use to provide the biggest benefit while limiting the side effects.
Now, Bitto et al. show that treating mice with rapamycin for a short period during middle age increases the life expectancy of the mice by up to 60%. In the experiments, mice were given two different doses of rapamycin for only three months starting at 20 months old (equivalent to about 60-65 years old in humans). After receiving the lower dose, both male and female mice lived about 50% longer than untreated mice, and showed improvements in their muscle strength and motor coordination. When given the higher dose, male mice showed an even greater increase in life expectancy, but the female mice did not. These female mice had an increased risk of developing rare and aggressive forms of blood cancer, but were protected from other types of cancer.
Both drug treatments also caused substantial changes in the gut bacteria of the male and female mice, which could be related to effects of rapamycin on metabolism, immunity and health. More studies are needed to uncover precisely how such short-term treatments can yield long-term changes in the body, and how such changes are related to lifespan and healthy aging.
PMCID: PMC4996648  PMID: 27549339
aging; longevity; mTOR; microbiome; cancer; healthspan; Mouse
22.  Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1 
eLife  null;5:e13424.
Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density.
eLife digest
The demands of modern society means that millions of people do not get sufficient sleep on a daily basis. Sleep deprivation, even if only for brief periods, can impair learning and memory. In many cases, this impairment appears to be related to changes in the activity of a brain region called the hippocampus. However, the exact processes responsible for producing the effects of sleep deprivation remain unclear.
During learning or forming a new memory, the connections between the relevant neurons in the brain change. Havekes et al. found that depriving mice of sleep for just five hours dramatically reduced the connectivity between neurons in the hippocampus. This reduction is caused by the increased activity of cofilin, a protein that breaks down the actin filaments that shape the connections between neurons.
Havekes et al. then used a virus to introduce an inactive version of cofilin into hippocampal neurons to suppress the activity of the naturally present cofilin. This manipulation prevented both the loss of the connections between neurons and the memory deficits normally associated with sleep deprivation. Havekes et al. also found that recovery sleep leads to the re-wiring of neurons in the hippocampus. Future studies are now needed to determine how the neurons are able to re-wire themselves during recovery sleep.
PMCID: PMC4996653  PMID: 27549340
Sleep loss; synaptic plasticity; hippocampus; Mouse
23.  Scaling-up an efficacious school-based physical activity intervention: Study protocol for the ‘Internet-based Professional Learning to help teachers support Activity in Youth’ (iPLAY) cluster randomized controlled trial and scale-up implementation evaluation 
BMC Public Health  2016;16(1):873.
Despite the health benefits of regular physical activity, most children are insufficiently active. Schools are ideally placed to promote physical activity; however, many do not provide children with sufficient in-school activity or ensure they have the skills and motivation to be active beyond the school setting. The aim of this project is to modify, scale up and evaluate the effectiveness of an intervention previously shown to be efficacious in improving children’s physical activity, fundamental movement skills and cardiorespiratory fitness. The ‘Internet-based Professional Learning to help teachers support Activity in Youth’ (iPLAY) study will focus largely on online delivery to enhance translational capacity.
The intervention will be implemented at school and teacher levels, and will include six components: (i) quality physical education and school sport, (ii) classroom movement breaks, (iii) physically active homework, (iv) active playgrounds, (v) community physical activity links and (vi) parent/caregiver engagement. Experienced physical education teachers will deliver professional learning workshops and follow-up, individualized mentoring to primary teachers (i.e., Kindergarten – Year 6). These activities will be supported by online learning and resources. Teachers will then deliver the iPLAY intervention components in their schools. We will evaluate iPLAY in two complementary studies in primary schools across New South Wales (NSW), Australia. A cluster randomized controlled trial (RCT), involving a representative sample of 20 schools within NSW (1:1 allocation at the school level to intervention and attention control conditions), will assess effectiveness and cost-effectiveness at 12 and 24 months. Students’ cardiorespiratory fitness will be the primary outcome in this trial. Key secondary outcomes will include students’ moderate-to-vigorous physical activity (via accelerometers), fundamental movement skill proficiency, enjoyment of physical education and sport, cognitive control, performance on standardized tests of numeracy and literacy, and cost-effectiveness. A scale-up implementation study guided by the RE-AIM framework will evaluate the reach, effectiveness, adoption, implementation, and maintenance of the intervention when delivered in 160 primary schools in urban and regional areas of NSW.
This project will provide the evidence and a framework for government to guide physical activity promotion throughout NSW primary schools and a potential model for adoption in other states and countries.
Trial registration
Australia and New Zealand Clinical Trials Registry (ACTRN12616000731493). Date of registration: June 3, 2016.
PMCID: PMC4997792  PMID: 27557641
Cardiorespiratory fitness; Physical activity; Teacher professional development; Teacher professional learning; Online; Internet
24.  Synthesis, characterization, applications, and challenges of iron oxide nanoparticles 
Recently, iron oxide nanoparticles (NPs) have attracted much consideration due to their unique properties, such as superparamagnetism, surface-to-volume ratio, greater surface area, and easy separation methodology. Various physical, chemical, and biological methods have been adopted to synthesize magnetic NPs with suitable surface chemistry. This review summarizes the methods for the preparation of iron oxide NPs, size and morphology control, and magnetic properties with recent bioengineering, commercial, and industrial applications. Iron oxides exhibit great potential in the fields of life sciences such as biomedicine, agriculture, and environment. Nontoxic conduct and biocompatible applications of magnetic NPs can be enriched further by special surface coating with organic or inorganic molecules, including surfactants, drugs, proteins, starches, enzymes, antibodies, nucleotides, nonionic detergents, and polyelectrolytes. Magnetic NPs can also be directed to an organ, tissue, or tumor using an external magnetic field for hyperthermic treatment of patients. Keeping in mind the current interest in iron NPs, this review is designed to report recent information from synthesis to characterization, and applications of iron NPs.
PMCID: PMC4998023  PMID: 27578966
superparamagnetism; iron oxide nanoparticles; surfactants; hyperthermia; biodistribution; bioelimination
25.  Genome sequencing of a single tardigrade Hypsibius dujardini individual 
Scientific Data  2016;3:160063.
Tardigrades are ubiquitous microscopic animals that play an important role in the study of metazoan phylogeny. Most terrestrial tardigrades can withstand extreme environments by entering an ametabolic desiccated state termed anhydrobiosis. Due to their small size and the non-axenic nature of laboratory cultures, molecular studies of tardigrades are prone to contamination. To minimize the possibility of microbial contaminations and to obtain high-quality genomic information, we have developed an ultra-low input library sequencing protocol to enable the genome sequencing of a single tardigrade Hypsibius dujardini individual. Here, we describe the details of our sequencing data and the ultra-low input library preparation methodologies.
PMCID: PMC4986543  PMID: 27529330
Genome; Zoology; Genomics; Transcriptomics

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