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1.  Room-temperature in situ nuclear spin hyperpolarization from optically pumped nitrogen vacancy centres in diamond 
Nature Communications  2015;6:8965.
Low detection sensitivity stemming from the weak polarization of nuclear spins is a primary limitation of magnetic resonance spectroscopy and imaging. Methods have been developed to enhance nuclear spin polarization but they typically require high magnetic fields, cryogenic temperatures or sample transfer between magnets. Here we report bulk, room-temperature hyperpolarization of 13C nuclear spins observed via high-field magnetic resonance. The technique harnesses the high optically induced spin polarization of diamond nitrogen vacancy centres at room temperature in combination with dynamic nuclear polarization. We observe bulk nuclear spin polarization of 6%, an enhancement of ∼170,000 over thermal equilibrium. The signal of the hyperpolarized spins was detected in situ with a standard nuclear magnetic resonance probe without the need for sample shuttling or precise crystal orientation. Hyperpolarization via optical pumping/dynamic nuclear polarization should function at arbitrary magnetic fields enabling orders of magnitude sensitivity enhancement for nuclear magnetic resonance of solids and liquids under ambient conditions.
Methods to increase nuclear spin polarization can enhance the sensitivity of magnetic resonance techniques however they are often limited to unfavourable conditions. Here, the authors achieve room temperature hyperpolarization of bulk 13C nuclear spins by exploiting the optical response of nitrogen vacancy centers in diamond crystals.
PMCID: PMC4686850  PMID: 26639147
2.  The Global Trachoma Mapping Project: Methodology of a 34-Country Population-Based Study 
Ophthalmic Epidemiology  2015;22(3):214-225.
Purpose: To complete the baseline trachoma map worldwide by conducting population-based surveys in an estimated 1238 suspected endemic districts of 34 countries.
Methods: A series of national and sub-national projects owned, managed and staffed by ministries of health, conduct house-to-house cluster random sample surveys in evaluation units, which generally correspond to “health district” size: populations of 100,000–250,000 people. In each evaluation unit, we invite all residents aged 1 year and older from h households in each of c clusters to be examined for clinical signs of trachoma, where h is the number of households that can be seen by 1 team in 1 day, and the product h × c is calculated to facilitate recruitment of 1019 children aged 1–9 years. In addition to individual-level demographic and clinical data, household-level water, sanitation and hygiene data are entered into the purpose-built LINKS application on Android smartphones, transmitted to the Cloud, and cleaned, analyzed and ministry-of-health-approved via a secure web-based portal. The main outcome measures are the evaluation unit-level prevalence of follicular trachoma in children aged 1–9 years, prevalence of trachomatous trichiasis in adults aged 15 + years, percentage of households using safe methods for disposal of human feces, and percentage of households with proximate access to water for personal hygiene purposes.
Results: In the first year of fieldwork, 347 field teams commenced work in 21 projects in 7 countries.
Conclusion: With an approach that is innovative in design and scale, we aim to complete baseline mapping of trachoma throughout the world in 2015.
PMCID: PMC4687001  PMID: 26158580
Blindness; mHealth; prevalence study; trachoma; trichiasis
3.  Novel Y-chromosome Short Tandem Repeat Variants Detected Through the Use of Massively Parallel Sequencing 
Massively parallel sequencing (MPS) technology is capable of determining the sizes of short tandem repeat (STR) alleles as well as their individual nucleotide sequences. Thus, single nucleotide polymorphisms (SNPs) within the repeat regions of STRs and variations in the pattern of repeat units in a given repeat motif can be used to differentiate alleles of the same length. In this study, MPS was used to sequence 28 forensically-relevant Y-chromosome STRs in a set of 41 DNA samples from the 3 major U.S. population groups (African Americans, Caucasians, and Hispanics). The resulting sequence data, which were analyzed with STRait Razor v2.0, revealed 37 unique allele sequence variants that have not been previously reported. Of these, 19 sequences were variations of documented sequences resulting from the presence of intra-repeat SNPs or alternative repeat unit patterns. Despite a limited sampling, two of the most frequently-observed variants were found only in African American samples. The remaining 18 variants represented allele sequences for which there were no published data with which to compare. These findings illustrate the great potential of MPS with regard to increasing the resolving power of STR typing and emphasize the need for sample population characterization of STR alleles.
PMCID: PMC4610967  PMID: 26391384
Y-STR; Sequence polymorphism; Allele variants; Massively parallel sequencing; Nextera; STRait Razor
4.  Component Separation with Porcine Acellular Dermal Reinforcement Is Superior to Traditional Bridged Mesh Repairs in the Open Repair of Significant Midline Ventral Hernia Defects 
The American surgeon  2014;80(8):725-731.
The optimal technique for complex ventral hernia repair (VHR) remains controversial. Component separation (CS) reinforced with porcine acellular dermal matrix (PADM) has shown favorable results compared with series of conventional bridged VHR, but few comparative studies exist. We conducted a retrospective cohort study comparing 40 randomly selected patients who underwent CS/PADM reinforcement against an identical number of patients who underwent conventional open VHR with mesh at our institution. Patient characteristics, operative findings, outcomes, complications, reoperations, and recurrences were obtained by chart review. Fisher’s exact/t test compared outcomes between the two cohorts. Statistical significance was set as P < 0.05. Mean follow-up was 33.1 months. Patient groups did not differ significantly in race (P = 1.00), age (P = 0.82), body mass index (P = 0.14), or comorbid conditions (smoking, chronic obstructive pulmonary disease, obesity, steroid use; P values 0.60, 0.29, 0.08, and 0.56, respectively). Defect size was greater in the CS/PADM group (mean, 372.5 vs 283.7 cm2, P = 0.01) as was the percentage Ventral Hernia Working Group Grade III/IV hernias (65.0 vs 30.0%, P = 0.03). Recurrences were lower in the CS/PADM group (13.2 vs 37.5%, P = 0.02). Mesh infection was lower in the CS/PADM group (0 vs 23% in the bridged group, P = 0.002), all of which occurred with synthetic mesh. Indications for reoperation (recurrence or complications requiring reoperation) were also lower in the CS/PADM group (17.5 vs 52.5%, P = 0.002). Superior results are achieved with CS/PADM reinforcement over traditional bridged VHR. This is evidenced by lower recurrence rates and overall complications requiring reoperation, particularly mesh infection. This is despite the greater use of CS in larger defects and contaminated hernias (VHWG Grade III and IV). CS/PADM reinforcement should be strongly considered for the repair of significant midline ventral hernia defects.
PMCID: PMC4476308  PMID: 25105388
6.  Blind study evaluation illustrates utility of the Ion PGM™ system for use in human identity DNA typing 
Croatian Medical Journal  2015;56(3):218-229.
To perform a blind study to assess the capability of the Ion Personal Genome Machine™ (PGM) system to sequence forensically relevant genetic marker panels and to characterize unknown individuals for ancestry and possible relatedness.
Twelve genomic samples were provided by a third party for blinded genetic analysis. For these 12 samples, the mitochondrial genome and three PGM™ panels containing human identity single nucleotide polymorphisms (SNPs), ancestry informative SNPs, and short tandem repeats (STRs) were sequenced on the PGM™ system and analyzed.
All four genetic systems were run and analyzed on the PGM™ system in a reasonably quick time frame. Completeness of genetic profiles, depth of coverage, strand balance, and allele balance were informative metrics that illustrated the quality and reliability of the data produced. SNP genotypes allowed for identification of sex, paternal lineage, and population ancestry. STR genotypes were shown to be in complete concordance with genotypes generated by standard capillary electrophoresis-based technologies. Variants in the mitochondrial genome data provided information on population background and maternal relationships.
All results from analysis of the 12 genomic samples were consistent with sample information provided by the sample providers at the end of the blinded study. The relatively easy identification of intra-STR allele SNPs offered the potential for increased discrimination power. The promising nature of these results warrants full validation studies of this massively parallel sequencing technology and its further development for forensic data analysis.
PMCID: PMC4500968  PMID: 26088846
7.  Overexpression and delocalization of claudin-3 protein in MCF-7 and MDA-MB-415 breast cancer cell lines 
Oncology Letters  2015;10(1):156-162.
Tumor-specific deregulated expression of claudins, integral membrane proteins found in tight junctions (TJs), has indicated a possible role for TJ disruption in cancer progression. The current study demonstrates the marked overexpression of claudin-3 protein in two breast cancer cell lines of metastatic origin (MCF-7 and MDA-MB-415). Immunofluorescence and differential detergent fractionation analyses revealed that, although claudin-3 was primarily localized at cell junctions, it was also detected intracellularly. Similarly, the siRNA-mediated suppression of claudin-3 did not considerably affect its pattern of subcellular distribution relative to mock-transfected cells. However, there appeared to be a preferential loss of claudin-3 signal in the cytoskeletal fraction. Wound-healing assays were conducted to assess the effect of endogenous overexpression versus siRNA-mediated suppression of claudin-3 on cellular motility in MCF-7 cells. Suppression of claudin-3 protein levels resulted in a marked decrease in the rate of cellular motility relative to mock-transfected cells. These findings suggest that overexpression of claudin-3 may be important in disrupting TJ integrity and thus contribute to enhanced cellular motility, a key component of tumor progression.
PMCID: PMC4487109  PMID: 26170992
cell motility; tight junctions; metastasis
8.  Robenacoxib versus meloxicam for the control of peri-operative pain and inflammation associated with orthopaedic surgery in cats: a randomised clinical trial 
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in veterinary medicine. Robenacoxib is a NSAID with high selectivity for the cyclo-oxygenase-2 enzyme. In this study, the efficacy and safety of robenacoxib were evaluated in a prospective, randomised, active- and placebo-controlled masked clinical trial in 147 cats undergoing orthopaedic surgery. Cats were randomised into two treatment groups: Group 1, robenacoxib (2 mg/kg) administered via subcutaneous (s.c.) injection before surgery, followed by robenacoxib tablets (1–2.4 mg/kg) administered post-operatively for approximately 9 days (n = 101) and Group 2, meloxicam (0.3 mg/kg) administered s.c. before surgery, followed by placebo tablets administered post-operatively for approximately 9 days (n = 46). Cats were assessed using numerical rating scales (NRSs) by clinicians before surgery and at 3, 8, 22 and 28 hours after surgery and at the final visit (VF on approximately Day 10), and daily by their owners from Day 1 to the VF.
The primary end point was the global investigator score which was the sum of clinician NRSs for posture, behaviour and pain on palpation/manipulation. The efficacy of the single robenacoxib injection, assessed during 3 to 22 hours, was statistically non-inferior to meloxicam, with a relative efficacy of 1.029 (95% confidence interval, 0.847–1.231). No significant differences were detected during the follow-up treatment with robenacoxib tablets for approximately 9 days compared with placebo via clinician assessments at 28 hours and the VF, or in owner assessments on Days 1–VF. There were no significant differences in frequencies of reported adverse events, clinical observations and haematology or clinical chemistry variables between the groups.
Single s.c. injection of robenacoxib before surgery had non-inferior efficacy compared with meloxicam in controlling post-operative pain and inflammation in cats undergoing orthopaedic surgery. Follow-up treatment with oral robenacoxib tablets for approximately 9 days was well tolerated, but there were no differences in the efficacy scores after Day 1 compared with the group receiving meloxicam s.c. followed by placebo control.
PMCID: PMC4379761  PMID: 25880535
Cat; Coxib; Non-steroidal anti-inflammatory drug; Pain; Peri-operative; Robenacoxib
10.  Dissecting the contributions of β-hairpin tyrosine pair to the folding and stability of long-lived human γD-crystallins 
Nanoscale  2014;6(3):1797-1807.
Ultraviolet-radiation-induced damage to and aggregation of human lens crystallin proteins are thought to be a significant pathway to age-related cataract. The aromatic residues within the duplicated Greek key domains of γ-and β-crystallins are the main ultraviolet absorbers and are susceptible to direct and indirect ultraviolet damage. The previous site-directed mutagenesis studies have revealed a striking difference for two highly conserved homologous β-hairpin Tyr pairs, at the N-terminal domain (N-td) and C-terminal domain (C-td) respectively, in their contribution to the overall stability of HγD-Crys, but why they behave so differently still remains a mystery. In this paper, we systematically investigated the underlying molecular mechanism and detailed contributions of these two Tyr pairs with large scale molecular dynamics simulations. A series of different tyrosine-to-alanine pair(s) substitutions were performed in either the N-td, the C-td, or both. Our results suggest that the Y45A/Y50A pair substitution in the N-td mainly affects the stability of the N-td itself, while the Y133A/Y138A pair substitution in the C-td leads to a more cooperative unfolding of both N-td and C-td. The stability of motif 2 in the N-td is mainly determined by the interdomain interface, while motif 1 in the N-td or motifs 3 and 4 in the C-td are mainly stabilized by the intradomain hydrophobic core. The damage to any tyrosine pair(s) can directly introduce some apparent water leakage to the hydrophobic core at the interface, which in turn causes a serious loss in stability of the N-td. However, for the C-td substitutions, it may further impair the stable “sandwich-like” Y133-R167-Y138 cluster (through cation-π interactions) in the wild-type, thus causing the loop regions near the residue A138 to undergo large fluctuations, which in turn results in the intrusion of water into the hydrophobic core of the C-td and induces the C-td to lose its stability. These findings help resolve the “mystery” on why these two Tyr pairs display such a striking difference in their contributions to the overall protein stability despite their highly homologous nature.
PMCID: PMC3976203  PMID: 24352614
γD-Crystallins; Cataract; Ultraviolet radiation; Tyrosine; Alanine; Protein unfolding; Molecular dynamics; Hydrophobic interactions; Ophthalmic disease
11.  Underlying Data for Sequencing the Mitochondrial Genome with the Massively Parallel Sequencing Platform Ion Torrent™ PGM™ 
BMC Genomics  2015;16(Suppl 1):S4.
Massively parallel sequencing (MPS) technologies have the capacity to sequence targeted regions or whole genomes of multiple nucleic acid samples with high coverage by sequencing millions of DNA fragments simultaneously. Compared with Sanger sequencing, MPS also can reduce labor and cost on a per nucleotide basis and indeed on a per sample basis. In this study, whole genomes of human mitochondria (mtGenome) were sequenced on the Personal Genome Machine (PGMTM) (Life Technologies, San Francisco, CA), the out data were assessed, and the results were compared with data previously generated on the MiSeqTM (Illumina, San Diego, CA). The objectives of this paper were to determine the feasibility, accuracy, and reliability of sequence data obtained from the PGM.
24 samples were multiplexed (in groups of six) and sequenced on the at least 10 megabase throughput 314 chip. The depth of coverage pattern was similar among all 24 samples; however the coverage across the genome varied. For strand bias, the average ratio of coverage between the forward and reverse strands at each nucleotide position indicated that two-thirds of the positions of the genome had ratios that were greater than 0.5. A few sites had more extreme strand bias. Another observation was that 156 positions had a false deletion rate greater than 0.15 in one or more individuals. There were 31-98 (SNP) mtGenome variants observed per sample for the 24 samples analyzed. The total 1237 (SNP) variants were concordant between the results from the PGM and MiSeq. The quality scores for haplogroup assignment for all 24 samples ranged between 88.8%-100%.
In this study, mtDNA sequence data generated from the PGM were analyzed and the output evaluated. Depth of coverage variation and strand bias were identified but generally were infrequent and did not impact reliability of variant calls. Multiplexing of samples was demonstrated which can improve throughput and reduce cost per sample analyzed. Overall, the results of this study, based on orthogonal concordance testing and phylogenetic scrutiny, supported that whole mtGenome sequence data with high accuracy can be obtained using the PGM platform.
PMCID: PMC4315160  PMID: 25924014
12.  Tyrosine/Cysteine Cluster Sensitizing Human γD-Crystallin to Ultraviolet Radiation-Induced Photoaggregation in Vitro 
Biochemistry  2014;53(6):979-990.
Ultraviolet radiation (UVR) exposure is a major risk factor for age-related cataract, a protein-aggregation disease of the human lens often involving the major proteins of the lens, the crystallins. γD-Crystallin (HγD-Crys) is abundant in the nucleus of the human lens, and its folding and aggregation have been extensively studied. Previous work showed that HγD-Crys photoaggregates in vitro upon exposure to UVA/UVB light and that its conserved tryptophans are not required for aggregation. Surprisingly, the tryptophan residues play a photoprotective role because of a distinctive energy-transfer mechanism. HγD-Crys also contains 14 tyrosine residues, 12 of which are organized as six pairs. We investigated the role of the tyrosines of HγD-Crys by replacing pairs with alanines and monitoring photoaggregation using light scattering and SDS-PAGE. Mutating both tyrosines in the Y16/Y28 pair to alanine slowed the formation of light-scattering aggregates. Further mutant studies implicated Y16 as important for photoaggregation. Mass spectrometry revealed that C18, in contact with Y16, is heavily oxidized during UVR exposure. Analysis of multiple mutant proteins by mass spectrometry suggested that Y16 and C18 likely participate in the same photochemical process. The data suggest an initial photoaggregation pathway for HγD-Crys in which excited-state Y16 interacts with C18, initiating radical polymerization.
PMCID: PMC3954642  PMID: 24410332
13.  Correcting Inconsistencies and Errors in Bacterial Genome Metadata Using an Automated Curation Tool in Excel (AutoCurE) 
Whole-genome data are invaluable for large-scale comparative genomic studies. Current sequencing technologies have made it feasible to sequence entire bacterial genomes with relative ease and time with a substantially reduced cost per nucleotide, hence cost per genome. More than 3,000 bacterial genomes have been sequenced and are available at the finished status. Publically available genomes can be readily downloaded; however, there are challenges to verify the specific supporting data contained within the download and to identify errors and inconsistencies that may be present within the organizational data content and metadata. AutoCurE, an automated tool for bacterial genome database curation in Excel, was developed to facilitate local database curation of supporting data that accompany downloaded genomes from the National Center for Biotechnology Information. AutoCurE provides an automated approach to curate local genomic databases by flagging inconsistencies or errors by comparing the downloaded supporting data to the genome reports to verify genome name, RefSeq accession numbers, the presence of archaea, BioProject/UIDs, and sequence file descriptions. Flags are generated for nine metadata fields if there are inconsistencies between the downloaded genomes and genomes reports and if erroneous or missing data are evident. AutoCurE is an easy-to-use tool for local database curation for large-scale genome data prior to downstream analyses.
PMCID: PMC4566056  PMID: 26442252
bacteria; genomes; metadata; database; curation; automation; AutoCurE
15.  Identifying the assembly pathway of cyanophage inside the marine bacterium using electron cryo-tomography 
Microbial cell  2014;1(1):45-47.
Advances in electron cryo-tomography open up a new avenue to visualize the 3-D internal structure of a single bacterium before and after its infection by bacteriophages in its native environment, without using chemical fixatives, fluorescent dyes or negative stains. Such direct observation reveals the presence of assembly intermediates of the bacteriophage and thus allows us to map out the maturation pathway of the bacteriophage inside its host.
PMCID: PMC4238041  PMID: 25419524
electron cryo-tomography; Zernike phase optics; marine cyanobacterium; phage assembly intermediates; transient biological processes; 3-D structures
16.  Efficacy, acceptability and tolerability of the new oral phosphate binder Lenziaren® in healthy cats fed a standard diet 
BMC Veterinary Research  2014;10:258.
The efficacy, acceptability and tolerability of the new oral phosphate binder Lenziaren® (SBR759) were evaluated in a randomized parallel-group design study in 36 healthy cats (n = 6 per group). Five groups were fed once daily with a commercial diet containing 0.2% phosphorus (“standard diet”) into which was mixed Lenziaren® at 0.25, 0.5, 1.0 or 2.0 g/day or no treatment (control group) daily for 30 days. A sixth group was fed a commercial diet containing lower amounts (0.12%) of phosphorus (“renal diet”) and no treatment.
When compared to the control group, Lenziaren® produced significant dose-related reductions in urine phosphate concentrations, urine phosphate excretion and fractional urinary phosphate excretion. Significant effects versus the control group were observed at the 0.5, 1.0 and 2.0 g/day dosages. Lenziaren® was well tolerated and was associated with higher food consumption and serum iron concentrations versus the control.
When compared to the control group, the renal diet was associated with significantly lower urine phosphate concentrations and loss of body weight. Lenziaren® had similar effects on urine phosphate concentrations compared to the renal diet, but was not associated with loss of body weight.
Lenziaren® was effective as an oral phosphate binder in cats fed with a standard diet containing 0.2% phosphorus. The acceptability and tolerability were good. Dosages of 0.5-1.0 g/cat per day are recommended for clinical testing in cats fed with a standard diet.
PMCID: PMC4226906  PMID: 25348573
Cat; Lenziaren; Phosphate; Phosphate binder; SBR759
17.  Two Novel Proteins of Cyanophage Syn5 Compose Its Unusual Horn Structure 
Journal of Virology  2014;88(4):2047-2055.
The marine cyanophage Syn5 can be propagated to a high titer in the laboratory on marine photosynthetic Synechococcus sp. strain WH8109. The purified particles carry a novel slender horn structure projecting from the vertex opposite the tail vertex. The genome of Syn5 includes a number of genes coding for novel proteins. Using immune-electron microscopy with gold-labeled antibodies, we show that two of these novel proteins, products of genes 53 and 54, are part of the horn structure. A third novel protein, the product of gene 58, is assembled onto the icosahedral capsid lattice. Characterization of radioactively labeled precursor procapsids by sucrose gradient centrifugation shows that there appear to be three classes of particles—procapsids, scaffold-deficient procapsids, and expanded capsids. These lack fully assembled horn appendages. The horn presumably assembles onto the virion just before or after DNA packaging. Antibodies raised to the recombinant novel Syn5 proteins did not interfere with phage infectivity, suggesting that the functions of these proteins are not directly involved in phage attachment or infection of the host WH8109. The horn structure may represent some adaption to the marine environment, whose function will require additional investigation.
PMCID: PMC3911526  PMID: 24307583
18.  Protruding knob-like proteins violate local symmetries in an icosahedral marine virus 
Nature Communications  2014;5:4278.
Marine viruses play crucial roles in shaping the dynamics of oceanic microbial communities and in the carbon cycle on Earth. Here we report a 4.7-Å structure of a cyanobacterial virus, Syn5, by electron cryo-microscopy and modelling. A Cα backbone trace of the major capsid protein (gp39) reveals a classic phage protein fold. In addition, two knob-like proteins protruding from the capsid surface are also observed. Using bioinformatics and structure analysis tools, these proteins are identified to correspond to gp55 and gp58 (each with two copies per asymmetric unit). The non 1:1 stoichiometric distribution of gp55/58 to gp39 breaks all expected local symmetries and leads to non-quasi-equivalence of the capsid subunits, suggesting a role in capsid stabilization. Such a structural arrangement has not yet been observed in any known virus structures.
Some viruses are spherical particles in which protein components are organized with well-defined icosahedral and local symmetries. Here, Gipson et al. describe a unique arrangement of proteins, breaking all expected local symmetries, in particles of a marine bacterial virus.
PMCID: PMC4102127  PMID: 24985522
19.  Ten-Year Effects of the ACTIVE Cognitive Training Trial on Cognition and Everyday Functioning in Older Adults 
To determine the effects of cognitive training on cognitive abilities and everyday function over 10 years.
Design, Setting, and Participants
Ten-year follow-up of a randomized, controlled single-blind trial with 3 intervention groups and a no-contact control group. A volunteer sample of 2832 persons (mean baseline age, 73.6 years; 26% African American) living independently in 6 US cities.
Ten-session training for memory, reasoning, or speed-of-processing.; 4-session booster training at 11 and at 35 months after training.
Objectively measured cognitive abilities and self-reported and performance-based measures of everyday function.
Participants in each intervention group reported less difficulty with instrumental activities of daily living (IADL) (memory: effect size, 0.48 [99% CI, 0.12-0.84]; reasoning: effect size, 0.38 [99% CI, 0.02-0.74]; speed-of-processing: effect size, 0.36 [99% CI, 0.01-0.72]). At mean age of 82 years, about 60% of trained participants compared to 50% of controls (p<.05) were at or above their baseline level of self-reported IADL function at 10 years. The reasoning and speed-of-processing interventions maintained their effects on their targeted cognitive abilities at 10 years (reasoning: effect size, 0.23 [99% CI, 0.09-0.38]; speed-of-processing: effect size, 0.66 [99% CI, 0.43-0.88]). Memory training effects were no longer maintained for memory performance. Booster training produced additional and durable improvement for the reasoning intervention for reasoning performance (effect size, 0.21 [99% CI, 0.01-0.41]) and the speed-of-processing intervention for speed-of-processing performance (effect size, 0.62 [99% CI, 0.31-0.93]).
Each ACTIVE cognitive intervention resulted in less decline in self-reported IADL compared with the control group. Reasoning and speed, but not memory, training resulted in improved targeted cognitive abilities for 10 years.
PMCID: PMC4055506  PMID: 24417410
cognitive training; elderly; cognitive abilities; everyday function; training maintenance
20.  Cardiac preconditioning with sphingosine-1-phosphate requires activation of signal transducer and activator of transcription-3 
Cardiovascular Journal of Africa  2014;25(3):118-123.
Sphingosine-1-phosphate (S1P) is a cardioprotective agent. Signal transducer and activator of transcription 3 (STAT-3) is a key mediator of many cardioprotective agents. We aimed to explore whether STAT-3 is a key mediator in S1P-induced preconditioning.
Langendorff-perfused hearts from Wistar rats and wild-type or cardiomyocyte-specific STAT-3 knockout mice were pre-treated with S1P (10 nmol/l), with or without the STAT-3 pathway inhibitor AG490, before an ischaemia–reperfusion insult. Triphenyltetrazolium chloride and Evans blue staining were used for the determination of infarct size. Western blot analysis was carried out on the S1P pre-treated hearts for detection of cytosolic, nuclear and mitochondrial phosphorylated and total STAT-3 proteins.
Pre-treatment with S1P decreased the infarct size in isolated rat (5 ± 3% vs control 26 ± 8%, p < 0.01) and wild-type mouse hearts (13 ± 1% vs control 33 ± 3%, p < 0.05). This protective effect was abolished in the rat hearts pre-treated with AG490 (30 ± 10%, p = ns vs control) and in the hearts from STAT-3 knockout mice (35 ± 4% vs control 30 ± 3%, p = ns). Levels of phosphorylated STAT-3 were significantly increased in both the nuclear (p < 0.05 vs control) and mitochondrial (p < 0.05 vs control) fractions in the S1P pre-treated hearts, but remained unchanged in the cytosolic fraction (p = ns vs control).
These novel results demonstrate that pharmacological preconditioning with S1P in the isolated heart is mediated by activation of mitochondrial and nuclear STAT-3, therefore suggesting that S1P may be a novel therapeutic target to modulate mitochondrial and nuclear function in cardiovascular disease in order to protect the heart against ischaemia–reperfusion.
PMCID: PMC4120131  PMID: 25000441
STAT-3; cardioprotection; preconditioning; sphingosine-1-phosphate; myocardial infarction
21.  Visualizing Virus Assembly Intermediates Inside Marine Cyanobacteria 
Nature  2013;502(7473):707-710.
Cyanobacteria are photosynthetic organisms responsible for ~25% of organic carbon fixation on earth. These bacteria began to convert solar energy and carbon dioxide into bioenergy and oxygen billions of years ago. Cyanophages, which infect these bacteria, play an important role in regulating the marine ecosystem by controlling cyanobacteria community organization and mediating lateral gene transfer. Here we visualize the maturation process of cyanophage Syn5 inside its host cell, Synechococcus, using Zernike Phase Contrast (ZPC) electron cryo-tomography (cryoET)1,2. This imaging modality yields significant enhancement of image contrast over conventional cryoET and thus facilitates the direct identification of subcellular components, including thylakoid membranes, carboxysomes and polyribosomes, as well as phages, inside the congested cytosol of the infected cell. By correlating the structural features and relative abundance of viral progeny within cells at different stages of infection, we identified distinct Syn5 assembly intermediates. Our results suggest that the procapsid releases scaffolding proteins and expands its volume at an early stage of genome packaging. Later in assembly, we detected full particles with a tail either with or without an additional horn. The morphogenetic pathway we describe herein is highly conserved and was probably established long before that of double stranded DNA (dsDNA) viruses infecting higher life forms.
PMCID: PMC3984937  PMID: 24107993
23.  Prevalence of Trachoma at Sub-District Level in Ethiopia: Determining When to Stop Mass Azithromycin Distribution 
To eliminate blinding trachoma, the World Health Organization emphasizes implementing the SAFE strategy, which includes annual mass drug administration (MDA) with azithromycin to the whole population of endemic districts. Prevalence surveys to assess impact at the district level are recommended after at least 3 years of intervention. The decision to stop MDA is based on a prevalence of trachomatous inflammation follicular (TF) among children aged 1–9 years below 5% at the sub-district level, as determined by an additional round of surveys limited within districts where TF prevalence is below 10%. We conducted impact surveys powered to estimate prevalence simultaneously at the sub-district and district in two zones of Amhara, Ethiopia to determine whether MDA could be stopped.
Seventy-two separate population-based, sub-district surveys were conducted in 25 districts. In each survey all residents from 10 randomly selected clusters were screened for clinical signs of trachoma. Data were weighted according to selection probabilities and adjusted for correlation due to clustering.
Principal Findings
Overall, 89,735 residents were registered from 21,327 households of whom 72,452 people (80.7%) were examined. The prevalence of TF in children aged 1–9 years was below 5% in six sub-districts and two districts. Sub-district level prevalence of TF in children aged 1–9 years ranged from 0.9–76.9% and district-level from 0.9–67.0%. In only one district was the prevalence of trichiasis below 0.1%.
The experience from these zones in Ethiopia demonstrates that impact assessments designed to give a prevalence estimate of TF at sub-district level are possible, although the scale of the work was challenging. Given the assessed district-level prevalence of TF, sub-district-level surveys would have been warranted in only five districts. Interpretation was not as simple as stopping MDA in sub-districts below 5% given programmatic challenges of exempting sub-districts from a highly regarded program and the proximity of hyper-endemic sub-districts.
Author Summary
Trachoma, the leading cause of preventable blindness, is targeted for “elimination as a public health problem” by the year 2020. National programs are implementing the recommended strategy of surgery, antibiotics, facial cleanliness, and environmental improvements (SAFE) to meet this target. Many programs are currently facing the decision of when to scale down interventions, particularly mass drug administration (MDA) of azithromycin. We implemented large population-based surveys in two different zones of the Amhara National Regional State of Ethiopia. Rather than conducting an impact assessment first at the district level, followed by additional sub-district-level surveys, we took a novel approach to measure the prevalence of trachoma at sub-district level to be able to make an immediate decision of whether to stop MDA. Over 72,000 people in 714 communities in 72 sub-districts were examined for clinical signs of trachoma. We identified only six sub-districts that met criteria for being able to stop MDA. Our work demonstrates that determining the prevalence of trachoma at sub-district level is feasible but requires significant resources. In this hyper-endemic setting, sub-district-level surveys were not needed in the majority of districts. Overall, the clinical data suggest some decline in trachoma within these areas since the SAFE strategy was implemented.
PMCID: PMC3953063  PMID: 24625539
24.  Cognition assessment using the NIH Toolbox 
Neurology  2013;80(11 Suppl 3):S54-S64.
Cognition is 1 of 4 domains measured by the NIH Toolbox for the Assessment of Neurological and Behavioral Function (NIH-TB), and complements modules testing motor function, sensation, and emotion. On the basis of expert panels, the cognition subdomains identified as most important for health, success in school and work, and independence in daily functioning were Executive Function, Episodic Memory, Language, Processing Speed, Working Memory, and Attention. Seven measures were designed to tap constructs within these subdomains. The instruments were validated in English, in a sample of 476 participants ranging in age from 3 to 85 years, with representation from both sexes, 3 racial/ethnic categories, and 3 levels of education. This report describes the development of the Cognition Battery and presents results on test-retest reliability, age effects on performance, and convergent and discriminant construct validity. The NIH-TB Cognition Battery is intended to serve as a brief, convenient set of measures to supplement other outcome measures in epidemiologic and longitudinal research and clinical trials. With a computerized format and national standardization, this battery will provide a “common currency” among researchers for comparisons across a wide range of studies and populations.
PMCID: PMC3662346  PMID: 23479546
25.  Assessing the WHO 50% Prevalence Threshold in School-Aged Children as Indication for Treatment of Urogenital Schistosomiasis in Adults in Central Nigeria 
Preventive chemotherapy with praziquantel is recommended in adults by the World Health Organization when prevalence of schistosomiasis in school-aged children (SAC) is ≥ 50%. This study ascertained the value of this threshold in predicting prevalence and intensity of Schistosoma hematobium (SH) infection in adults in central Nigeria. We evaluated urogenital schistosomiasis prevalence in 1,164 adults: 659 adults in 12 communities where mean hematuria among SAC in 2008 was 26.6% and 505 adults in 7 communities where the mean hematuria among SAC in 2008 was 70.4%. No statistically significant differences were found between the two groups of adults in prevalence of hematuria, prevalence of SH eggs, or intensity of infections. We conclude that, in this setting, the SAC threshold is not useful for treatment decisions in adults. Given the increased risk of subtle morbidity or urogenital schistosomiasis as a risk factor for human immunodeficiency virus (HIV), more liberal treatment of adults with praziquantel is warranted.
PMCID: PMC3592522  PMID: 23382170

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