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  • Open Access
    Authors: 
    Travis G. Wentz; Travis G. Wentz; Travis G. Wentz; Benjamin J. M. Tremblay; Marite Bradshaw; Andrew C. Doxey; Shashi K. Sharma; John-Demian Sauer; Sabine Pellett;
    Publisher: Frontiers Media SA
    Project: NIH | Characteristics of Botuli... (1R01AI139306-01A1)

    Most strains of proteolytic group I Clostridium botulinum (G1 C. botulinum) and some strains of Clostridium sporogenes possess genes encoding botulinum neurotoxin (BoNT), a potent neuroparalytic agent. Within G1 C. botulinum, conserved bont gene clusters of three major toxin serotypes (bont/A/B/F) can be found on conjugative plasmids and/or within chromosomal pathogenicity islands. CRISPR-Cas systems enable site-specific targeting of previously encountered mobile genetic elements (MGE) such as plasmids and bacteriophage through the creation of a spacer library complementary to protospacers within the MGEs. To examine whether endogenous CRISPR-Cas systems restrict the transfer of bont gene clusters across strains we conducted a bioinformatic analysis profiling endogenous CRISPR-Cas systems from 241 G1 C. botulinum and C. sporogenes strains. Approximately 6,200 CRISPR spacers were identified across the strains and Type I-B, III-A/B/D cas genes and CRISPR array features were identified in 83% of the strains. Mapping the predicted spacers against the masked strain and RefSeq plasmid dataset identified 56,000 spacer–protospacer matches. While spacers mapped heavily to targets within bont(+) plasmids, no protospacers were identified within the bont gene clusters. These results indicate the toxin is not a direct target of CRISPR-Cas but the plasmids predominantly responsible for its mobilization are. Finally, while the presence of a CRISPR-Cas system did not reliably indicate the presence or absence of a bont gene cluster, comparative genomics across strains indicates they often occupy the same hypervariable loci common to both species, potentially suggesting similar mechanisms are involved in the acquisition and curation of both genomic features.

  • Open Access
    Authors: 
    Nicolaas H. Fourie; Ralph M. Peace; Sarah K. Abey; LeeAnne B. Sherwin; John W. Wiley; Wendy A. Henderson;
    Publisher: MyJove Corporation
    Project: NIH | Symptom Distress Mechanis... (1ZIANR000018-01)

    The gene expression platform assay allows for robust and highly reproducible quantification of the expression of up to 800 transcripts (mRNA or miRNAs) in a single reaction. The miRNA assay counts transcripts by directly imaging and digitally counting miRNA molecules that are labeled with color-coded fluorescent barcoded probe sets (a reporter probe and a capture probe). Barcodes are hybridized directly to mature miRNAs that have been elongated by ligating a unique oligonucleotide tag (miRtag) to the 3' end. Reverse transcription and amplification of the transcripts are not required. Reporter probes contain a sequence of six color positions populated using a combination of four fluorescent colors. The four colors over six positions are used to construct a gene-specific color barcode sequence. Post-hybridization processing is automated on a robotic prep station. After hybridization, the excess probes are washed away, and the tripartite structures (capture probe-miRNA-reporter probe) are fixed to a streptavidin-coated slide via the biotin-labeled capture probe. Imaging and barcode counting is done using a digital analyzer. The immobilized barcoded miRNAs are visualized and imaged using a microscope and camera, and the unique barcodes are decoded and counted. Data quality control (QC), normalization, and analysis are facilitated by a custom-designed data processing and analysis software that accompanies the assay software. The assay demonstrates high linearity over a broad range of expression, as well as high sensitivity. Sample and assay preparation does not involve enzymatic reactions, reverse transcription, or amplification; has few steps; and is largely automated, reducing investigator effects and resulting in high consistency and technical reproducibility. Here, we describe the application of this technology to identifying circulating miRNA perturbations in irritable bowel syndrome.

  • Open Access
    Authors: 
    Francois L. Mayer; James W. Kronstad; Aaron P. Mitchell;
    Publisher: American Society for Microbiology
    Project: NIH | Cryptococcus knockout and... (5R01AI100272-08), CIHR

    ABSTRACT Human fungal pathogens cause over 2 million infections per year and are major drivers of morbidity and mortality. Cryptococcus neoformans and Candida albicans are two of the most common fungal pathogens of humans, together accounting for a staggering 1.4 million infections annually, with very high mortality rates. Patients with dysfunctional immune systems, such as individuals with HIV/AIDS, are particularly susceptible to fungal infections. Unfortunately, relatively few antifungal drugs are currently available and fungi frequently develop resistance, further complicating treatment approaches. In this study, we screened the Pathogen Box chemical library (Medicines for Malaria Venture, Switzerland) in an effort to identify novel antifungal compounds. This approach led to the discovery of a novel, highly potent antifungal agent with activity against both C. neoformans and C. albicans. Our initial study of the mechanism of action suggested that this novel compound prevents fungal proliferation by targeting the ability of C. neoformans to withstand stress at the plasma membrane and cell wall. Because this compound had previously been shown to have low toxicity for mammalian cells, we propose that it represents an attractive lead compound for further antifungal drug development. IMPORTANCE Cryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions. Cryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions.

  • Open Access
    Authors: 
    Julia A. Scott; Duygu Tosun; Meredith N. Braskie; Pauline Maillard; Paul M. Thompson; Michael W. Weiner; Charles DeCarli; Owen Carmichael;
    Publisher: Elsevier BV
    Country: United States
    Project: NIH | CORE-- CLINICAL (3P30AG010129-11S1), NIH | ENIGMA Center for Worldwi... (3U54EB020403-04S1), CIHR , NIH | Alzheimers Disease Neuroi... (1U01AG024904-01)

    The purpose of this study was to determine whether white matter microstructure measured by diffusion magnetic resonance imaging (dMRI) provides independent information about baseline level or change in executive function (EF) or memory (MEM) in older adults with and without cognitive impairment. Longitudinal data was acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study from phases GO and 2 (2009–2015). ADNI participants included were diagnosed as cognitively normal (n = 46), early mild cognitive impairment (MCI) (n = 48), late MCI (n = 29), and dementia (n = 39) at baseline. We modeled the association between dMRI-based global white matter mean diffusivity (MD) and baseline level and change in EF and MEM composite scores, in models controlling for baseline bilateral hippocampal volume, regional cerebral FDG PET metabolism and global cerebral AV45 PET uptake. EF and MEM composite scores were measured at baseline, 6, 12, 24 and 36 months. In the baseline late MCI and dementia groups, greater global MD was associated with lesser baseline EF, but not EF change nor MEM baseline or change. As expected, lesser hippocampal volume and lesser FDG PET metabolism was associated with greater rates of EF and MEM decline. In ADNI-GO/2 participants, white matter integrity provided independent information about current executive function, but was not sensitive to future cognitive change. Since individuals experiencing executive function declines progress to dementia more rapidly than those with only memory impairment, better biomarkers of future executive function decline are needed. Highlights • In the ADNI cohort, MRI and PET predictors of baseline and change in executive function were tested. • Global mean diffusivity was associated with baseline, but not change in, executive function. • Diffusion MRI provides independent information on current executive function in older adults.

  • Open Access
    Authors: 
    Davide F. Robbiani; Christian Gaebler; Frauke Muecksch; Julio Cetrulo Lorenzi; Zijun Wang; Alice Cho; Marianna Agudelo; Chris P. Barnes; Shlomo Finkin; Thomas Hagglof; +36 more
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | Classifying DNA Mismatch ... (5R01CA164944-03), NIH | Protocol Review and Monit... (3P30CA042014-23S1)

    ABSTRACTPart 1Development and calibration of suitably accurate functional assays for BRCA1 RING domain and BRCT domain missense substitutions could dramatically accelerate clinical classification of rare missense substitutions observed in that gene. Leveraging data from 68,000 full sequence tests of BRCA1 and BRCA2, plus data from the limited number of already classified BRCA1 RING domain missense substitutions, we used logistic regression and related techniques to evaluate three BRCA1 RING domain assays. These were recently described high throughput yeast 2-hybrid and E3 ubiquitin ligase assays, plus a newly developed mammalian 2-hybrid assay. While there were concerns about the accuracy of the yeast 2-hybrid assay and the indirect nature of the ubiquitin ligase assay, the mammalian 2-hybrid assay had excellent correlation with existing missense substitution classifications. After calibration, this assay contributed to classification of one newly reported BRCA1 missense substitution. In principal, the mammalian 2-hybrid assay could be converted to a high-throughput format that would likely retain suitable accuracy.Part 2How does one achieve clinically applicable classification of the vast majority of all possible sequence variants in disease susceptibility genes? BRCA1 is a high-risk susceptibility gene for breast and ovarian cancer. Pathogenic protein truncating variants are scattered across the open reading frame, but all known missense substitutions that are pathogenic because of missense dysfunction are located in either the amino-terminal RING domain or the carboxy-terminal BRCT domain. Heterodimerization of the BRCA1 and BARD1 RING domains is a molecularly defined obligate activity. Hence, we tested every BRCA1 RING domain missense substitution that can be created by a single nucleotide change for heterodimerization with BARD1 in a Mammalian 2-hybrid (M2H) assay. Downstream of the M2H laboratory assay, we addressed three additional challenges: assay calibration, validation thereof, and integration of the calibrated results with other available data such as computational evidence and patient/population observational data to achieve clinically applicable classification. Overall, we found that about 20% of BRCA1 RING domain missense substitutions are pathogenic. Using a Bayesian point system for data integration and variant classification, we achieved clinical classification of about 89% of observed missense substitutions. Moreover, among missense substitutions not present in the human observational data used here, we find an additional 47 with concordant computational and functional assay evidence in favor of pathogenicity; these are particularly likely to be classified as Likely Pathogenic once human observational data become available.

  • Open Access
    Authors: 
    Sergio E. Baranzini; Parvin Mousavi; Jordi Río; Stacy J. Caillier; Althea Stillman; Pablo Villoslada; Matthew M Wyatt; Manuel Comabella; Larry D. Greller; Roland Somogyi; +2 more
    Publisher: Public Library of Science (PLoS)
    Country: Spain
    Project: NIH | MECHANISMS OF ORAL TOLERA... (5R01AI042911-03)

    Changes in cellular functions in response to drug therapy are mediated by specific transcriptional profiles resulting from the induction or repression in the activity of a number of genes, thereby modifying the preexisting gene activity pattern of the drug-targeted cell(s). Recombinant human interferon beta (rIFNβ) is routinely used to control exacerbations in multiple sclerosis patients with only partial success, mainly because of adverse effects and a relatively large proportion of nonresponders. We applied advanced data-mining and predictive modeling tools to a longitudinal 70-gene expression dataset generated by kinetic reverse-transcription PCR from 52 multiple sclerosis patients treated with rIFNβ to discover higher-order predictive patterns associated with treatment outcome and to define the molecular footprint that rIFNβ engraves on peripheral blood mononuclear cells. We identified nine sets of gene triplets whose expression, when tested before the initiation of therapy, can predict the response to interferon beta with up to 86% accuracy. In addition, time-series analysis revealed potential key players involved in a good or poor response to interferon beta. Statistical testing of a random outcome class and tolerance to noise was carried out to establish the robustness of the predictive models. Large-scale kinetic reverse-transcription PCR, coupled with advanced data-mining efforts, can effectively reveal preexisting and drug-induced gene expression signatures associated with therapeutic effects. By studying gene expression in patients with multiple sclerosis before and after therapy with beta interferon, it is possible to identify gene expression signatures that are associated with therapeutic effects

  • Open Access
    Authors: 
    Andrew R Kerrigan; Nadi Nina Kaonga; Alice M. Tang; Michael R. Jordan; Steven Y. Hong;
    Publisher: Informa UK Limited
    Project: NIH | Namibia ART Patient Traci... (1K23AI097010-01A1), CIHR

    Mobile phones are increasingly being used to support health activities, including the care and management of people living with HIV/AIDS. Short message service (SMS), in particular, has been explored as a means to optimize and support behaviour change. However, there is minimal guidance on messaging content development. The purpose of this review was to help inform the content of SMS messages for mobile health (mHealth) initiatives designed to support anti-retroviral therapy (ART) adherence and clinic appointment keeping in resource-limited settings. PubMed, OvidMedline, Google Scholar, K4Health’s mHealth Evidence database, the mHealth Working Group project resource, and Health COMpass were searched. A request to online communities for recommendations on message content was also made. 1010 unique sources were identified, of which 51 were included in this review. The information was organized into three categories: pre-message development, message development, and security and privacy. Fifteen of the publications explicitly provided their message content. Important lessons when developing the content of SMS were: 1) conducting formative research; 2) grounding content in behaviour change theory; and 3) reviewing proposed content with experts. Best practices exist for developing message content for behaviour change. Efforts should be continued to apply lessons learned from the existing literature to inform mHealth initiatives supporting HIV/AIDS care and treatment.

  • Open Access
    Authors: 
    Eric Berg; Xuezhu Zhang; Julien Bec; Martin S. Judenhofer; Brijesh Patel; Qiyu Peng; M. Kapusta; Matthias J. Schmand; Michael E. Casey; Alice F. Tarantal; +3 more
    Publisher: Society of Nuclear Medicine
    Project: NIH | EXPLORER: Changing the Mo... (1R01CA206187-01), NSERC

    We describe a long axial field-of-view (FOV) PET scanner for high-sensitivity and total-body imaging of nonhuman primates and present the physical performance and first phantom and animal imaging results. Methods: The mini-EXPLORER PET scanner was built using the components of a clinical scanner reconfigured with a detector ring diameter of 43.5 cm and an axial length of 45.7 cm. National Electrical Manufacturers Association (NEMA) NU-2 and NU-4 phantoms were used to measure sensitivity and count rate performance. Reconstructed spatial resolution was investigated by imaging a radially stepped point source and a Derenzo phantom. The effect of the wide acceptance angle was investigated by comparing performance with maximum acceptance angles of 14°–46°. Lastly, an initial assessment of the in vivo performance of the mini-EXPLORER was undertaken with a dynamic 18F-FDG nonhuman primate (rhesus monkey) imaging study. Results: The NU-2 total sensitivity was 5.0%, and the peak noise-equivalent count rate measured with the NU-4 monkey scatter phantom was 1,741 kcps, both obtained using the maximum acceptance angle (46°). The NU-4 scatter fraction was 16.5%, less than 1% higher than with a 14° acceptance angle. The reconstructed spatial resolution was approximately 3.0 mm at the center of the FOV, with a minor loss in axial spatial resolution (0.5 mm) when the acceptance angle increased from 14° to 46°. The rhesus monkey 18F-FDG study demonstrated the benefit of the high sensitivity of the mini-EXPLORER, including fast imaging (1-s early frames), excellent image quality (30-s and 5-min frames), and late-time-point imaging (18 h after injection), all obtained at a single bed position that captured the major organs of the rhesus monkey. Conclusion: This study demonstrated the physical performance and imaging capabilities of a long axial FOV PET scanner designed for high-sensitivity imaging of nonhuman primates. Further, the results of this study suggest that a wide acceptance angle can be used with a long axial FOV scanner to maximize sensitivity while introducing only minor trade-offs such as a small increase in scatter fraction and slightly degraded axial spatial resolution.

  • Open Access
    Authors: 
    Joey W. Trampush; M. L. Z. Yang; Jin Yu; Emma Knowles; Gary Davies; David C. Liewald; John M. Starr; Srdjan Djurovic; Ingrid Melle; Kjetil Sundet; +56 more
    Publisher: Springer Science and Business Media LLC
    Countries: United States, Norway, Finland, United Kingdom, Ireland
    Project: NIH | CORONARY HEART DISEASE &S... (N01HC085081-016), NIH | CORONARY HEART DISEASE AN... (N01HC085085-006), NIH | CTSA INFRASTRUCTURE FOR A... (1UL1RR033176-01), NIH | A Longitudinal Study of A... (5R01MH066140-08), NIH | Striatal D2/D3 Dopamine r... (1P50MH080173-01A1), NIH | Neurodevelopmental Genomi... (5RC2MH089983-02), NIH | Neural signatures of heal... (1R01AG049789-01), NIH | 1/2 Schizophrenia Heterog... (5R01MH092515-03), NIH | CARDIOVASCULAR HEALTH STU... (N01HC035129-010), NIH | Twin Study of ADHD, CD an... (5R01DA013240-10),...

    Abstract The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10−8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

  • Open Access
    Authors: 
    Montserrat Garcia-Closas; Sara Lindström; Kyriaki Michailidou; Marjanka K. Schmidt; Mark N. Brook; Elio Riboli; Loic Le Marchand; Diana Eccles; Penelope Miron; Peter A. Fasching; +201 more
    Publisher: Springer Science and Business Media LLC
    Countries: Netherlands, United Kingdom, Italy, Ireland
    Project: NIH | Characterizing Genetic Su... (5U01CA098710-06), WT , NIH | Breast &prostate cancer &... (1U01CA098216-01), NIH | Characterizing Genetic Su... (5U01CA098233-06), NIH | Genetic epidemiology of c... (3R01CA122340-03S1), EC | COGS (223175), CIHR , NIH | Discovery Expansion and R... (5U19CA148065-04), NIH | Breast &Prostate Cancer &... (1U01CA098758-01)

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a metaanalysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P= 2.1 x 10(-12) and LGR6, P = 1.4 x 10(-8)), 2p24.1 (P = 4.6 x 10(-8)) and 16q12.2 (FTO, P = 4.0 x 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P&gt; 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

Include:
24,775 Research products, page 1 of 2,478
  • Open Access
    Authors: 
    Travis G. Wentz; Travis G. Wentz; Travis G. Wentz; Benjamin J. M. Tremblay; Marite Bradshaw; Andrew C. Doxey; Shashi K. Sharma; John-Demian Sauer; Sabine Pellett;
    Publisher: Frontiers Media SA
    Project: NIH | Characteristics of Botuli... (1R01AI139306-01A1)

    Most strains of proteolytic group I Clostridium botulinum (G1 C. botulinum) and some strains of Clostridium sporogenes possess genes encoding botulinum neurotoxin (BoNT), a potent neuroparalytic agent. Within G1 C. botulinum, conserved bont gene clusters of three major toxin serotypes (bont/A/B/F) can be found on conjugative plasmids and/or within chromosomal pathogenicity islands. CRISPR-Cas systems enable site-specific targeting of previously encountered mobile genetic elements (MGE) such as plasmids and bacteriophage through the creation of a spacer library complementary to protospacers within the MGEs. To examine whether endogenous CRISPR-Cas systems restrict the transfer of bont gene clusters across strains we conducted a bioinformatic analysis profiling endogenous CRISPR-Cas systems from 241 G1 C. botulinum and C. sporogenes strains. Approximately 6,200 CRISPR spacers were identified across the strains and Type I-B, III-A/B/D cas genes and CRISPR array features were identified in 83% of the strains. Mapping the predicted spacers against the masked strain and RefSeq plasmid dataset identified 56,000 spacer–protospacer matches. While spacers mapped heavily to targets within bont(+) plasmids, no protospacers were identified within the bont gene clusters. These results indicate the toxin is not a direct target of CRISPR-Cas but the plasmids predominantly responsible for its mobilization are. Finally, while the presence of a CRISPR-Cas system did not reliably indicate the presence or absence of a bont gene cluster, comparative genomics across strains indicates they often occupy the same hypervariable loci common to both species, potentially suggesting similar mechanisms are involved in the acquisition and curation of both genomic features.

  • Open Access
    Authors: 
    Nicolaas H. Fourie; Ralph M. Peace; Sarah K. Abey; LeeAnne B. Sherwin; John W. Wiley; Wendy A. Henderson;
    Publisher: MyJove Corporation
    Project: NIH | Symptom Distress Mechanis... (1ZIANR000018-01)

    The gene expression platform assay allows for robust and highly reproducible quantification of the expression of up to 800 transcripts (mRNA or miRNAs) in a single reaction. The miRNA assay counts transcripts by directly imaging and digitally counting miRNA molecules that are labeled with color-coded fluorescent barcoded probe sets (a reporter probe and a capture probe). Barcodes are hybridized directly to mature miRNAs that have been elongated by ligating a unique oligonucleotide tag (miRtag) to the 3' end. Reverse transcription and amplification of the transcripts are not required. Reporter probes contain a sequence of six color positions populated using a combination of four fluorescent colors. The four colors over six positions are used to construct a gene-specific color barcode sequence. Post-hybridization processing is automated on a robotic prep station. After hybridization, the excess probes are washed away, and the tripartite structures (capture probe-miRNA-reporter probe) are fixed to a streptavidin-coated slide via the biotin-labeled capture probe. Imaging and barcode counting is done using a digital analyzer. The immobilized barcoded miRNAs are visualized and imaged using a microscope and camera, and the unique barcodes are decoded and counted. Data quality control (QC), normalization, and analysis are facilitated by a custom-designed data processing and analysis software that accompanies the assay software. The assay demonstrates high linearity over a broad range of expression, as well as high sensitivity. Sample and assay preparation does not involve enzymatic reactions, reverse transcription, or amplification; has few steps; and is largely automated, reducing investigator effects and resulting in high consistency and technical reproducibility. Here, we describe the application of this technology to identifying circulating miRNA perturbations in irritable bowel syndrome.

  • Open Access
    Authors: 
    Francois L. Mayer; James W. Kronstad; Aaron P. Mitchell;
    Publisher: American Society for Microbiology
    Project: NIH | Cryptococcus knockout and... (5R01AI100272-08), CIHR

    ABSTRACT Human fungal pathogens cause over 2 million infections per year and are major drivers of morbidity and mortality. Cryptococcus neoformans and Candida albicans are two of the most common fungal pathogens of humans, together accounting for a staggering 1.4 million infections annually, with very high mortality rates. Patients with dysfunctional immune systems, such as individuals with HIV/AIDS, are particularly susceptible to fungal infections. Unfortunately, relatively few antifungal drugs are currently available and fungi frequently develop resistance, further complicating treatment approaches. In this study, we screened the Pathogen Box chemical library (Medicines for Malaria Venture, Switzerland) in an effort to identify novel antifungal compounds. This approach led to the discovery of a novel, highly potent antifungal agent with activity against both C. neoformans and C. albicans. Our initial study of the mechanism of action suggested that this novel compound prevents fungal proliferation by targeting the ability of C. neoformans to withstand stress at the plasma membrane and cell wall. Because this compound had previously been shown to have low toxicity for mammalian cells, we propose that it represents an attractive lead compound for further antifungal drug development. IMPORTANCE Cryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions. Cryptococcus neoformans and Candida albicans are two major human fungal pathogens and together account for over 1.4 million infections annually, with very high mortality rates. These fungi often infect immunocompromised individuals, such as HIV/AIDS patients. In an effort to identify novel drugs with antifungal activity, we have screened the Pathogen Box for compounds with anticryptococcal and anticandidal activities. This approach led to the discovery of a promising lead compound (MMV688271) with strong antifungal potency under nutrient-limited conditions.

  • Open Access
    Authors: 
    Julia A. Scott; Duygu Tosun; Meredith N. Braskie; Pauline Maillard; Paul M. Thompson; Michael W. Weiner; Charles DeCarli; Owen Carmichael;
    Publisher: Elsevier BV
    Country: United States
    Project: NIH | CORE-- CLINICAL (3P30AG010129-11S1), NIH | ENIGMA Center for Worldwi... (3U54EB020403-04S1), CIHR , NIH | Alzheimers Disease Neuroi... (1U01AG024904-01)

    The purpose of this study was to determine whether white matter microstructure measured by diffusion magnetic resonance imaging (dMRI) provides independent information about baseline level or change in executive function (EF) or memory (MEM) in older adults with and without cognitive impairment. Longitudinal data was acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study from phases GO and 2 (2009–2015). ADNI participants included were diagnosed as cognitively normal (n = 46), early mild cognitive impairment (MCI) (n = 48), late MCI (n = 29), and dementia (n = 39) at baseline. We modeled the association between dMRI-based global white matter mean diffusivity (MD) and baseline level and change in EF and MEM composite scores, in models controlling for baseline bilateral hippocampal volume, regional cerebral FDG PET metabolism and global cerebral AV45 PET uptake. EF and MEM composite scores were measured at baseline, 6, 12, 24 and 36 months. In the baseline late MCI and dementia groups, greater global MD was associated with lesser baseline EF, but not EF change nor MEM baseline or change. As expected, lesser hippocampal volume and lesser FDG PET metabolism was associated with greater rates of EF and MEM decline. In ADNI-GO/2 participants, white matter integrity provided independent information about current executive function, but was not sensitive to future cognitive change. Since individuals experiencing executive function declines progress to dementia more rapidly than those with only memory impairment, better biomarkers of future executive function decline are needed. Highlights • In the ADNI cohort, MRI and PET predictors of baseline and change in executive function were tested. • Global mean diffusivity was associated with baseline, but not change in, executive function. • Diffusion MRI provides independent information on current executive function in older adults.

  • Open Access
    Authors: 
    Davide F. Robbiani; Christian Gaebler; Frauke Muecksch; Julio Cetrulo Lorenzi; Zijun Wang; Alice Cho; Marianna Agudelo; Chris P. Barnes; Shlomo Finkin; Thomas Hagglof; +36 more
    Publisher: Cold Spring Harbor Laboratory
    Project: NIH | Classifying DNA Mismatch ... (5R01CA164944-03), NIH | Protocol Review and Monit... (3P30CA042014-23S1)

    ABSTRACTPart 1Development and calibration of suitably accurate functional assays for BRCA1 RING domain and BRCT domain missense substitutions could dramatically accelerate clinical classification of rare missense substitutions observed in that gene. Leveraging data from 68,000 full sequence tests of BRCA1 and BRCA2, plus data from the limited number of already classified BRCA1 RING domain missense substitutions, we used logistic regression and related techniques to evaluate three BRCA1 RING domain assays. These were recently described high throughput yeast 2-hybrid and E3 ubiquitin ligase assays, plus a newly developed mammalian 2-hybrid assay. While there were concerns about the accuracy of the yeast 2-hybrid assay and the indirect nature of the ubiquitin ligase assay, the mammalian 2-hybrid assay had excellent correlation with existing missense substitution classifications. After calibration, this assay contributed to classification of one newly reported BRCA1 missense substitution. In principal, the mammalian 2-hybrid assay could be converted to a high-throughput format that would likely retain suitable accuracy.Part 2How does one achieve clinically applicable classification of the vast majority of all possible sequence variants in disease susceptibility genes? BRCA1 is a high-risk susceptibility gene for breast and ovarian cancer. Pathogenic protein truncating variants are scattered across the open reading frame, but all known missense substitutions that are pathogenic because of missense dysfunction are located in either the amino-terminal RING domain or the carboxy-terminal BRCT domain. Heterodimerization of the BRCA1 and BARD1 RING domains is a molecularly defined obligate activity. Hence, we tested every BRCA1 RING domain missense substitution that can be created by a single nucleotide change for heterodimerization with BARD1 in a Mammalian 2-hybrid (M2H) assay. Downstream of the M2H laboratory assay, we addressed three additional challenges: assay calibration, validation thereof, and integration of the calibrated results with other available data such as computational evidence and patient/population observational data to achieve clinically applicable classification. Overall, we found that about 20% of BRCA1 RING domain missense substitutions are pathogenic. Using a Bayesian point system for data integration and variant classification, we achieved clinical classification of about 89% of observed missense substitutions. Moreover, among missense substitutions not present in the human observational data used here, we find an additional 47 with concordant computational and functional assay evidence in favor of pathogenicity; these are particularly likely to be classified as Likely Pathogenic once human observational data become available.

  • Open Access
    Authors: 
    Sergio E. Baranzini; Parvin Mousavi; Jordi Río; Stacy J. Caillier; Althea Stillman; Pablo Villoslada; Matthew M Wyatt; Manuel Comabella; Larry D. Greller; Roland Somogyi; +2 more
    Publisher: Public Library of Science (PLoS)
    Country: Spain
    Project: NIH | MECHANISMS OF ORAL TOLERA... (5R01AI042911-03)

    Changes in cellular functions in response to drug therapy are mediated by specific transcriptional profiles resulting from the induction or repression in the activity of a number of genes, thereby modifying the preexisting gene activity pattern of the drug-targeted cell(s). Recombinant human interferon beta (rIFNβ) is routinely used to control exacerbations in multiple sclerosis patients with only partial success, mainly because of adverse effects and a relatively large proportion of nonresponders. We applied advanced data-mining and predictive modeling tools to a longitudinal 70-gene expression dataset generated by kinetic reverse-transcription PCR from 52 multiple sclerosis patients treated with rIFNβ to discover higher-order predictive patterns associated with treatment outcome and to define the molecular footprint that rIFNβ engraves on peripheral blood mononuclear cells. We identified nine sets of gene triplets whose expression, when tested before the initiation of therapy, can predict the response to interferon beta with up to 86% accuracy. In addition, time-series analysis revealed potential key players involved in a good or poor response to interferon beta. Statistical testing of a random outcome class and tolerance to noise was carried out to establish the robustness of the predictive models. Large-scale kinetic reverse-transcription PCR, coupled with advanced data-mining efforts, can effectively reveal preexisting and drug-induced gene expression signatures associated with therapeutic effects. By studying gene expression in patients with multiple sclerosis before and after therapy with beta interferon, it is possible to identify gene expression signatures that are associated with therapeutic effects

  • Open Access
    Authors: 
    Andrew R Kerrigan; Nadi Nina Kaonga; Alice M. Tang; Michael R. Jordan; Steven Y. Hong;
    Publisher: Informa UK Limited
    Project: NIH | Namibia ART Patient Traci... (1K23AI097010-01A1), CIHR

    Mobile phones are increasingly being used to support health activities, including the care and management of people living with HIV/AIDS. Short message service (SMS), in particular, has been explored as a means to optimize and support behaviour change. However, there is minimal guidance on messaging content development. The purpose of this review was to help inform the content of SMS messages for mobile health (mHealth) initiatives designed to support anti-retroviral therapy (ART) adherence and clinic appointment keeping in resource-limited settings. PubMed, OvidMedline, Google Scholar, K4Health’s mHealth Evidence database, the mHealth Working Group project resource, and Health COMpass were searched. A request to online communities for recommendations on message content was also made. 1010 unique sources were identified, of which 51 were included in this review. The information was organized into three categories: pre-message development, message development, and security and privacy. Fifteen of the publications explicitly provided their message content. Important lessons when developing the content of SMS were: 1) conducting formative research; 2) grounding content in behaviour change theory; and 3) reviewing proposed content with experts. Best practices exist for developing message content for behaviour change. Efforts should be continued to apply lessons learned from the existing literature to inform mHealth initiatives supporting HIV/AIDS care and treatment.

  • Open Access
    Authors: 
    Eric Berg; Xuezhu Zhang; Julien Bec; Martin S. Judenhofer; Brijesh Patel; Qiyu Peng; M. Kapusta; Matthias J. Schmand; Michael E. Casey; Alice F. Tarantal; +3 more
    Publisher: Society of Nuclear Medicine
    Project: NIH | EXPLORER: Changing the Mo... (1R01CA206187-01), NSERC

    We describe a long axial field-of-view (FOV) PET scanner for high-sensitivity and total-body imaging of nonhuman primates and present the physical performance and first phantom and animal imaging results. Methods: The mini-EXPLORER PET scanner was built using the components of a clinical scanner reconfigured with a detector ring diameter of 43.5 cm and an axial length of 45.7 cm. National Electrical Manufacturers Association (NEMA) NU-2 and NU-4 phantoms were used to measure sensitivity and count rate performance. Reconstructed spatial resolution was investigated by imaging a radially stepped point source and a Derenzo phantom. The effect of the wide acceptance angle was investigated by comparing performance with maximum acceptance angles of 14°–46°. Lastly, an initial assessment of the in vivo performance of the mini-EXPLORER was undertaken with a dynamic 18F-FDG nonhuman primate (rhesus monkey) imaging study. Results: The NU-2 total sensitivity was 5.0%, and the peak noise-equivalent count rate measured with the NU-4 monkey scatter phantom was 1,741 kcps, both obtained using the maximum acceptance angle (46°). The NU-4 scatter fraction was 16.5%, less than 1% higher than with a 14° acceptance angle. The reconstructed spatial resolution was approximately 3.0 mm at the center of the FOV, with a minor loss in axial spatial resolution (0.5 mm) when the acceptance angle increased from 14° to 46°. The rhesus monkey 18F-FDG study demonstrated the benefit of the high sensitivity of the mini-EXPLORER, including fast imaging (1-s early frames), excellent image quality (30-s and 5-min frames), and late-time-point imaging (18 h after injection), all obtained at a single bed position that captured the major organs of the rhesus monkey. Conclusion: This study demonstrated the physical performance and imaging capabilities of a long axial FOV PET scanner designed for high-sensitivity imaging of nonhuman primates. Further, the results of this study suggest that a wide acceptance angle can be used with a long axial FOV scanner to maximize sensitivity while introducing only minor trade-offs such as a small increase in scatter fraction and slightly degraded axial spatial resolution.

  • Open Access
    Authors: 
    Joey W. Trampush; M. L. Z. Yang; Jin Yu; Emma Knowles; Gary Davies; David C. Liewald; John M. Starr; Srdjan Djurovic; Ingrid Melle; Kjetil Sundet; +56 more
    Publisher: Springer Science and Business Media LLC
    Countries: United States, Norway, Finland, United Kingdom, Ireland
    Project: NIH | CORONARY HEART DISEASE &S... (N01HC085081-016), NIH | CORONARY HEART DISEASE AN... (N01HC085085-006), NIH | CTSA INFRASTRUCTURE FOR A... (1UL1RR033176-01), NIH | A Longitudinal Study of A... (5R01MH066140-08), NIH | Striatal D2/D3 Dopamine r... (1P50MH080173-01A1), NIH | Neurodevelopmental Genomi... (5RC2MH089983-02), NIH | Neural signatures of heal... (1R01AG049789-01), NIH | 1/2 Schizophrenia Heterog... (5R01MH092515-03), NIH | CARDIOVASCULAR HEALTH STU... (N01HC035129-010), NIH | Twin Study of ADHD, CD an... (5R01DA013240-10),...

    Abstract The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10−8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

  • Open Access
    Authors: 
    Montserrat Garcia-Closas; Sara Lindström; Kyriaki Michailidou; Marjanka K. Schmidt; Mark N. Brook; Elio Riboli; Loic Le Marchand; Diana Eccles; Penelope Miron; Peter A. Fasching; +201 more
    Publisher: Springer Science and Business Media LLC
    Countries: Netherlands, United Kingdom, Italy, Ireland
    Project: NIH | Characterizing Genetic Su... (5U01CA098710-06), WT , NIH | Breast &prostate cancer &... (1U01CA098216-01), NIH | Characterizing Genetic Su... (5U01CA098233-06), NIH | Genetic epidemiology of c... (3R01CA122340-03S1), EC | COGS (223175), CIHR , NIH | Discovery Expansion and R... (5U19CA148065-04), NIH | Breast &Prostate Cancer &... (1U01CA098758-01)

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a metaanalysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P= 2.1 x 10(-12) and LGR6, P = 1.4 x 10(-8)), 2p24.1 (P = 4.6 x 10(-8)) and 16q12.2 (FTO, P = 4.0 x 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P&gt; 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.