Publications by authors named "J Michael Cherry"

982 Publications

Study of retinal structural-functional relationship in choroideremia using fundus autofluorescence and optical coherence tomography.

Eye (Lond) 2021 Feb 16. Epub 2021 Feb 16.

University of Pittsburgh School of Medicine, Medical Retina and Vitreoretinal Surgery, Pittsburg, PA, USA.

Objective: The objective of this study was to assess the structural-functional relationship in choroideremia (CHM) patients using optical coherence tomography (OCT) and autofluorescence (AF) images.

Methods: In this study, 53 eyes of 28 CHM patients were included. Demographic, ocular and clinical fundus features were recorded. Fundus AF and OCT images were analysed. Patients were classified into two groups based on AF features: group 1, CHM patients where the foveal island was present and group 2, CHM patients where the foveal island was absent. Inner and outer retinal layer thicknesses, retinal pigment epithelium (RPE) and subfoveal choroidal thickness (SFCT) were measured and correlated with visual acuity (VA).

Results: There were 26 eyes in group 1 and 27 eyes in group 2. Mean age in groups 1 and 2 were 51.7 ± 13.4 and 63.6 ± 11.6 years, respectively. Age (p = 0.001) and VA (p < 0.001) between the two groups were significantly different. The retinal and SFCT showed significant differences that were analysed for each eye between the two groups. Reduced VA was noted with increasing age (r = 0.483; p ≤ 0.001), thin total retina (r = -0.378; p = 0.005), inner (r = -0.512; p < 0.001), outer (r = -0.59; p < 0.001) retinal thicknesses and thin RPE (r = -0.653; p < 0.001). Multivariate analysis showed RPE thickness (p = 0.001) as the most important index that affected VA.

Conclusion: RPE thinning contributes to poor VA in patients with advanced CHM. Further studies are needed to evaluate the role of retinal thickness and SFCT and its relationship to VA.
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http://dx.doi.org/10.1038/s41433-021-01441-0DOI Listing
February 2021

Zika Virus Neutralizing Antibody Kinetics in Antenatally Exposed Infants.

J Infect Dis 2021 Feb 2. Epub 2021 Feb 2.

Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil.

Background: Zika virus (ZIKV) is associated with severe congenital abnormalities and laboratory diagnosis of antenatal infection is difficult. Here we evaluated ZIKV neutralizing antibody (Nab) kinetics in infants born to mothers with PCR-confirmed ZIKV infection during pregnancy.

Methods: Neonates (n=98) had serum specimens tested repeatedly for ZIKV Nab over the first two years of life using virus neutralization test (VNT). ZIKV neonatal infection was confirmed by RT-PCR in blood or urine and/or presence of ZIKV IgM antibodies, and results were correlated with infant clinical features.

Results: Postnatal laboratory evidence of ZIKV vertical transmission was obtained for 60.2% of children, while 32.7% exhibited clinical abnormalities. Congenital abnormalities were found in 37.3% of children with confirmed ZIKV infection and 31.0% of children without confirmed infection (p=0.734). All but one child displayed a physiologic decline in ZIKV Nab, reflecting maternal antibody decay, despite an early ZIKV-IgM response in 1/3 of infants.

Conclusions: Infants with antenatal ZIKV exposure do not develop ZIKV Nab despite an early IgM response. Therefore, ZIKV VNT in children is not useful for diagnosis of congenital infection. In light of these findings, it remains to be determined if children infected in utero are potentially susceptible to reinfection.
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http://dx.doi.org/10.1093/infdis/jiab054DOI Listing
February 2021

Restoring Fringing Tidal Marshes for Ecological Function and Ecosystem Resilience to Moderate Sea-level Rise in the Northern Gulf of Mexico.

Environ Manage 2021 Feb 11;67(2):384-397. Epub 2021 Jan 11.

University of Alabama, Department of Biological Sciences and New College, Box 870334, Tuscaloosa, AL, 35487, USA.

Tidal marshes are increasingly vulnerable to degradation or loss from eutrophication, land-use changes, and accelerating sea-level rise, making restoration necessary to recover ecosystem services. To evaluate effects of restoration planting density and sea-level rise on ecosystem function (i.e., nitrogen removal), we restored three marshes, which differed in elevation, at Weeks Bay National Estuarine Research Reserve, Alabama, USA and planted them with Juncus roemerianus sods at 0, 25, 50, 75, or 100% initial cover. We simulated future sea level using passive weirs that increased flooding during low tide. Because additional species emerged shortly after transplantation, we also tested for treatment effects on community structure. In all marshes, species richness increased following restoration, regardless of treatments, while relative abundances of new species tended to increase with increasing initial cover. Plant percent cover increased with increasing initial cover in all marshes, with similar vegetated cover at 50, 75, and 100% after 3 years in the highest elevation marsh. Porewater dissolved inorganic nitrogen concentrations ([DIN]) decreased with increasing initial cover in all marshes, and were significantly lower in 50, 75, and 100% treatments than 0 or 25% after 1 year. Furthermore, [DIN] was similarly low among 50, 75, and 100% treatments when elevation capital was highest. These results suggest that intermediate initial cover (50%) can recover plant cover and promote nitrogen removal when elevation capital is adequate at relatively lower labor and material costs than planting at higher cover, thereby maximizing restoration outcomes in the face of low to moderate sea-level rise.
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http://dx.doi.org/10.1007/s00267-020-01410-5DOI Listing
February 2021

CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy.

J Neuroinflammation 2020 Dec 5;17(1):370. Epub 2020 Dec 5.

Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.

Background: Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. Past work has implicated early and sustained activation of microglia as a potential driver of tau pathology within the frontal cortex in CTE. However, the RHI induced signals required to recruit microglia to areas of damage and pathology are unknown.

Methods: Postmortem brain tissue was obtained from 261 individuals across multiple brain banks. Comparisons were made using cases with CTE, cases with Alzheimer's disease (AD), and cases with no neurodegenerative disease and lacked exposure to RHI (controls). Recruitment of Iba1+ cells around the CTE perivascular lesion was compared to non-lesion vessels. TMEM119 staining was used to characterize microglia or macrophage involvement. The potent chemoattractant CCL2 was analyzed using frozen tissue from the dorsolateral frontal cortex (DLFC) and the calcarine cortex. Finally, the amounts of hyperphosphorylated tau (pTau) and Aβ were compared to CCL2 levels to examine possible mechanistic pathways.

Results: An increase in Iba1+ cells was found around blood vessels with perivascular tau pathology compared to non-affected vessels in individuals with RHI. TMEM119 staining revealed the majority of the Iba1+ cells were microglia. CCL2 protein levels in the DLFC were found to correlate with greater years of playing American football, the density of Iba1+ cells, the density of CD68+ cells, and increased CTE severity. When comparing across multiple brain regions, CCL2 increases were more pronounced in the DLFC than the calcarine cortex in cases with RHI but not in AD. When examining the individual contribution of pathogenic proteins to CCL2 changes, pTau correlated with CCL2, independent of age at death and Aβ in AD and CTE. Although levels of Aβ were not correlated with CCL2 in cases with CTE, in males in the AD group, Aβ trended toward an inverse relationship with CCL2 suggesting possible gender associations.

Conclusion: Overall, CCL2 is implicated in the pathways recruiting microglia and the development of pTau pathology after exposure to RHI, and may represent a future therapeutic target in CTE.
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http://dx.doi.org/10.1186/s12974-020-02036-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718711PMC
December 2020

Inter-observer agreement and sensitivity of Optomap images for screening peripheral retinal lesions in patients undergoing refractive surgery.

Indian J Ophthalmol 2020 Dec;68(12):2930-2934

Department of Retina and Vitreous, Narayana Nethralaya, Bengaluru, Karnataka, India.

Purpose: The aim of this study was to compute the sensitivity, specificity and inter-reader variability of ultra-widefield retinal imaging (Optomap 200Tx) for screening retinal lesions before myopic refractive surgery.

Methods: Two hundred and eight eyes of 109 consecutive refractive surgery candidates were included in this study. All subjects underwent Optomap 200Tx, mydriatic slit-lamp lens examination and dilated retinal examination with scleral indentation by a retinal specialist. Retinal findings by indirect dilated examination by retinal specialist was considered as the gold-standard. Sensitivity analyses for the readers were calculated between the Optomap images and the gold-standard retinal examination.

Results: Seventy-three of the 208 eyes (35.1%) had peripheral retinal lesions diagnosed by the retinal specialist on dilated fundus examination. Peripheral lesions were seen on the Optomap images in 111 (53.4%) eyes. Compared to the dilated retinal examination, the detection rate with the Optomap 200Tx was 78.1% and specificity rate was 60%. The accuracy rate between the 3 readers ranged from 72% to 87%. The highest accuracy was noted with the reader post 1 year of retinal training (86.54%).

Conclusion: The Optomap 200Tx showed a high sensitivity and moderate specificity for identifying peripheral retinal lesions in eyes undergoing refractive surgery. The Optomap examination is a convenient, fast and feasible method for detecting the pathological fundus changes in myopic eyes. The reliability of the examination improves when the images are interpreted by a reader with prior retinal training.
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http://dx.doi.org/10.4103/ijo.IJO_2239_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856983PMC
December 2020

Perceptions of Aboriginal and Torres Strait Islander Australians toward cardiovascular primary prevention programs: A qualitative systematic review.

Public Health Nurs 2020 Nov 20. Epub 2020 Nov 20.

School of Nursing, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia.

Objective: To synthesize the best available qualitative evidence on the perceptions of Aboriginal and Torres Strait Islander Australians (hereafter, respectfully referred to as Indigenous Australians) toward participation in cardiovascular primary prevention programs.

Background: In 2017, cardiovascular disease was the leading cause of premature mortality in Indigenous Australians, accounting for 11.5% of all deaths. Health risk behaviors such as smoking, physical inactivity, poor nutrition, and obesity largely contribute to this burden of disease.

Methods: A search using MEDLINE, CINAHL, EMBASE, PubMed, Google Scholar, MedNar, ProQuest and Index to Theses for published and unpublished studies was conducted in January 2020. The methodological quality of the included studies was independently assessed by two reviewers using the Joanna Briggs Institute (JBI) critical appraisal tool. Data extraction and meta-aggregation were conducted in accordance with JBI methodology.

Results: Eleven studies were included. Three synthesized findings were developed (a) social and community support affect participants' experiences of prevention programs; (b) structural drivers and social determinants influence Indigenous Australians experiences and participation in prevention programs and health risk behavioral change; and (c) a personal desire to change behaviors and participate in prevention programs requires development of knowledge regarding healthy lifestyles and creation of new social norms.

Conclusions: Indigenous Australians participation in primary prevention for cardiovascular risk factors and adoption of a healthy lifestyle are influenced by social support, social determinants, and personal desire. Future programs need to tackle the structural drivers and facilitate a supportive environment to assist in health risk behavior change.
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http://dx.doi.org/10.1111/phn.12837DOI Listing
November 2020

Chlorinated Ethene Degradation Rate Coefficients Simulated with Intact Sandstone Core Microcosms.

Environ Sci Technol 2020 12 19;54(24):15829-15839. Epub 2020 Nov 19.

Department of Environmental Engineering and Earth Sciences, Clemson University, Clemson, South Carolina 29634, United States.

Abiotic transformation of trichloroethene (TCE) in fractured porous rock such as sandstone is challenging to characterize and quantify. The objective of this study was to estimate the pseudo first-order abiotic reaction rate coefficients in diffusion-dominated intact core microcosms. The microcosms imitated clean flow through a fracture next to a contaminated rock matrix by exchanging uncontaminated groundwater, unamended or lactate-amended, in a chamber above a TCE-infused sandstone core. Rate coefficients were assessed using a numerical model of the microcosms that were calibrated to monitoring data. Average initial rate coefficients for complete dechlorination of TCE to acetylene, ethene, and ethane were estimated as 0.019 y in unamended microcosms and 0.024 y in lactate-amended microcosms. Moderately higher values (0.026 y for unamended and 0.035 y for lactate-amended) were obtained based on C enrichment data. Abiotic transformation rate coefficients based on gas formation were decreased in unamended microcosms after ∼25 days, to an average of 0.0008 y. This was presumably due to depletion of reductive capacity (average values of 0.12 ± 0.10 μeeq/g iron and 18 ± 15 μeeq/g extractable iron). Model-derived rate coefficients and reductive capacities for the intact core microcosms aligned well with results from a previous microcosm study using crushed sandstone from the same site.
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http://dx.doi.org/10.1021/acs.est.0c05083DOI Listing
December 2020

Data Sanitization to Reduce Private Information Leakage from Functional Genomics.

Cell 2020 Nov;183(4):905-917.e16

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Department of Computer Science, Yale University, New Haven, CT 06520, USA; Department of Statistics and Data Science, Yale University, New Haven, CT 06520, USA. Electronic address:

The generation of functional genomics datasets is surging, because they provide insight into gene regulation and organismal phenotypes (e.g., genes upregulated in cancer). The intent behind functional genomics experiments is not necessarily to study genetic variants, yet they pose privacy concerns due to their use of next-generation sequencing. Moreover, there is a great incentive to broadly share raw reads for better statistical power and general research reproducibility. Thus, we need new modes of sharing beyond traditional controlled-access models. Here, we develop a data-sanitization procedure allowing raw functional genomics reads to be shared while minimizing privacy leakage, enabling principled privacy-utility trade-offs. Our protocol works with traditional Illumina-based assays and newer technologies such as 10x single-cell RNA sequencing. It involves quantifying the privacy leakage in reads by statistically linking study participants to known individuals. We carried out these linkages using data from highly accurate reference genomes and more realistic environmental samples.
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http://dx.doi.org/10.1016/j.cell.2020.09.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672785PMC
November 2020

Association of probable REM sleep behavior disorder with pathology and years of contact sports play in chronic traumatic encephalopathy.

Acta Neuropathol 2020 12 17;140(6):851-862. Epub 2020 Sep 17.

Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA.

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.
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http://dx.doi.org/10.1007/s00401-020-02206-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669574PMC
December 2020

Characterizing tau deposition in chronic traumatic encephalopathy (CTE): utility of the McKee CTE staging scheme.

Acta Neuropathol 2020 10 11;140(4):495-512. Epub 2020 Aug 11.

Department of Neurology, Boston University Alzheimer's Disease and CTE Centers, Boston University School of Medicine, Boston, USA.

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive head impacts (RHI) that has been neuropathologically diagnosed in American football players and other contact sport athletes. In 2013, McKee and colleagues proposed a staging scheme for characterizing the severity of the hyperphosphorylated tau (p-tau) pathology, the McKee CTE staging scheme. The staging scheme defined four pathological stages of CTE, stages I(mild)-IV(severe), based on the density and regional deposition of p-tau. The objective of this study was to test the utility of the McKee CTE staging scheme, and provide a detailed examination of the regional distribution of p-tau in CTE. We examined the relationship between the McKee CTE staging scheme and semi-quantitative and quantitative assessments of regional p-tau pathology, age at death, dementia, and years of American football play among 366 male brain donors neuropathologically diagnosed with CTE (mean age 61.86, SD 18.90). Spearman's rho correlations showed that higher CTE stage was associated with higher scores on all semi-quantitative and quantitative assessments of p-tau severity and density (p's < 0.001). The severity and distribution of CTE p-tau followed an age-dependent progression: older age was associated with increased odds for having a higher CTE stage (p < 0.001). CTE stage was independently associated with increased odds for dementia (p < 0.001). K-medoids cluster analysis of the semi-quantitative scales of p-tau across 14 regions identified 5 clusters of p-tau that conformed to increasing CTE stage (stage IV had 2 slightly different clusters), age at death, dementia, and years of American football play. There was a predilection for p-tau pathology in five regions: dorsolateral frontal cortex (DLF), superior temporal cortex, entorhinal cortex, amygdala, and locus coeruleus (LC), with CTE in the youngest brain donors and lowest CTE stage restricted to DLF and LC. These findings support the usefulness of the McKee CTE staging scheme and demonstrate the regional distribution of p-tau in CTE.
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http://dx.doi.org/10.1007/s00401-020-02197-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914059PMC
October 2020

Expanded encyclopaedias of DNA elements in the human and mouse genomes.

Nature 2020 07 29;583(7818):699-710. Epub 2020 Jul 29.

University of Massachusetts Medical School, Program in Bioinformatics and Integrative Biology, Worcester, MA, USA.

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE and Roadmap Epigenomics data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.
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http://dx.doi.org/10.1038/s41586-020-2493-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410828PMC
July 2020

Perspectives on ENCODE.

Nature 2020 07 29;583(7818):693-698. Epub 2020 Jul 29.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.

The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.
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http://dx.doi.org/10.1038/s41586-020-2449-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410827PMC
July 2020

An atlas of dynamic chromatin landscapes in mouse fetal development.

Nature 2020 07 29;583(7818):744-751. Epub 2020 Jul 29.

Ludwig Institute for Cancer Research, La Jolla, CA, USA.

The Encyclopedia of DNA Elements (ENCODE) project has established a genomic resource for mammalian development, profiling a diverse panel of mouse tissues at 8 developmental stages from 10.5 days after conception until birth, including transcriptomes, methylomes and chromatin states. Here we systematically examined the state and accessibility of chromatin in the developing mouse fetus. In total we performed 1,128 chromatin immunoprecipitation with sequencing (ChIP-seq) assays for histone modifications and 132 assay for transposase-accessible chromatin using sequencing (ATAC-seq) assays for chromatin accessibility across 72 distinct tissue-stages. We used integrative analysis to develop a unified set of chromatin state annotations, infer the identities of dynamic enhancers and key transcriptional regulators, and characterize the relationship between chromatin state and accessibility during developmental gene regulation. We also leveraged these data to link enhancers to putative target genes and demonstrate tissue-specific enrichments of sequence variants associated with disease in humans. The mouse ENCODE data sets provide a compendium of resources for biomedical researchers and achieve, to our knowledge, the most comprehensive view of chromatin dynamics during mammalian fetal development to date.
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http://dx.doi.org/10.1038/s41586-020-2093-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398618PMC
July 2020

The Role of Face Protection for Respiratory Viral Infections: A Historical Perspective.

Authors:
James D Cherry

J Pediatric Infect Dis Soc 2020 Sep;9(4):411-412

Department of Pediatrics, David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, California, USA.

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http://dx.doi.org/10.1093/jpids/piaa082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454694PMC
September 2020

The Groundwater Project: Democratizing Groundwater Knowledge.

Authors:
John Cherry

Ground Water 2020 Sep 30;58(5):682-683. Epub 2020 Jul 30.

G360 Institute for Groundwater Research, University of Guelph, Guelph, ON, Canada.

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http://dx.doi.org/10.1111/gwat.13029DOI Listing
September 2020

Repetitive Head Trauma Induces Chronic Traumatic Encephalopathy by Multiple Mechanisms.

Semin Neurol 2020 08 16;40(4):430-438. Epub 2020 Jul 16.

Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, Massachusetts.

Exposure to repetitive neurotrauma increases lifetime risk for developing progressive cognitive deficits, neurobehavioral abnormalities, and chronic traumatic encephalopathy (CTE). CTE is a tau protein neurodegenerative disease first identified in boxers and recently described in athletes participating in other contact sports (notably American football, ice hockey, rugby, and wrestling) and in military veterans with blast exposure. Currently, CTE can only be diagnosed by neuropathological examination of the brain after death. The defining diagnostic lesion of CTE consists of patchy perivascular accumulations of hyperphosphorylated tau protein that localize in the sulcal depths of the cerebral cortex. Neuronal abnormalities, axonopathy, neurovascular dysfunction, and neuroinflammation are triggered by repetitive head impacts (RHIs) and likely act as catalysts for CTE pathogenesis and progression. However, the specific mechanisms that link RHI to CTE are unknown. This review will explore two important areas of CTE pathobiology. First, we will review what is known about the biomechanical properties of RHI that initiate CTE-related pathologies. Second, we will provide an overview of key features of CTE neuropathology and how these contribute to abnormal tau hyperphosphorylation, accumulation, and spread.
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http://dx.doi.org/10.1055/s-0040-1713620DOI Listing
August 2020

Zika virus vertical transmission in children with confirmed antenatal exposure.

Nat Commun 2020 07 14;11(1):3510. Epub 2020 Jul 14.

David Geffen UCLA School of Medicine, Los Angeles, CA, 90095, USA.

We report Zika virus (ZIKV) vertical transmission in 130 infants born to PCR+ mothers at the time of the Rio de Janeiro epidemic of 2015-2016. Serum and urine collected from birth through the first year of life were tested by quantitative reverse transcriptase polymerase chain reaction (PCR) and/or IgM Zika MAC-ELISA. Four hundred and seven specimens are evaluated; 161 sera tested by PCR and IgM assays, 85 urines by PCR. Sixty-five percent of children (N = 84) are positive in at least one assay. Of 94 children tested within 3 months of age, 70% are positive. Positivity declines to 33% after 3 months. Five children are PCR+ beyond 200 days of life. Concordance between IgM and PCR results is 52%, sensitivity 65%, specificity 40% (positive PCR results as gold standard). IgM and serum PCR are 61% concordant; serum and urine PCR 55%. Most children (65%) are clinically normal. Equal numbers of children with abnormal findings (29 of 45, 64%) and normal findings (55 of 85, 65%) have positive results, p = 0.98. Earlier maternal trimester of infection is associated with positive results (p = 0.04) but not clinical disease (p = 0.98). ZIKV vertical transmission is frequent but laboratory confirmed infection is not necessarily associated with infant abnormalities.
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http://dx.doi.org/10.1038/s41467-020-17331-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360785PMC
July 2020

Neuropathological profile of long-duration amyotrophic lateral sclerosis in military Veterans.

Brain Pathol 2020 11 4;30(6):1028-1040. Epub 2020 Aug 4.

VA Boston Healthcare System, Boston, MA.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Although ALS typically leads to death within 3 to 5 years after initial symptom onset, approximately 10% of patients with ALS live more than 10 years after symptom onset. We set out to determine similarities and differences in clinical presentation and neuropathology in persons with ALS with long vs. those with standard duration. Participants were United States military Veterans with a pathologically confirmed diagnosis of ALS (n = 179), dichotomized into standard duration (<10 years) and long-duration (≥10 years). The ALS Functional Rating Scale-Revised (ALSFRS-R) was administered at study entry and semi-annually thereafter until death. Microglial density was determined in a subset of participants. long-duration ALS occurred in 76 participants (42%) with a mean disease duration of 16.3 years (min/max = 10.1/42.2). Participants with long-duration ALS were younger at disease onset (P = 0.002), had a slower initial ALS symptom progression on the ALSFRS-R (P < 0.001) and took longer to diagnose (P < 0.002) than standard duration ALS. Pathologically, long-duration ALS was associated with less frequent TDP-43 pathology (P < 0.001). Upper motor neuron degeneration was similar; however, long-duration ALS participants had less severe lower motor neuron degeneration at death (P < 0.001). In addition, the density of microglia was decreased in the corticospinal tract (P = 0.017) and spinal cord anterior horn (P = 0.009) in long-duration ALS. Notably, many neuropathological markers of ALS were similar between the standard and long-duration groups and there was no difference in the frequency of known ALS genetic mutations. These findings suggest that the lower motor neuron system is relatively spared in long-duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers.
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http://dx.doi.org/10.1111/bpa.12876DOI Listing
November 2020

Clinical outcomes and ultrasonographic viability of GraftJacket® augmented rotator cuff repair: a prospective follow-up study with mean follow-up of forty-one months.

J Clin Orthop Trauma 2020 May 6;11(Suppl 3):S372-S377. Epub 2019 Sep 6.

Perth Royal Infirmary, Taymount Terrace, Perth, PH1 1NX, UK.

Background: The management of large rotator cuff tears in patients without evidence of glenohumeral arthritis is challenging and controversial. We wished to investigate the viability of Graft Jacket® augmentation and assess the clinical and radiological outcomes in a prospective study with a select cohort of patients.

Methods: All procedures were performed by a single shoulder surgeon over a three-year period. Inclusion criteria were patients with large cuff tears (size 3-5 cm) not amenable to end-to-end repair. Patients with radiographic evidence of glenohumeral arthritis or cuff tear arthropathy were excluded. Open rotator cuff repair followed by bridging with GraftJacket® Regenerative Tissue Matrix was performed. Outcome was assessed with Constant scores (CS), QuickDash (QD) and Oxford Shoulder scores (OSS) at minimum twenty-two months and ultrasound assessment at nine months post-operatively.

Results: Thirteen patients were identified who fit inclusion criteria (one bilateral). No patients were lost to follow up. At final follow-up thirteen shoulders had achieved function range of movement. Mean CS was 83 (range 70-100), mean Quick DASH was 5.4 (range 0-18.2), and mean OSS was 46 (range 41-48). Shoulder ultrasound revealed an intact Graft Jacket® in these patients.One patient had lower functional movement and worse CS (34), QD (34.1) and OSS (25) and ultrasound assessment identified a re-rupture.

Discussion: This study indicates that augmentation of large rotator cuff repairs with a GraftJacket® scaffold is a viable option and has good functional results and sustained viability.

Level Of Evidence: Level 4.
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http://dx.doi.org/10.1016/j.jcot.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275267PMC
May 2020

Evolution of neuronal and glial tau isoforms in chronic traumatic encephalopathy.

Brain Pathol 2020 09 2;30(5):913-925. Epub 2020 Jul 2.

Neuropathology Brain Bank & Research CoRE, Department of Pathology, Nash Family Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by accumulation of hyperphosphorylated tau (p-tau) in perivascular aggregates in neurons and glia at the depths of neocortical sulci and progresses to diffuse neocortical, allocortical and brainstem structures. The strongest risk factor is exposure to repetitive head impacts acquired most commonly through contact sports and military service. Given that CTE can only be definitively diagnosed after death, a better understanding of the cellular and molecular changes in CTE brains may lead to identification of mechanisms that could be used for novel biomarkers, monitoring progression or therapeutic development. Disruption of alternative pre-mRNA splicing of tau mRNA plays a pathogenic role in tauopathy, with multiple characteristic patterns of isoform accumulation varying among tauopathies. Limited data are available on CTE, particularly at early stages. Using biochemical and histological approaches, we performed a detailed characterization of tau isoform signatures in post-mortem human brain tissue from individuals with a range of CTE stages (n = 99). In immunoblot analyses, severity was associated with decreased total monomeric tau and increased total oligomeric tau. Immunoblot with isoform-specific antisera revealed that oligomeric tau with three and four microtubule binding domain repeats (3R and 4R) also increased with CTE severity. Similarly, immunohistochemical studies revealed p-tau accumulation consisting of both 3R and 4R in perivascular lesions. When the ratio of 4R:3R was analyzed, there was mixed expression throughout CTE stages, although 4R predominated in early CTE stages (I-II), a 3R shift was observed in later stages (III-IV). While neurons were found to contain both 3R and 4R, astrocytes only contained 4R. These 4R-positive cells were exclusively neuronal at early stages. Overall, these findings demonstrate that CTE is a mixed 4R/3R tauopathy. Furthermore, histologic analysis reveals a progressive shift in tau isoforms that correlates with CTE stage and extent of neuronal pathology.
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http://dx.doi.org/10.1111/bpa.12867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484331PMC
September 2020

Highlights of the 12th International Bordetella Symposium.

Clin Infect Dis 2020 Dec;71(9):2521-2526

Laboratory of Vaccinology and Mucosal Immunity, Université Libre de Bruxelles, Brussels, Belgium.

To commemorate the 100th anniversary of the Nobel prize being awarded to Jules Bordet, the discoverer of Bordetella pertussis, the 12th International Bordetella Symposium was held from 9 to 12 April 2019 at the Université Libre de Bruxelles, where Jules Bordet studied and was Professor of Microbiology. The symposium attracted more than 300 Bordetella experts from 34 countries. They discussed the latest epidemiologic data and clinical aspects of pertussis, Bordetella biology and pathogenesis, immunology and vaccine development, and genomics and evolution. Advanced technological and methodological tools provided novel insights into the genomic diversity of Bordetella and a better understanding of pertussis disease and vaccine performance. New molecular approaches revealed previously unrecognized complexity of virulence gene regulation. Innovative insights into the immune responses to infection by Bordetella resulted in the development of new vaccine candidates. Such discoveries will aid in the design of more effective approaches to control pertussis and other Bordetella-related diseases.
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http://dx.doi.org/10.1093/cid/ciaa651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713684PMC
December 2020

The sociology of the antivaccine movement.

Emerg Top Life Sci 2020 09;4(2):241-245

Department of Pediatrics, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., MDCC 22-442, Los Angeles, CA 90095-1752, U.S.A.

Skepticism and misinformation relating to vaccines is not new. The benefits of all our present routinely used vaccines outweigh any risks. In relatively recent times there has been a 'war on science' and relating to this, is the present antivaccine movement. Today, social media is a major contributor to vaccine misinformation. A recent Gallup poll noted that public support for vaccines today is significantly lower than it was in 2001. Social scientists have presented the problem of the antivaccine movement quite well; but mechanisms for addressing it are far from clear. We suggest that physicians and other health care workers should not use social media for vaccine messages. A long-term approach would be to introduce science/epidemiological education in grade school and high school as well as in college.
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http://dx.doi.org/10.1042/ETLS20190198DOI Listing
September 2020

CNN-Peaks: ChIP-Seq peak detection pipeline using convolutional neural networks that imitate human visual inspection.

Sci Rep 2020 05 13;10(1):7933. Epub 2020 May 13.

Department of Genetics, Stanford University, Stanford, 94305, USA.

ChIP-seq is one of the core experimental resources available to understand genome-wide epigenetic interactions and identify the functional elements associated with diseases. The analysis of ChIP-seq data is important but poses a difficult computational challenge, due to the presence of irregular noise and bias on various levels. Although many peak-calling methods have been developed, the current computational tools still require, in some cases, human manual inspection using data visualization. However, the huge volumes of ChIP-seq data make it almost impossible for human researchers to manually uncover all the peaks. Recently developed convolutional neural networks (CNN), which are capable of achieving human-like classification accuracy, can be applied to this challenging problem. In this study, we design a novel supervised learning approach for identifying ChIP-seq peaks using CNNs, and integrate it into a software pipeline called CNN-Peaks. We use data labeled by human researchers who annotate the presence or absence of peaks in some genomic segments, as training data for our model. The trained model is then applied to predict peaks in previously unseen genomic segments from multiple ChIP-seq datasets including benchmark datasets commonly used for validation of peak calling methods. We observe a performance superior to that of previous methods.
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http://dx.doi.org/10.1038/s41598-020-64655-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220942PMC
May 2020

Incorporation of a unified protein abundance dataset into the Saccharomyces genome database.

Database (Oxford) 2020 01;2020

Department of Genetics, Stanford University, 3165 Porter Drive, Palo Alto, CA 94304, USA.

The identification and accurate quantitation of protein abundance has been a major objective of proteomics research. Abundance studies have the potential to provide users with data that can be used to gain a deeper understanding of protein function and regulation and can also help identify cellular pathways and modules that operate under various environmental stress conditions. One of the central missions of the Saccharomyces Genome Database (SGD; https://www.yeastgenome.org) is to work with researchers to identify and incorporate datasets of interest to the wider scientific community, thereby enabling hypothesis-driven research. A large number of studies have detailed efforts to generate proteome-wide abundance data, but deeper analyses of these data have been hampered by the inability to compare results between studies. Recently, a unified protein abundance dataset was generated through the evaluation of more than 20 abundance datasets, which were normalized and converted to common measurement units, in this case molecules per cell. We have incorporated these normalized protein abundance data and associated metadata into the SGD database, as well as the SGD YeastMine data warehouse, resulting in the addition of 56 487 values for untreated cells grown in either rich or defined media and 28 335 values for cells treated with environmental stressors. Abundance data for protein-coding genes are displayed in a sortable, filterable table on Protein pages, available through Locus Summary pages. A median abundance value was incorporated, and a median absolute deviation was calculated for each protein-coding gene and incorporated into SGD. These values are displayed in the Protein section of the Locus Summary page. The inclusion of these data has enhanced the quality and quantity of protein experimental information presented at SGD and provides opportunities for researchers to access and utilize the data to further their research.
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http://dx.doi.org/10.1093/database/baaa008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054198PMC
January 2020

The Susceptibility to Other Infectious Diseases Following Measles During a Three Year Observation Period in Switzerland.

Pediatr Infect Dis J 2020 06;39(6):478-482

From the Infectious Diseases and Vaccinology, University of Basel Children's Hospital, Basel, Switzerland.

Background: Measles virus infection leads to significant immunosuppression. In developing countries, this translates to an increased nonspecific mortality, whereas its effects in developed countries are less clear.

Methods: We performed a cohort study to investigate whether children hospitalized with measles (cases) between 2000 and 2015 in Switzerland would have a higher frequency of hospital admissions due to other infectious diseases thereafter than children who did not have measles (controls). Cases were identified by ICD-10 discharge diagnoses for measles and/or keyword search and matched to 2 controls by time of hospitalization, age and sex. All hospitalizations ≤3 years after original admission, infectious or noninfectious in origin, were identified in cases and controls.

Results: One hundred thirteen cases (56% males), mean age 9.0 years (range 2 weeks-17.8 years), and 196 controls were identified. Twelve rehospitalizations due to an infectious disease occurred in 11 cases and 6 in 6 controls (episode rates 0.106 versus 0.031 per person; ratio 3.47; 95% CI: 1.20-11.3; P = 0.012) in 3 years of follow-up. Of these, 9 and 3 occurred in cases and controls, respectively, during year 1 [ratio 5.20 (95% CI: 1.30-29.88; P = 0.012)]. Infectious diseases following measles affected various organ systems, were neither particularly severe nor fatal and revealed no specific pattern.

Conclusions: The increased risk for nonspecific infectious disease hospitalizations supports the concept of immunologic amnesia after measles. Universal immunization against measles provides additional benefit beyond protection against measles itself.
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http://dx.doi.org/10.1097/INF.0000000000002599DOI Listing
June 2020

Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ε4 genotype.

Sci Rep 2020 02 19;10(1):2924. Epub 2020 Feb 19.

Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, 02118, USA.

Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. The apolipoprotein E (APOE) ε4 allele is the most common genetic risk factor for AD and is related to a pro-inflammatory state. To test the hypothesis that microglia and AD-implicated cytokines were differentially associated with AD pathology based on the presence of APOE ε4, we examined the dorsolateral frontal cortex from deceased participants within a community-based aging cohort (n = 154). Cellular density of Iba1, a marker of microglia, was positively associated with tau pathology only in APOE ε4 positive participants (p = 0.001). The cytokines IL-10, IL-13, IL-4, and IL-1α were negatively associated with tau pathology, independent of Aβ levels, only in APOE ε4 negative participants. Overall, the association of mostly anti-inflammatory cytokines with less tau pathology suggests a protective effect in APOE ε4 negative participants. These associations are largely absent in the presence of APOE ε4 where tau pathology was significantly associated with increased microglial cell density. Taken together, these results suggest that APOE ε4 mediates an altered inflammatory response and increased tau pathology independent of Aβ pathology.
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http://dx.doi.org/10.1038/s41598-020-59869-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031423PMC
February 2020

Measles antibody levels among vaccinated and unvaccinated children 6-59 months of age in the Democratic Republic of the Congo, 2013-2014.

Vaccine 2020 02;38(9):2258-2265

Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA 90095, United States. Electronic address:

Background: Measles is endemic in the Democratic Republic of the Congo (DRC), and 89-94% herd immunity is required to halt its transmission. Much of the World Health Organization African Region, including the DRC, has vaccination coverage below the 95% level required to eliminate measles, heightening concern of inadequate measles immunity.

Methods: We assessed 6706 children aged 6-59 months whose mothers were selected for interview in the 2013-2014 DRC Demographic and Health Survey. History of measles was obtained by maternal report, and classification of children who had measles was completed using maternal recall and measles immunoglobulin G serostatus obtained from a multiplex chemiluminescent automated immunoassay dried blood spot analysis. A logistic regression model was used to identify associations of covariates with measles and seroprotection, and vaccine effectiveness (VE) was calculated.

Results: Out of our sample, 64% of children were seroprotected. Measles vaccination was associated with protection against measles (OR: 0.15, 95% CI: 0.03, 0.81) when administered to children 12 months of age or older. Vaccination was predictive of seroprotection at all ages. VE was highest (88%) among children 12-24 months of age.

Conclusion: Our results demonstrated lower than expected seroprotection against measles among vaccinated children. Understanding the factors that affect host immunity to measles will aid in developing more efficient and effective immunization programs in DRC.
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http://dx.doi.org/10.1016/j.vaccine.2019.09.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026690PMC
February 2020

Selection-Driven Gene Inactivation in Salmonella.

Authors:
Joshua L Cherry

Genome Biol Evol 2020 03;12(3):18-34

National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland.

Bacterial genes are sometimes found to be inactivated by mutation. This inactivation may be observable simply because selection for function is intermittent or too weak to eliminate inactive alleles quickly. Here, I investigate cases in Salmonella enterica where inactivation is instead positively selected. These are identified by a rate of introduction of premature stop codons to a gene that is higher than expected under selective neutrality, as assessed by comparison to the rate of synonymous changes. I identify 84 genes that meet this criterion at a 10% false discovery rate. Many of these genes are involved in virulence, motility and chemotaxis, biofilm formation, and resistance to antibiotics or other toxic substances. It is hypothesized that most of these genes are subject to an ongoing process in which inactivation is favored under rare conditions, but the inactivated allele is deleterious under most other conditions and is subsequently driven to extinction by purifying selection.
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http://dx.doi.org/10.1093/gbe/evaa010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144821PMC
March 2020