Publications

Is returning to work during the COVID-19 pandemic stressful? A study on immediate mental health status and psychoneuroimmunity prevention measures of Chinese workforce.

Brain Behav Immun. 2020 07;87:84-92

Authors: Tan W, Hao F, McIntyre RS, Jiang L, Jiang X, Zhang L, Zhao X, Zou Y, Hu Y, Luo X, Zhang Z, Lai A, Ho R, Tran B, Ho C, Tam W

Abstract
This study aimed to quantify the immediate psychological effects and psychoneuroimmunity prevention measures of a workforce returning to work during the COVID-19 epidemic. Workforce returning to work was invited to complete an online questionnaire regarding their attitude toward the COVID-19 epidemic and return-to-work along with psychological parameters including the Impact of Event Scale-Revised, Depression, Anxiety, Stress Scale- 21 (DASS-21) and Insomnia Severity Index (ISI). Psychoneuroimmunity prevention measures include precautions at personal and organization levels. From 673 valid questionnaires, we found that 10.8% of respondents met the diagnosis of post-traumatic stress disorder (PTSD) after returning to work. The respondents reported a low prevalence of anxiety (3.8%), depression (3.7%), stress (1.5%) and insomnia (2.3%). There were no significant differences in the severity of psychiatric symptoms between workers/technicians and executives/managers. >95% reported psychoneuroimmunity prevention measures including good ventilation in the workplace and wore a face mask as protective. Factors that were associated with the severity of psychiatric symptoms in the workforce were marital status, presence of physical symptom, poor physical health and viewing return to work as a health hazard (p < 0.05). In contrast, personal psychoneuroimmunity prevention measures including hand hygiene and wearing face masks as well as organizational measures including significant improvement of workplace hygiene and concerns from the company were associated with less severe psychiatric symptoms (p < 0.05). Contrary to expectations, returning to work had not caused a high level of psychiatric symptoms in the workforce. The low prevalence of psychiatric symptoms could be due to confidence instilled by psychoneuroimmunity prevention measures before the resumption of work. Our findings would provide information for other countries during the COVID-19 pandemic.

PMID: 32335200 [PubMed - indexed for MEDLINE]

A novel C-terminal degron identified in bacterial aldehyde decarbonylases using directed evolution.

Biotechnol Biofuels. 2020;13:114

Authors: Liu Y, Chen J, Khusnutdinova AN, Correia K, Diep P, Batyrova KA, Nemr K, Flick R, Stogios P, Yakunin AF, Mahadevan R

Abstract
Background: Aldehyde decarbonylases (ADs), which convert acyl aldehydes into alkanes, supply promising solution for producing alkanes from renewable feedstock. However the instability of ADs impedes their further application. Therefore, the current study aimed to investigate the degradation mechanism of ADs and engineer it towards high stability.
Results: Here, we describe the discovery of a degradation tag (degron) in the AD from marine cyanobacterium Prochlorococcus marinus using error-prone PCR-based directed evolution system. Bioinformatic analysis revealed that this C-terminal degron is common in bacterial ADs and identified a conserved C-terminal motif, RMSAYGLAAA, representing the AD degron (ADcon). Furthermore, we demonstrated that the ATP-dependent proteases ClpAP and Lon are involved in the degradation of AD-tagged proteins in E. coli, thereby limiting alkane production. Deletion or modification of the degron motif increased alkane production in vivo.
Conclusion: This work revealed the presence of a novel degron in bacterial ADs responsible for its instability. The in vivo experiments proved eliminating or modifying the degron could stabilize AD, thereby producing higher titers of alkanes.

PMID: 32612677 [PubMed]

Targeted Mass Spectrometry of a Clinically Relevant PSA Variant from Post-DRE Urines for Quantitation and Genotype Determination.

Proteomics Clin Appl. 2020 Jul 02;:e2000012

Authors: Otto JJ, Correll VL, Engstroem HA, Hitefield NL, Main BP, Albracht B, Johnson-Pais T, Yang LF, Liss M, Boutros PC, Kislinger T, Leach RJ, Semmes OJ, Nyalwidhe JO

Abstract
PURPOSE: The rs17632542 SNP results in lower serum PSA levels which may further mitigate against its clinical utility as a prostate cancer biomarker. Post-DRE urine is a minimally invasive fluid that is currently utilized in prostate cancer diagnosis. We have used targeted MS to detect and quantitate the variant protein in urine.
EXPERIMENTAL DESIGN: Fifty-three post-DRE urines from rs17632542 genotyped individuals were processed and analyzed by LC-MS in a double-blinded randomized study. The ability to distinguish between homozygous wild-type, heterozygous, or homozygous variant was examined before unblinding.
RESULTS: Stable-isotope labeled peptides were used in the detection and quantitation of three peptides of interest in each sample using an LC-MS-PRM method. Analysis of the raw data using Skyline allowed for peak detection and area extraction. Using these data, groupings were predicted using hierarchical clustering in R. Accuracy of the predictions showed 100% concordance across the 53 samples, including individuals homozygous and heterozygous for the SNP.
CONCLUSIONS AND CLINICAL RELEVANCE: The study demonstrates that MS based peptide variant quantitation in urine could be useful in determining patient genotype expression. Our assay provides a tool to evaluate the utility of PSA variant (rs17632542) assessment in parallel with current and forthcoming urine biomarker panels. This article is protected by copyright. All rights reserved.

PMID: 32614141 [PubMed - as supplied by publisher]

Comparison of Co-housing and Littermate Methods for Microbiota Standardization in Mouse Models.

Cell Rep. 2019 05 07;27(6):1910-1919.e2

Authors: Robertson SJ, Lemire P, Maughan H, Goethel A, Turpin W, Bedrani L, Guttman DS, Croitoru K, Girardin SE, Philpott DJ

Abstract
The intestinal microbiota is a fundamental factor that broadly influences physiology. Thus, studies using transgenic animals should be designed to limit the confounding effects of microbiota variation between strains. Here, we report the impact on intestinal microbiota of co-housed versus F2-generation littermates, two commonly used techniques to standardize microbiota in animal models. Our results establish that while fecal microbiota is partially normalized by extended co-housing, mucosal communities associated with the proximal colon and terminal ileum remain stable and distinct. In contrast, strain inter-crossing to generate F2 littermates allows robust microbiota standardization in fecal, colon, and ileum sampling locations. Using reciprocal inter-crosses of P1 parents, we identify dissymmetry in F2 community structures caused by maternal transmission, in particular of the Verrucomicrobiaceae. Thus, F2 littermate animals from a unidirectional P1 cross should be used as a standard method to minimize the influence of the microbiota in genotype-phenotype studies.

PMID: 31067473 [PubMed - indexed for MEDLINE]

YeastSpotter: accurate and parameter-free web segmentation for microscopy images of yeast cells.

Bioinformatics. 2019 11 01;35(21):4525-4527

Authors: Lu AX, Zarin T, Hsu IS, Moses AM

Abstract
SUMMARY: We introduce YeastSpotter, a web application for the segmentation of yeast microscopy images into single cells. YeastSpotter is user-friendly and generalizable, reducing the computational expertise required for this critical preprocessing step in many image analysis pipelines.
AVAILABILITY AND IMPLEMENTATION: YeastSpotter is available at http://yeastspotter.csb.utoronto.ca/. Code is available at https://github.com/alexxijielu/yeast_segmentation.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 31095270 [PubMed - indexed for MEDLINE]

Glyphosate use and associations with non-Hodgkin lymphoma major histological sub-types: findings from the North American Pooled Project.

Scand J Work Environ Health. 2019 11 01;45(6):600-609

Authors: Pahwa M, Beane Freeman LE, Spinelli JJ, Blair A, McLaughlin JR, Zahm SH, Cantor KP, Weisenburger DD, Punam Pahwa PP, Dosman JA, Demers PA, Harris SA

Abstract
Objectives Some epidemiological studies have suggested positive associations between glyphosate use and non-Hodgkin lymphoma (NHL), but evidence is inconsistent and few studies could evaluate histological sub-types. Here, associations between glyphosate use and NHL incidence overall and by histological sub-type were evaluated in a pooled analysis of case-control studies. Methods The analysis included 1690 NHL cases [647 diffuse large B-cell lymphoma (DLBCL), 468 follicular lymphoma (FL), 171 small lymphocytic lymphoma (SLL), and 404 other sub-types] and 5131 controls. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for NHL overall and sub-types with self-reported ever/never, duration, frequency, and lifetime-days of glyphosate use. Results Subjects who ever used glyphosate had an excess of NHL overall (OR 1.43, 95% CI 1.11-1.83). After adjustment for other pesticides, the OR for NHL overall with "ever use" was 1.13 (95% CI 0.84-1.51), with a statistically significant association for handling glyphosate >2 days/year (OR 1.73, 95% CI 1.02-2.94, P-trend=0.2). In pesticide-adjusted sub-type analyses, the ordinal measure of lifetime-days was statistically significant (P=0.03) for SLL, and associations were elevated, but not statistically significant, for ever years or days/year of use. Handling glyphosate >2 days/year had an excess of DLBCL (OR 2.14, 95% CI 1.07-4.28; P-trend=0.2). However, as with the other sub-types, consistent patterns of association across different metrics were not observed. Conclusions There was some limited evidence of an association between glyphosate use and NHL in this pooled analysis. Suggestive associations, especially for SLL, deserve additional attention.

PMID: 31246262 [PubMed - indexed for MEDLINE]

Determining the Impact of Spatial Heterogeneity on Genomic Prognostic Biomarkers for Localized Prostate Cancer.

Eur Urol Oncol. 2020 Jun 27;:

Authors: Brastianos HC, Murgic J, Salcedo A, Chua MLK, Meng A, Fraser M, Brundage M, Fleshner NE, van der Kwast T, Bristow RG, Boutros PC, Berlin A

Abstract
Localized prostate tumors show remarkably diverse clinical courses, with some being cured by local therapy alone, while others rapidly relapse and have a lethal course despite precision surgery or radiotherapy. Many genomic biomarkers have been developed to predict this clinical behavior, but these are confounded by the extreme spatial heterogeneity of prostate tumors: most are multifocal and harbor multiple subclonal populations. To quantify the influence of spatial heterogeneity on genomic prognostic biomarkers, we developed a case-control high-risk cohort (n = 42) using a prospective registry, risk matched by clinicopathologic prognostic indices. Half of the cohort had early biochemical recurrence (BCR; ie, ≤18 mo), while half remained without evidence of disease for at least 48 mo after radical prostatectomy. We then genomically profiled multiple tumor foci per patient, analyzing 119 total specimens. These data allowed us to validate three published genomic prognostic biomarkers and quantify their sensitivity to tumor spatial heterogeneity. Remarkably, all three biomarkers robustly predicted early BCR, and all three were robust to spatiogenomic variability. These data suggest that DNA-based genomic biomarkers can overcome intratumoral heterogeneity: single biopsies may be sufficient to estimate the risk of early BCR after radical treatment in patients with high-risk disease. PATIENT SUMMARY: We investigated whether heterogeneity between tumor regions within the prostate affects the accuracy of DNA-based biomarkers predicting early relapse after prostatectomy. We observed persistent accuracy in predicting disease relapse, suggesting that spatial heterogeneity may not hinder biomarker performance.

PMID: 32605887 [PubMed - as supplied by publisher]

European genetic ancestry associated with risk of childhood ependymoma.

Neuro Oncol. 2020 Jun 02;:

Authors: Zhang C, Ostrom QT, Hansen HM, Gonzalez-Maya J, Hu D, Ziv E, Morimoto L, de Smith AJ, Muskens IS, Kline CN, Vaksman Z, Hakonarson H, Diskin SJ, Kruchko C, Barnholtz-Sloan JS, Ramaswamy V, Ali-Osman F, Bondy ML, Taylor MD, Metayer C, Wiemels JL, Walsh KM

Abstract
BACKGROUND: Ependymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations.
METHODS: In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS).
RESULTS: CBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08-1.59, Pmeta = 6.7 × 10-3). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45-2.73; P = 2.2 × 10-5) but which was not validated in an independent set of posterior fossa type A patients.
CONCLUSIONS: Interethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies.

PMID: 32607579 [PubMed - as supplied by publisher]

Natural environments in the urban context and gut microbiota in infants.

Environ Int. 2020 Jun 27;142:105881

Authors: Nielsen CC, Gascon M, Osornio-Vargas AR, Shier C, Guttman DS, Becker AB, Azad MB, Sears MR, Lefebvre DL, Moraes TJ, Turvey SE, Subbarao P, Takaro TK, Brook JR, Scott JA, Mandhane PJ, Tun HM, Kozyrskyj AL

Abstract
The biodiversity hypothesis that contact with natural environments (e.g. native vegetation) and biodiversity, through the influence of environmental microbes, may be beneficial for human commensal microbiota has been insufficiently tested. We aimed to study the association between living near natural environments in the urban context, and gut microbiota diversity and composition in young infants. Based on data linkage between the unique Urban Primary Land and Vegetation Inventory (uPLVI) for the city of Edmonton and 355 infants in the CHILD Cohort Study, infant exposure to natural environments (any and specific types, yes/no) was determined within 500 m and 1000 m of their home residence. Gut microbiota composition and diversity at age 4 months was assessed in infant fecal samples. Adjusted for covariates, we observed a reduced odds of high microbial alpha-diversity in the gut of infants exposed to any natural environment within 500 m [Shannon index aOR (95%CI) = 0.63 (0.40, 0.98) and Simpson index = 0.63 (0.41, 0.98)]. In stratified analyses, these associations remained only among infants not breastfed or living with household pets. When doubly stratifying by these variables, the reduced likelihood of high alpha-diversity was present only among infants who were not breastfed and lived with household pets [9% of the study population, Shannon index = 0.07 (0.01, 0.49) and Simpson index = 0.11 (0.02, 0.66)]. Differences in beta-diversity was also seen (p = 0.04) with proximity to a nature space in not breastfed and pets-exposed infants. No associations were observed among infants who were fully formula-fed but without pets at home. When families and their pets had close access to a natural environment, Verrucomicrobiales colonization was reduced in the gut microbiota of formula-fed infants, the abundance of Clostridiales was depleted, whereas the abundance of Enterobacteriales was enriched. Our double-stratified results indicate that proximity to a natural environment plus pet ownership has the capacity to alter the gut microbiota of formula-fed infants. Further research is needed to replicate and better interpret these results, as well as to understand their health consequences.

PMID: 32610248 [PubMed - as supplied by publisher]

gpart: human genome partitioning and visualization of high-density SNP data by identifying haplotype blocks.

Bioinformatics. 2019 11 01;35(21):4419-4421

Authors: Kim SA, Brossard M, Roshandel D, Paterson AD, Bull SB, Yoo YJ

Abstract
SUMMARY: For the analysis of high-throughput genomic data produced by next-generation sequencing (NGS) technologies, researchers need to identify linkage disequilibrium (LD) structure in the genome. In this work, we developed an R package gpart which provides clustering algorithms to define LD blocks or analysis units consisting of SNPs. The visualization tool in gpart can display the LD structure and gene positions for up to 20 000 SNPs in one image. The gpart functions facilitate construction of LD blocks and SNP partitions for vast amounts of genome sequencing data within reasonable time and memory limits in personal computing environments.
AVAILABILITY AND IMPLEMENTATION: The R package is available at https://bioconductor.org/packages/gpart.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 31070701 [PubMed - indexed for MEDLINE]

Impact of DNA source on genetic variant detection from human whole-genome sequencing data.

J Med Genet. 2019 12;56(12):809-817

Authors: Trost B, Walker S, Haider SA, Sung WWL, Pereira S, Phillips CL, Higginbotham EJ, Strug LJ, Nguyen C, Raajkumar A, Szego MJ, Marshall CR, Scherer SW

Abstract
BACKGROUND: Whole blood is currently the most common DNA source for whole-genome sequencing (WGS), but for studies requiring non-invasive collection, self-collection, greater sample stability or additional tissue references, saliva or buccal samples may be preferred. However, the relative quality of sequencing data and accuracy of genetic variant detection from blood-derived, saliva-derived and buccal-derived DNA need to be thoroughly investigated.
METHODS: Matched blood, saliva and buccal samples from four unrelated individuals were used to compare sequencing metrics and variant-detection accuracy among these DNA sources.
RESULTS: We observed significant differences among DNA sources for sequencing quality metrics such as percentage of reads aligned and mean read depth (p<0.05). Differences were negligible in the accuracy of detecting short insertions and deletions; however, the false positive rate for single nucleotide variation detection was slightly higher in some saliva and buccal samples. The sensitivity of copy number variant (CNV) detection was up to 25% higher in blood samples, depending on CNV size and type, and appeared to be worse in saliva and buccal samples with high bacterial concentration. We also show that methylation-based enrichment for eukaryotic DNA in saliva and buccal samples increased alignment rates but also reduced read-depth uniformity, hampering CNV detection.
CONCLUSION: For WGS, we recommend using DNA extracted from blood rather than saliva or buccal swabs; if saliva or buccal samples are used, we recommend against using methylation-based eukaryotic DNA enrichment. All data used in this study are available for further open-science investigation.

PMID: 31515274 [PubMed - indexed for MEDLINE]

Long Noncoding RNAs and Repetitive Elements: Junk or Intimate Evolutionary Partners?

Trends Genet. 2019 12;35(12):892-902

Authors: Lee H, Zhang Z, Krause HM

Abstract
Our recent ability to sequence entire genomes, along with all of their transcribed RNAs, has led to the surprising finding that only ∼1% of the human genome is used to encode proteins. This finding has led to vigorous debate over the functional importance of the transcribed but untranslated portions of the genome. Currently, scientists tend to assume coding genes are functional until proven not to be, while the opposite is true for noncoding genes. This review takes a new look at the evidence for and against widespread noncoding gene functionality. We focus in particular on long noncoding RNA (noncoding RNAs longer than 200 nucleotides) genes and their 'junk' associates, transposable elements, and satellite repeats. Taken together, the suggestion put forward is that more of this junk DNA may be functional than nonfunctional and that noncoding RNAs and transposable elements act symbiotically to drive evolution.

PMID: 31662190 [PubMed - indexed for MEDLINE]

Precision Health Resource of Control iPSC Lines for Versatile Multilineage Differentiation.

Stem Cell Reports. 2019 12 10;13(6):1126-1141

Authors: Hildebrandt MR, Reuter MS, Wei W, Tayebi N, Liu J, Sharmin S, Mulder J, Lesperance LS, Brauer PM, Mok RSF, Kinnear C, Piekna A, Romm A, Howe J, Pasceri P, Meng G, Rozycki M, Rodrigues DC, Martinez EC, Szego MJ, Zúñiga-Pflücker JC, Anderson MK, Prescott SA, Rosenblum ND, Kamath BM, Mital S, Scherer SW, Ellis J

Abstract
Induced pluripotent stem cells (iPSC) derived from healthy individuals are important controls for disease-modeling studies. Here we apply precision health to create a high-quality resource of control iPSCs. Footprint-free lines were reprogrammed from four volunteers of the Personal Genome Project Canada (PGPC). Multilineage-directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users demonstrated versatility by generating kidney organoids, T lymphocytes, and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole-genome sequencing-based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harbored at least one pre-existing or acquired variant with cardiac, neurological, or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cells from six tissues for disease modeling, and variant-preferred healthy control lines were identified for specific disease settings.

PMID: 31813827 [PubMed - indexed for MEDLINE]

Understanding the association between osteoarthritis and social participation: a CLSA population-based study.

Arthritis Care Res (Hoboken). 2020 Jun 29;:

Authors: Perruccio AV, Yip C, Power JD, Canizares M, Gignac MA, Badley EM

Abstract
OBJECTIVE: The focus on disability in osteoarthritis (OA) has largely been on performing specific activities, neglecting wider implications for social participation (SP). We investigated the association between OA and SP considering activity limitations (AL) and instrumental supports (IS) as intervening variables in the association.
METHODS: Data were from 21,214 respondents aged 45-85 from cycle 1, Canadian Longitudinal Study on Aging. The questionnaire elicited: self-reported doctor-diagnosed OA; difficulty with 14 activities; perceived availability and receipt of IS; and 17 SP activities. Structural equation modeling was used.
PRIMARY OUTCOME: SP; Primary predictor: OA; Intervening variables: AL, received IS, perceived IS. Latent variables were developed for intervening and SP variables. Covariates: age, sex, body mass index, income, education, smoking, comorbidity count.
RESULTS: Mean age was 63 years, 51% were female, and 26.5% reported OA. Two distinct SP indicators were identified, SP-Diversity and SP-Intensity. Without considering intervening variables, minimal/no association was found between OA and SP. When considered, unique pathways linking OA and SP were found. The overall negative association between AL and SP was, in part, direct and, in part, buffered by both receipt and perceived availability of IS. Absent AL, OA was associated with greater SP.
CONCLUSIONS: Enhanced SP in people with OA without AL may reflect proactive steps taken by those with mild OA to maintain activity and social engagement. For those with AL, findings highlight the need for interventions to mitigate limitations and draw particular attention to the importance of both provision and awareness of available IS in maintaining SP.

PMID: 32598513 [PubMed - as supplied by publisher]

Altered Connectivity During a False-Belief Task in Adults With Autism Spectrum Disorder.

Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Apr 24;:

Authors: Yuk V, Anagnostou E, Taylor MJ

Abstract
BACKGROUND: Deficits in social communication are one of the main features of autism spectrum disorder (ASD). Adults with ASD show atypical brain activity during false-belief understanding, an aspect of social communication involving the ability to infer that an individual can have an incorrect belief about a situation. Our study is the first to investigate whether adults with ASD exhibit differences in frequency-specific functional connectivity patterns during false-belief reasoning.
METHODS: We used magnetoencephalography to contrast functional connectivity underlying false-belief understanding between 40 adults with ASD and 39 control adults. We examined whole-brain phase synchrony measures during a false-belief task in 3 frequency bands: theta (4-7 Hz), alpha (8-14 Hz), and beta (15-30 Hz).
RESULTS: Adults with ASD demonstrated reduced theta-band connectivity compared with control adults between several right-lateralized and midline regions such as the medial prefrontal cortex, right temporoparietal junction, right inferior frontal gyrus, and right superior temporal gyrus. During false-belief trials, they also recruited a network in the beta band that included primary visual regions such as the bilateral inferior occipital gyri and the left anterior temporoparietal junction.
CONCLUSIONS: Reduced theta-band synchrony between areas associated with mentalizing, inhibition, and visual processing implies some difficulty in communication among these functions in ASD. This impairment in top-down control in the theta band may be counterbalanced by their engagement of a beta-band network because both the left anterior temporoparietal junction and beta-band oscillations are associated with attentional processes. Thus, adults with ASD demonstrate alternative neural mechanisms for successful false-belief reasoning.

PMID: 32600899 [PubMed - as supplied by publisher]

Toward a systematic design of smart probiotics.

Curr Opin Biotechnol. 2020 Jun 27;64:199-209

Authors: Choudhary R, Mahadevan R

Abstract
Synthetic biology has been instrumental in turning microbes into cell-factories capable of diverse processes. A recent application has been to convert them into living therapeutics with diagnostic and production capabilities. These smart probiotics act as living medicines inside the body capable of diagnosing and responding to environmental cues in real time. Many companies and research groups have reported success with smart probiotics with several advancing to human clinical trials. Despite the promise, engineered probiotics are unable to replicate their functionality in a more complex environment. A rich environment, such as the gut, imposes restrictions on probiotic durability and effectiveness, hindering its ability to reach its full potential. Scientists have a plethora of advanced tools available today that enable enhanced strain engineering decisions to increase the production of fuels and commodity chemicals. However, these tools have not yet found mainstream application in building smart probiotics. Majority of the work in this field still relies on rational engineering. This review will propose strategies, with a focus on model-based approaches, that can help bridge the gap to systematic design and optimization of smart probiotics.

PMID: 32603961 [PubMed - as supplied by publisher]

Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H2 O2 emission during impaired oxidative phosphorylation.

J Cachexia Sarcopenia Muscle. 2019 06;10(3):643-661

Authors: Hughes MC, Ramos SV, Turnbull PC, Rebalka IA, Cao A, Monaco CMF, Varah NE, Edgett BA, Huber JS, Tadi P, Delfinis LJ, Schlattner U, Simpson JA, Hawke TJ, Perry CGR

Abstract
BACKGROUND: Muscle wasting and weakness in Duchenne muscular dystrophy (DMD) causes severe locomotor limitations and early death due in part to respiratory muscle failure. Given that current clinical practice focuses on treating secondary complications in this genetic disease, there is a clear need to identify additional contributions in the aetiology of this myopathy for knowledge-guided therapy development. Here, we address the unresolved question of whether the complex impairments observed in DMD are linked to elevated mitochondrial H2 O2 emission in conjunction with impaired oxidative phosphorylation. This study performed a systematic evaluation of the nature and degree of mitochondrial-derived H2 O2 emission and mitochondrial oxidative dysfunction in a mouse model of DMD by designing in vitro bioenergetic assessments that attempt to mimic in vivo conditions known to be critical for the regulation of mitochondrial bioenergetics.
METHODS: Mitochondrial bioenergetics were compared with functional and histopathological indices of myopathy early in DMD (4 weeks) in D2.B10-DMDmdx /2J mice (D2.mdx)-a model that demonstrates severe muscle weakness. Adenosine diphosphate's (ADP's) central effect of attenuating H2 O2 emission while stimulating respiration was compared under two models of mitochondrial-cytoplasmic phosphate exchange (creatine independent and dependent) in muscles that stained positive for membrane damage (diaphragm, quadriceps, and white gastrocnemius).
RESULTS: Pathway-specific analyses revealed that Complex I-supported maximal H2 O2 emission was elevated concurrent with a reduced ability of ADP to attenuate emission during respiration in all three muscles (mH2 O2 : +17 to +197% in D2.mdx vs. wild type). This was associated with an impaired ability of ADP to stimulate respiration at sub-maximal and maximal kinetics (-17 to -72% in D2.mdx vs. wild type), as well as a loss of creatine-dependent mitochondrial phosphate shuttling in diaphragm and quadriceps. These changes largely occurred independent of mitochondrial density or abundance of respiratory chain complexes, except for quadriceps. This muscle was also the only one exhibiting decreased calcium retention capacity, which indicates increased sensitivity to calcium-induced permeability transition pore opening. Increased H2 O2 emission was accompanied by a compensatory increase in total glutathione, while oxidative stress markers were unchanged. Mitochondrial bioenergetic dysfunctions were associated with induction of mitochondrial-linked caspase 9, necrosis, and markers of atrophy in some muscles as well as reduced hindlimb torque and reduced respiratory muscle function.
CONCLUSIONS: These results provide evidence that Complex I dysfunction and loss of central respiratory control by ADP and creatine cause elevated oxidant generation during impaired oxidative phosphorylation. These dysfunctions may contribute to early stage disease pathophysiology and support the growing notion that mitochondria are a potential therapeutic target in this disease.

PMID: 30938481 [PubMed - indexed for MEDLINE]

Exploring whole-genome duplicate gene retention with complex genetic interaction analysis.

Science. 2020 Jun 26;368(6498):

Authors: Kuzmin E, VanderSluis B, Nguyen Ba AN, Wang W, Koch EN, Usaj M, Khmelinskii A, Usaj MM, van Leeuwen J, Kraus O, Tresenrider A, Pryszlak M, Hu MC, Varriano B, Costanzo M, Knop M, Moses A, Myers CL, Andrews BJ, Boone C

Abstract
Whole-genome duplication has played a central role in the genome evolution of many organisms, including the human genome. Most duplicated genes are eliminated, and factors that influence the retention of persisting duplicates remain poorly understood. We describe a systematic complex genetic interaction analysis with yeast paralogs derived from the whole-genome duplication event. Mapping of digenic interactions for a deletion mutant of each paralog, and of trigenic interactions for the double mutant, provides insight into their roles and a quantitative measure of their functional redundancy. Trigenic interaction analysis distinguishes two classes of paralogs: a more functionally divergent subset and another that retained more functional overlap. Gene feature analysis and modeling suggest that evolutionary trajectories of duplicated genes are dictated by combined functional and structural entanglement factors.

PMID: 32586993 [PubMed - in process]

Occurrence and partitioning of brominated flame retardants (BFRs) in indoor air and dust: a 15-month case study in a test home.

Environ Sci Pollut Res Int. 2020 Jun 25;:

Authors: Guo JQ, Li YF, Liu LY, Huo CY, Sun Y, Ma WL, Zhang ZF, Li YF

Abstract
Ten polybrominated diphenyl ethers (PBDEs) and 16 novel brominated flame retardants (NBFRs) were measured in air and dust samples collected in a test home in Harbin, China, from January 2017 to June 2018. The PBDE and NBFR concentrations in indoor air were in the ranges of 0.598-14.5 pg m-3 and 9.28-686 pg m-3, respectively. The ranges of the PBDE and NBFR concentrations in indoor dust were 221-1060 ng g-1 and 71.9-1160 ng g-1, respectively. Brominated flame retardant (BFR) concentrations in indoor air were affected by the temperature, relative humidity (RH), and ventilation. The BFR concentrations in indoor dust did not show temperature dependence. All dust samples were sieved into 6 size fractions (F1-F6: 1000-2000 μm, 500-1000 μm, 250-500 μm, 125-250 μm, 63-125 μm, and < 63 μm). The mass percentage of BFRs in F6 was the highest. The BFR concentrations did not increase constantly with a particle size decrease, and the concentrations in F2 were higher than those in F3. The partitioning behavior of BFRs illustrates that the dust-air partitioning coefficient approximately approached equilibrium within F5, F6, and the total dust fraction (FA) in the test home when logKOA was between 9.1 and 11.32. Air-dust fugacity fractions were calculated, and the results suggested that most of the BFRs were mainly transferred from air to dust in the indoor environment for F1-F6.

PMID: 32588303 [PubMed - as supplied by publisher]

FARP-1 deletion is associated with lack of response to autism treatment by early start denver model in a multiplex family.

Mol Genet Genomic Med. 2020 Jun 25;:e1373

Authors: Cucinotta F, Ricciardello A, Turriziani L, Calabrese G, Briguglio M, Boncoddo M, Bellomo F, Tomaiuolo P, Martines S, Bruschetta M, La Fauci Belponer F, Di Bella T, Colombi C, Baccarin M, Picinelli C, Castronovo P, Lintas C, Sacco R, Biederer T, Kellam B, Scherer SW, Persico AM

Abstract
BACKGROUND: Children with autism spectrum disorder (ASD) display impressive clinical heterogeneity, also involving treatment response. Genetic variants can contribute to explain this large interindividual phenotypic variability.
METHODS: Array-CGH (a-CGH) and whole genome sequencing (WGS) were performed on a multiplex family with two small children diagnosed with ASD at 17 and 18 months of age. Both brothers received the same naturalistic intervention for one year according to the Early Start Denver Model (ESDM), applied by the same therapists, yielding dramatically different treatment outcomes.
RESULTS: The older sibling came out of the autism spectrum, while the younger sibling displayed very little, in any, improvement. This boy was subsequently treated applying a structured Early Intensive Behavioral Intervention paired with Augmentative Alternative Communication, which yielded a partial response within another year. The ESDM nonresponsive child carries a novel maternally inherited 65 Kb deletion at chr. 13q32.2 spanning FARP1. Farp1 is a synaptic scaffolding protein, which plays a significant role in neural plasticity.
CONCLUSION: These results represent a paradigmatic example of the heuristic potential of genetic markers in predicting treatment response and possibly in supporting the targeted prescription of specific early intervention approaches.

PMID: 32588496 [PubMed - as supplied by publisher]