Biology subjects

Chow, E.

Publications and source records attributed to Chow, E..

8 recordsLinked to original sources

bioRxiv2022

Higher habitual FODMAP intake is associated with lower body mass index, lower insulin resistance and higher short-chain fatty acid-producing microbiota in people with prediabetes

Aims/hypothesisThe quantity and quality of FODMAPs can alter the relative abundance of gut microbiota with metabolic consequences although similar data are lacking in people with prediabetes. We investigated associations between habitual FODMAP contents, gut microbiota and glucose/insulin responses in subjects with prediabetes. MethodsIn this prospective cross-sectional study, ninety-eight subjects with impaired glucose tolerance (IGT) (mean age: 57{+/-}7 years, 43 % men) had assessment of body composition, 6-point oral glucose tolerance tests (OGTT), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and 3-day dietary intake. We analysed faecal samples in a sub-group of 20 subjects with IGT and 10 subjects with normal glucose tolerance by 16S rRNA microbiome analysis. ResultsObese subjects with IGT had the lowest daily FODMAP intake compared with their non-overweight and non-obese counterparts (5.7 (3.9-7.9) vs 7.1 (5.0-11.3) vs 9.9 (4.1-22.4) g/day, p=0.024) despite having similar total daily energy intake. Total content of FODMAPs was negatively correlated with body fat. After adjustment for age and gender, total FODMAPs were negatively associated with BMI and HOMA-IR. This remained significant after adjustment for macronutrients and physical activity (p=0.032 and p=0.036 respectively). FODMAP contents were strongly associated with short-chain fatty acid (SCFA)-producing bacteria, such as Lactobacillus (p=0.011), Akkermansia muciniphila (p=0.012), and Bifidobacterium longum (p=0.010), the abundance of which were negatively correlated with 2-hr plasma glucose (r = -0.524, p =0.003). ConclusionIn individuals with IGT, higher habitual FODMAP intake was associated with lower body fat and insulin resistance and increased abundance of SCFA-producing bacteria, calling for interventional studies to evaluate the effects of FODMAP intake in prediabetes.

microbiology↗

bioRxiv2022

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS and sporadic congenital heart disease

BackgroundCongenital heart disease (CHD) affecting the conotruncal region of the heart, occur in half of patients with 22q11.2 deletion syndrome. This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, mapped to the 22q11.2 region, encoding a T-box transcription factor, is one of the main genes for the etiology of the syndrome. We suggest that genetic modifiers of CHD in patients with 22q11.2 deletion syndrome may be in the TBX1 gene network. MethodsTo identify genetic modifiers of 22q11.2 deletion syndrome, we analyzed whole genome sequence of subjects with 22q11.2DS, of which 456 were cases with conotruncal heart defects and 537 were controls with normal cardiac structures. We retained the most damaging rare coding variants and examined 19 functional gene sets for association that were weighted upon expression of genes in cardiac progenitor cells in mouse embryos identified by RNA-sequencing. ResultsWe identified rare damaging coding variants in chromatin regulatory genes as modifiers of conotruncal heart defects in 22q11.2DS. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2 deletion syndrome cases. Many of these genes were identified as risk factors for sporadic CHD in the general population increasing the likelihood that these genes are medically important contributors for CHD. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. Some of the genes identified, such as KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models, providing mechanistic validation of these genes found. ConclusionsOur findings indicate that disturbance of chromatin regulatory genes impact a TBX1 gene network serving as genetic modifiers of 22q11.2 deletion syndrome. Since some of these chromatin regulatory genes were found in individuals with sporadic CHD, we suggest that there are shared mechanisms involving the TBX1 gene network in the etiology of CHD.

genetics↗

bioRxiv2022

Investigating mouse motor coordination using quantitative trait locus analysis to model the genetic underpinnings of developmental coordination disorder

The fundamental skills for motor coordination and motor control emerge through development, from infancy to late childhood years. Neurodevelopmental disorders such as Developmental Coordination Disorder (DCD) lead to impaired acquisition of motor skills. This study investigated motor behaviors that reflect the core symptoms of human DCD through the use of BXD recombinant inbred lines of mice that are known to have divergent phenotypes in many behavioral traits, including motor activity. We sought to correlate behavior in basic motor control tasks with the known genotypes of these reference populations of mice using quantitative trait locus (QTL) mapping. We used twelve BXD lines with an average of 16 mice per group to assess the onset of reflexes during the early neonatal stage of life and differences in motor coordination using the open field, rotarod, and gait analyses during the adolescent/young adulthood period. Results indicated significant variability between lines in as to when neonatal reflexes appeared as well as significant line differences for all measures of motor coordination. Five lines (BXD15, BXD27, BXD28, BXD75, and BXD86) struggled with sensorimotor coordination as seen in gait analysis, rotarod, and open field, similar to human presentation of DCD. We identified three significant quantitative trait loci for gait on proximal Chr 3, Chr 4 and distal Chr 6. Based on expression, function, and polymorphism within the mapped QTL intervals, 7 candidate genes (Gpr63, Spata5, Trpc3, Cntn6, Chl1, Grm7 and Ogg1) emerged. This study offers new insights into mouse motor behavior which promises to be a first murine model to explore the genetics and neural correlates of DCD.

neuroscience↗

bioRxiv2022

Developmental Coordination Disorder: What Can We Learn From Recombinant Inbred Mice Using Motor Learning Tasks and Quantitative Trait Locus Analysis

Developmental Coordination Disorder (DCD) is a motor skills disorder that affects 5-6% of all school-aged children. There is an indication that DCD has an underlying genetic component due to its high heritability. Therefore, we we have explored the use of a recombinant inbred family of mice known as the BXD panel to understand the genetic basis of complex traits (i.e., motor learning) through identification of Quantitative Trait Loci (QTLs). The overall aim of this study was to utilize the QTL approach to evaluate the genome-to-phenome correlation in BXD strains of mice in order to to better understanding the human presentation of DCD. Results in this current study indicate there is a spectrum of motor learning in the pre-selected BXD strains of mice with a spectrum between high and low learning capabilities. Five lines - BXD15, BXD27, BXD28, BXD75, and BXD86 - exhibited the most DCD-like phenotype, when compared to other BXD lines of interest. The results indicate that BXD15 and BXD75 struggled primarily with gross motor skills, BXD28 primarily had difficulties with fine motor skills, and BXD27 and BXD28 lines struggled with both fine and gross motor skills. The functional roles of significant QTL genes were assessed in relation to DCD-like behavior. Only Rab3a (Ras-related protein Rab-3A) emerged as a best candidate gene for the horizontal ladder rung task. This gene is found to be associated with brain and skeletal muscle development. This is the first study to specifically examine the genetic linkage of DCD using BXD lines of mice.

neuroscience↗

bioRxiv2022

Discovery and Visualization of Age-dependent Patterns in the Diurnal Transcriptome of Drosophila

Many critical life processes are regulated by input from 24-hour external light/dark cycles, such as metabolism, cellular homeostasis, and detoxification. The circadian clock, which helps coordinate the response to these diurnal light/dark cycles, remains rhythmic across lifespan; however, rhythmic transcript expression is altered during normal aging. To better understand how aging impacts diurnal expression, we present an improved Fourier-based method for detecting and visualizing rhythmicity that is based on the relative power of the 24-hour period compared to other periods (RP24). We apply RP24 to transcript-level expression profiles from the heads of young (5-day) and old (55-day) Drosophila melanogaster, and reveal novel age-dependent rhythmicity changes that may be masked at the gene level. We show that core clock transcripts phase advance during aging, while most rhythmic transcripts phase delay. Transcripts rhythmic only in young flies tend to peak before lights on, while transcripts only rhythmic in old peak after lights on. We show that several pathways including glutathione metabolism, gain or lose coordinated rhythmic expression with age providing insight into possible mechanisms of age-onset neurodegeneration. Remarkably, we find that many pathways show very robust coordinated rhythms across lifespan, highlighting their putative roles in promoting neural health. We investigate statistically enriched transcription factor binding site motifs that may be involved in these rhythmicity changes.

systems biology↗

bioRxiv2021

Fecal microbiota transplantation derived from Alzheimer's disease mice worsens brain trauma outcomes in young C57BL/6 mice

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration, both which increase the risk and accelerate the progression of Alzheimers disease (AD). The gut microbiome is an essential modulator of the immune system, impacting in the brain. AD has been related with reduced diversity and alterations in the community composition of the gut microbiota. This study aimed to determine whether the gut microbiota from AD mice exacerbates neurological deficits after TBI in control mice. We prepared fecal microbiota transplants from 18-24 months old 3xTg-AD (FMT-AD) and from healthy controls (FMT-young) mice. FMTs were administered orally to young control C57BL/6 (wild-type, WT) mice after they underwent controlled cortical impact (CCI) injury, as a model of TBI. Then, we characterized the microbiota composition of the fecal samples by full-length 16S rRNA gene sequencing analysis. We collected the blood, brain, and gut tissues for protein and immunohistochemical analysis. Our results showed that FMT-AD administration stimulates a higher relative abundance of the genus Muribaculum and a decrease in Lactobacillus johnsonii compared to FMT-young in WT mice. Furthermore, WT mice exhibited larger lesion, increased activated microglia/macrophages, and reduced motor recovery after FMT-AD compared to FMT-young one day after TBI. In summary, we observed gut microbiota from AD mice to have a detrimental effect and aggravate the neuroinflammatory response and neurological outcomes after TBI in young WT mice.

neuroscience↗

bioRxiv2018

Exploration of Anti-Yo and Anti-Hu paraneoplastic neurological disorders by PhIP-Seq reveals a highly restricted pattern of antibody epitopes

Paraneoplastic neurological disorders (PNDs) are immune-mediated diseases of the nervous system understood to manifest as part of a misdirected anti-tumor immune response. Identifying PND-associated autoantibodies and their cognate antigens can assist with proper diagnosis and treatment while also enhancing our understanding of tumor-associated immune processes, triggers for autoimmune disease, and the functional significance of onconeuronal proteins. Here, we employed an enhanced version of phage display immunoprecipitation and sequencing (PhIP-Seq) leveraging a library of over 731,000 unique phage clones tiling across the entire human proteome to detect autoantibodies and create high-resolution epitope profiles in serum and CSF samples from patients suffering from two common PNDs, the anti-Yo (n = 36 patients) and anti-Hu syndromes (n = 44 patients). All patient samples positive for anti-Yo antibody by a validated clinical assay yielded polyspecific enrichment of phage presenting peptides from the canonical anti-Yo (CDR2 and CDR2L) antigens, while 38% of anti-Hu patients (17/44) had a serum and/or CSF sample that significantly enriched peptides deriving from the ELAVL family of proteins, the anti-Hu autoantigenic target. The anti-Hu antibodies showed a remarkably convergent antigenic signature across 15/17 patients corresponding to residues surrounding and including the degenerate motif, RLDxLL, shared by ELAVL2, 3 and 4. Lastly, PhIP-Seq identified several known and novel autoantigens in these same patient samples, representing potential biomarkers that could aid in the diagnosis and prognosis of PND and cancer.

immunology↗

bioRxiv2017

Metagenomic DNA sequencing for the diagnosis of intraocular infections

PurposeTo compare the performance of unbiased high-throughput sequencing with pathogen directed PCR using DNA isolated from archived ocular fluid, approaches that are compatible with the current sample handling practice of ophthalmologists.\n\nDesignRetrospective molecular study of banked vitreous samples.\n\nMethodsWe evaluated a metagenomic DNA sequencing-based approach (DNA-seq) using archived positive (n = 31) and negative (n=36) vitreous specimens as determined by reference pathogen-specific PCR assays (herpes simplex virus 1 and 2, cytomegalovirus, varicella-zoster virus, and Toxoplasma gondii). Pathogens were identified using a rapid computational pipeline to analyze the non-host sequences obtained from DNA-seq. Clinical samples were de-identified and laboratory personnel handling the samples and interpreting the data were masked.\n\nResultsMetagenomic DNA sequencing detected 87% of positive reference samples. In the presumed negative reference samples, DNA-seq detected an additional 6 different pathogens in 8 samples (22% of negative samples) that were either not detected or not targeted with pathogen-specific PCR assays. Infectious agents identified only with DNA-seq were Candida dubliniensis, Klebsiella pneumoniae, human herpesvirus 6 (HHV-6), and human T-cell leukemia virus type 1 (HTLV-1). Discordant samples were independently verified in CLIA-certified laboratories. CMV sequences were compared against the antiviral mutation database and 3 of the samples were found to have mutations conferring ganciclovir resistance.\n\nConclusionsMetagenomic DNA sequencing was highly concordant with pathogen-directed PCRs. The unbiased nature of metagenomics DNA sequencing allowed an expanded scope of pathogen detection, including bacteria, fungal species, and viruses, resolving 22% of cases that had previously escaped detection by routine pathogen-specific PCRs. The detection of drug resistance mutations highlights the potential for unbiased sequencing to provide clinically actionable information beyond pathogen species detection.

genomics↗