False Discovery Rate Threshold Research Articles

Genetic Variants Associated with Elevated Plasma Ceramides in Individuals with Metabolic Syndrome.

Metabolic syndrome (MetS) is a complex condition of metabolic disorders and shows a steady onset globally. Ceramides are known as intracellular signaling molecules that influence key metabolism through various pathways such as MetS and insulin resistance. Therefore, it is important to identify novel genetic factors related to increased plasma ceramides in subjects with MetS. Here we first measured plasma ceramides levels in 37 subjects with MetS and in 38 healthy subjects by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Specifically, levels of C16 ceramide (Cer-16), C18 ceramide (Cer-18), C20 ceramide (Cer-20), C18 dihydroceramide (DhCer-18), C24 dihydroceramide (DhCer-24), and C24:1 dihydroceramide (DhCer-24:1) were significantly increased in MetS group (p < 5.0 × 10−2). We then performed single nucleotide polymorphism (SNP) genotyping to identify variants associated with elevated plasma ceramides in MetS group using Axiom® Korea Biobank Array v1.1 chip. We also performed linear regression analysis on genetic variants involved in ceramide synthesis and significantly elevated plasma ceramides and dihydroceramides. Ten variants (rs75397325, rs4246316, rs80165332, rs62106618, rs12358192, rs11006229, rs10826014, rs149162405, rs6109681, and rs3906631) across six genes (ACER1, CERS3, CERS6, SGMS1, SPTLC2, and SPTLC3) functionally involved in ceramide biosynthesis showed significant associations with the elevated levels of at least one of the ceramide species in MetS group at a statistically significant threshold of false discovery rate (FDR)-adjusted p < 5.0 × 10−2. Our findings suggest that the variants may be genetic determinants associated with increased plasma ceramides in individuals with MetS.

Impact of Multidomain Lifestyle Intervention on Cerebral Cortical Thickness and Serum Brain-Derived Neurotrophic Factor: the SUPERBRAIN Exploratory Sub-study

In the SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at-risk elderly people (SUPERBRAIN), we evaluated the impact of a 24-week facility-based multidomain intervention (FMI) and home-based MI (HMI) on cortical thickness, brain volume, and the serum brain-derived neurotrophic factor (BDNF). Totally, 152 participants, aged 60–79 years without dementia but with ≥ 1 modifiable dementia risk factor, were randomly assigned to the FMI, HMI, or control groups. Among them, 55 participants (20 FMI, 19 HMI, and 16 controls) underwent brain MRI at baseline and 24 weeks. We compared changes in global/regional mean cortical thickness at the region-of-interest (ROI) between the intervention and control groups. The changes in the total cortical gray matter volume and global mean cortical thickness were compared using analysis of covariance with age, sex, and education as covariates. ComBat site harmonization was applied for cortical thickness values across the scanners. ROI-based analysis was controlled for multiple comparisons, with a false discovery rate threshold of p < 0.05. Serum BDNF levels were significantly higher in the FMI group than in the control group (p = 0.029). Compared with the control group, the mean global cortical thickness increased in the FMI group (0.033 ± 0.070 vs. − 0.003 ± 0.040, p = 0.013); particularly, cortical thickness of the bilateral frontotemporal lobes, cingulate gyri, and insula increased. The increase in cortical thickness and serum BDNF in the FMI group suggests that group preventive strategies at the facility may be beneficial through structural neuroplastic changes in brain areas, which facilitates learning and neurotrophic factors.

Genetic Architecture of Powdery Mildew Resistance Revealed by a Genome-Wide Association Study of a Worldwide Collection of Flax (Linum usitatissimum L.)

Powdery mildew is one of the most important diseases of flax and is particularly prejudicial to its yield and oil or fiber quality. This disease, caused by the obligate biotrophic ascomycete Oïdium lini, is progressing in France. Genetic resistance of varieties is critical for the control of this disease, but very few resistance genes have been identified so far. It is therefore necessary to identify new resistance genes to powdery mildew suitable to the local context of pathogenicity. For this purpose, we studied a worldwide diversity panel composed of 311 flax genotypes both phenotyped for resistance to powdery mildew resistance over 2 years of field trials in France and resequenced. Sequence reads were mapped on the CDC Bethune reference genome revealing 1,693,910 high-quality SNPs, further used for both population structure analysis and genome-wide association studies (GWASs). A number of four major genetic groups were identified, separating oil flax accessions from America or Europe and those from Asia or Middle-East and fiber flax accessions originating from Eastern Europe and those from Western Europe. A number of eight QTLs were detected at the false discovery rate threshold of 5%, located on chromosomes 1, 2, 4, 13, and 14. Taking advantage of the moderate linkage disequilibrium present in the flax panel, and using the available genome annotation, we identified potential candidate genes. Our study shows the existence of new resistance alleles against powdery mildew in our diversity panel, of high interest for flax breeding program.

Gut dysbiosis in cutaneous T-cell lymphoma is characterized by shifts in relative abundances of specific bacterial taxa and decreased diversity in more advanced disease.

BackgroundCutaneous T‐cell lymphoma (CTCL) patients often suffer from recurrent skin infections and profound immune dysregulation in advanced disease. The gut microbiome has been recognized to influence cancers and cutaneous conditions; however, it has not yet been studied in CTCL.ObjectivesTo investigate the gut microbiome in patients with CTCL and in healthy controls.MethodsA case‐control study was conducted between January 2019 and November 2020 at Northwestern’s busy multidisciplinary CTCL clinic (Chicago, Illinois, USA) utilizing 16S ribosomal RNA gene amplicon sequencing and bioinformatics analyses to characterize the microbiota present in fecal samples of CTCL patients (n = 38) and age‐matched healthy controls (n = 13) from the same geographical region.ResultsGut microbial α‐diversity trended lower in patients with CTCL and was significantly lower in patients with advanced CTCL relative to controls (P = 0.015). No differences in β‐diversity were identified. Specific taxa were significantly reduced in patient samples; significance was determined using adjusted P‐values (q‐values) that accounted for a false discovery rate threshold of 0.05. Significantly reduced taxa in patient samples included the phylum Actinobacteria (q = 0.0002), classes Coriobacteriia (q = 0.002) and Actinobacteria (q = 0.03), order Coriobacteriales (q = 0.003), and genus Anaerotruncus (q = 0.01). The families Eggerthellaceae (q = 0.0007) and Lactobacillaceae (q = 0.02) were significantly reduced in patients with high skin disease burden.ConclusionsGut dysbiosis can be seen in patients with CTCL compared to healthy controls and is pronounced in more advanced CTCL. The taxonomic shifts associated with CTCL are similar to those previously reported in atopic dermatitis and opposite those of psoriasis, suggesting microbial parallels to the immune profile and skin barrier differences between these conditions. These findings may suggest new microbial disease biomarkers and reveal a new angle for intervention.

Single-Nuclear RNA-Sequencing Identifies Cell-Specific Transcriptional Programs in Cardiac Allograft Vasculopathy

<h3>Purpose</h3> Cardiac allograft vasculopathy (CAV) is the leading cause of late graft failure and mortality after heart transplantation (HT). Current therapies have limited efficacy in preventing or stalling the progression of CAV. Improved understanding of CAV biology is needed to identify novel therapeutics. <h3>Methods</h3> We performed single-nuclear RNA sequencing (snRNA-seq) on human cardiac tissue obtained by endomyocardial biopsy from the right ventricle of 3 HT recipients without CAV and at the time of heart explant in 3 HT recipients with severe CAV. Differentially expressed genes (DEGs) between cohorts were identified with DESeq2 using a 5% false discovery rate threshold for significant genes. <h3>Results</h3> Unsupervised clustering of 38,211 nuclei identified 15 major cell types (Figure A). Relative to cells from non-CAV hearts, endothelial cells and fibroblasts from hearts with severe CAV showed enrichment for genes and pathways associated with inflammation, angiogenesis, and extracellular matrix organization (Figure B and C; endothelial cells). Intersecting these DEGs with the druggable genome identified novel cell-specific drug targets. <h3>Conclusion</h3> We show feasibility of performing snRNA-seq from human endomyocardial biopsy samples and identify cell-specific transcriptional programs that are unique to patients with severe CAV. These data lay the groundwork for larger-scale studies that can accelerate mechanistic understanding of CAV development.

Pharmacometabonomic association of cyclophosphamide 4-hydroxylation in hematopoietic cell transplant recipients.

The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug‐metabolizing enzymes that metabolize CY to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY’s cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY), and 24 h after the first dose of PT‐CY (24‐h post‐CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre‐CY time point, no EMCs were associated at FDR less than 0.1. At pre‐HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre‐graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24‐h post‐CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY.

Psychiatric symptoms of frontotemporal dementia and subcortical (co-)pathology burden: new insights.

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Besides the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study was to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from The Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-β, and α-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local false discovery rate threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-β (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-β burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of α-synuclein co-pathology in the substantia nigra correlated with disinhibition (R = 0.24), tau pathology in the substantia nigra correlated with depression (R = 0.25) and in the locus coeruleus with both depression and perseverative/compulsive behaviour (R = 0.26 and R = 0.32). The quantitative assessment of TDP-43 in the granular layer validated the higher burden of TDP-43 pathology in brain donors with hallucinations compared to those without hallucinations (P = 0.007). Our results show that psychiatric symptoms of FTLD are linked to subcortical pathology burden in the hippocampus, and hallucinations are linked to a higher burden of TDP-43 in the granular layer. Co-occurring non-FTLD pathologies in subcortical regions could contribute to configuring the clinical phenotype of FTLD.

Neighborhood characteristics and breast tumor methylation: using epigenomics to explore cancer outcome disparities.

Social exposures may drive epigenetic alterations that affect racial disparities in breast cancer outcomes. This study examined the association between neighborhood-level factors and DNA methylation in non-Hispanic Black and White women diagnosed with breast cancer. Genome-wide DNA methylation was measured using the EPIC array in the tumor tissue of 96 women. Linear regression models were used to examine the association between nine neighborhood-level factors and methylation, regressing β values for each cytosine-phosphate guanine dinucleotide (CpG) site on neighborhood-level factors while adjusting for covariates. Neighborhood data were obtained from the Opportunity Atlas. We used a false discovery rate (FDR) threshold < 0.05, and for CpGs below this threshold, we examined interactions with race. We employed multivariable Cox proportional-hazards models to estimate whether aberrant methylation was associated with all-cause mortality. 26 of the CpG sites were associated with job density or college education (FDR < 0.05). Further exploration of these 26 CpG sites revealed no interactions by race, but a single probe in TMEM204 was associated with all-cause mortality. We identified novel associations between neighborhood-level factors and the breast tumor DNA methylome. Our data are the first to show that dysregulation in neighborhood associated CpG sites may be associated with all-cause mortality. Neighborhood-level factors may contribute to differential tumor methylation in genes related to tumor progression and metastasis. This contributes to the increasing body of evidence that area-level factors (such as neighborhood characteristics) may play an important role in cancer disparities through modulation of the breast tumor epigenome.

Abstract PR-03: Neighborhood-level redlining-associated methylation in breast tumors: The impact of structural racism on the tumor epigenome

Abstract Background: Structural racism has been associated with breast cancer mortality. Exposure to adverse inequities may drive epigenetic perturbations that affect racial disparities in breast cancer outcomes. This study examined the association between neighborhood-level redlining and DNA methylation in non-Hispanic Black and White women diagnosed with breast cancer. Methods: Genome-wide DNA methylation was measured using the EPIC array in the tumor tissue of 84 women. Linear regression models were used to examine the association between neighborhood-level redlining and methylation, regressing β values for each cytosine-phosphate-guanine dinucleotide (CpG) site on redlining while adjusting for covariates. Redlining was derived for census tracts using the Home Mortgage Disclosure Act database. We used a false discovery rate (FDR) threshold &amp;lt;0.1, and for CpGs below this threshold, we examined interactions with Estrogen Receptor (ER) status. We employed multivariable Cox-proportional hazard models to estimate whether aberrant methylation was associated with all-cause mortality. Results: 36 of the CpG sites were associated with neighborhood-level redlining (FDR&amp;lt;0.1). The majority of genes are implicated in carcinogenesis including genes in immune function (BANP, IGDCC3, GPR15), oncogenic signaling (IGFALS, RNLS, RTP3), and angiogenesis (ANGPT1). Further exploration of these 36 CpG sites revealed no interactions by ER status, no probes were associated with all-cause mortality. Conclusions: We identified novel associations between neighborhood-level redlining and the breast tumor DNA methylome. Our data are the first to show that structural racism impacts the breast tumor epigenome. Citation Format: Jasmine M Miller-Kleinhenz, Leah Moubadder, Kirsten M. Beyer, Yuhong Zhou, Anne H. Gaglioti, Jazib Gohar, Lindsay J. Collin, Kashari Henry, Karen M. Conneely, Uma Krishnamurti, Olivia D'Angelo, Keerthi Gogineni, Mylin Torres, Sheryl Gabram-Mendola, Lauren E. McCullough. Neighborhood-level redlining-associated methylation in breast tumors: The impact of structural racism on the tumor epigenome [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PR-03.

Neuroanatomy of FTD: Whole‐brain correlations between symptoms and pathologies

Distinct pathologies accumulate in multiple brain regions (BR) and shape the heterogeneous clinical presentation of frontotemporal dementia (FTD). It is unknown how regional pathological burden links to symptoms, what the role of co-occurring pathologies is, and whether the localization of pathology might be a bigger contributor to symptoms than the type of pathology. Our aim is to investigate how early FTD symptoms correlate to the burden of multiple pathologies throughout the brain.Post-mortem brain tissue of frontotemporal lobar degeneration (FTLD) donors from the Netherlands brain bank was dissected into twenty standard BR and stained for TAR DNA-binding protein 43 (TDP-43), tau, fused-in-sarcoma (FUS), amyloid-beta (Aβ), and alpha-synuclein. The burden of each pathological protein in each BR was quantified. All clinical records were reviewed to assess psychiatric, behavioral, language, and motor symptoms in the first three years from disease onset. Whole-brain clinico-pathological partial correlations were assessed using the heterogeneous correlation function (R 3.6.1). The local false discovery rate threshold was set at 0.01.Eighty-eight FTLD brain donors were studied, including 46 TDP-43, 35 tau, and 7 FUS. Significant positive partial correlations (p < 0.01) were found between hippocampal TDP-43 pathology and hallucinations (R = 0.23), perseverative-compulsive behavior (R = 0.25), depression (R = 0.28), and mania (R = 0.32). Tau pathology in the substantia nigra and locus coeruleus was linked to depression (R = 0.25, R = 0.24). Both TDP-43 and Aβ in the subthalamus were associated with severe disinhibition (R = 0.23, R = 0.25), while apathy correlated with both TDP-43 and tau burden in the parietal lobe (R = 0.27, R = 0.24). Parkinsonism was linked to TDP-43 burden in the substantia nigra (R = 0.33).Neuropsychiatric symptoms of FTD are linked to pathology burden in BR beyond the frontal lobes, including subcortical structures such as the hippocampus, the substantia nigra and locus coeruleus. Co-occurring pathologies are not simple bystanders, but could play a role in configuring FTD clinical phenotype. Different pathologies in the same BR correlate with the same symptoms.

Impact on ALFF and ReHO mapping of lifestyle multidomain intervention: The SUPERBRAIN study

AbstractBackgroundIn the South Korean study to prevent cognitive impairment and protect brain health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN), we explored impact on amplitude of low‐frequency fluctuation (ALFF) and regional homogeneity (ReHo) mapping of 24‐week facility‐based multidomain intervention (FMI) and home‐based MI (HMI).MethodA total of 152 participants, aged 60‐79 years without dementia but with ≥ 1 modifiable dementia risk factor, were randomly assigned to the FMI, HMI, or control groups. Among them, 56 participants (20 FMI, 20 HMI, and 16 control) took brain MRIs at baseline and 24 weeks. We compared between each intervention and control groups in change of ALFF and ReHo mapping. The changes in ALFF and ReHo mapping were compared using analysis of covariance with age, sex, education, and scan centers as covariates. ROI‐based analysis was controlled for multiple comparisons with a false discovery rate threshold of P &lt; 0.05.ResultOnly in the FMI group, a significant increase of ALFF in left medial orbitofrontal gyrus was observed after intervention. When 24‐week ALFF change in the left medial orbitofrontal gyrus was compared between each intervention and control groups, there was no difference. In HMI, increased ReHo was evident in right cuneus at follow‐up, whereas increased ReHo in left medial orbitofrontal gyrus and left anterior cingulate and decreased ReHo in right superior parietal lobule and right precuneus were observed in FMI group. The ReHo change in right cuneus was significantly higher in HMI group compared to the control group. The ReHo change in left medial orbitofrontal gyrus was notably higher in FMI compared to the control group. The correlation analysis revealed a positive correlation between the ReHo change in left medial orbitofrontal gyrus and change of serum brain‐derived neurotrophic factor (BDNF) levels in FMI group.ConclusionSignificant differences between the FMI and control groups on changes in ReHo in at‐risk elderly without substantial impairment in the SUPERBRAIN suggest that group preventive strategies at the facility may be beneficial on cognition through neuroplastic changes of functional processing circuits in the brain areas which play a crucial role in processing social information.

Body mass index predicts lower connectivity in associational fibers of the temporal lobe in older men

Increased body mass index (BMI) is related to changes in white matter (WM) connectivity1 . We investigated whether WM connectivity patterns as a function of BMI varies across sex differences.We enrolled 289 individuals (58 CDR=0 & 231 CDR=0.5) from the Knight Alzheimer Disease Research Center (ADRC) (Table 1). Participants were included if they had a physical evaluation within 12 months of a diffusion MRI scan and excluded if they had clinical dementia. Connectome analyses were performed using the DSI Studio software (http://dsi-studio.labsolver.org/). Diffusion data were reconstructed in the MNI space using q-space diffeomorphic reconstruction (QSDR)2 . The quantitative anisotropy was extracted as the local connectome fingerprint. A multi-regression model were used to derive the correlation and a false discovery rate threshold of 0.05 was adopted to select tracts using a deterministic fiber tracking algorithm.A positive association between connectivity in the left arcuate fasciculus (AF) and the left middle cerebellar peduncle in men did not survive regression for age (Figure 1-A). Men also showed a statistically significant negative association between connectivity in the bilateral inferior longitudinal fasciculi (ILF), right inferior fronto-occipital fasciculus (IFOF), the frontoparietal and parahippocampal parts of the right cingulum, the tapetum part of the corpus callosum (CC), right fornix and right corticospinal, corticostriatal, and corticopontine tracts. All of these relationships persisted when co-varying for age (Figure 1-B). Results in women revealed a significant positive correlation between connectivity of the right IFOF, right superior longitudinal fasciculus (SLF), right corticopontine, corticospinal tracts, bilateral reticulospinal tracts, and left arcuate fasciculus (AF) (Figure 2-A) even when controlling for age. Connectivity in the bilateral ILF, right IFOF and the tapetum part of the CC showed an inverse correlation with BMI in women (Figure 2-B).Increased BMI is related to lower structural connectivity in important associational WM fibers of the temporal lobe, particularly in older men.

Impact on cerebral cortical thickness of lifestyle multidomain intervention: The SUPERBRAIN study

AbstractBackgroundIn the South Korean study to prevent cognitive impairment and protect brain health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN), we explored impact on cortical thickness of 24‐week facility‐based multidomain intervention (FMI) and home‐based MI (HMI).MethodA total of 152 participants, aged 60‐79 years without dementia but with ≥ 1 modifiable dementia risk factor, were randomly assigned to the FMI, HMI, or control groups. Among them, 55 participants (20 FMI, 19 HMI, and 16 control) took brain MRIs at baseline and 24 weeks. We compared between each intervention and control groups in change of global/regional mean cortical thickness at 76 region‐of‐interest (ROI)s of the automated anatomical labelling (AAL); the total scale index score of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS); and Serum brain‐derived neurotrophic factor (BDNF) levels. The changes in mean cortical thickness were compared using analysis of covariance with age, sex, education, and scan centers as covariates. ROI‐based analysis was controlled for multiple comparisons with a false discovery rate threshold of P &lt; 0.05.ResultComparing with the control group, the total scale index score of RBANS was more significantly improved in both FMI group (p=0.002) and HMI group (p=0.013), respectively. The serum BDNF more significantly increased only in the FMI group (p=0.029). Mean global cortical thickness more significantly increased only in the FMI group (0.033±0.070 vs ‐0.003±0.040, p=0.035). ROI‐based analysis showed more significantly increased cortical thickness of the orbital, medial, medial orbital parts of right superior frontal gyrus, right olfactory cortex, right rectal gyrus, right anterior cingulate and paracingulate gyri, right middle temporal gyrus, medial orbital and dorsolateral parts of the left superior frontal gyrus, the orbital part of the left middle frontal gyrus, left middle occipital gyrus, and left middle temporal gyrus in the FMI group.ConclusionSignificant differences between the FMI and control groups on changes in cortical thicknesses in at‐risk elderly without substantial impairment in the SUPERBRAIN suggest that group preventive strategies at the facility may be beneficial on cognition through structural neuroplastic changes in the brain areas which play a crucial role in processing social information.

Changes of cerebral cortical structure and cognitive dysfunction in \u201chealthy hemisphere\u201d after stroke: a study about cortical complexity and sulcus patterns in bilateral ischemic adult moyamoya disease

BackgroundMoyamoya disease (MMD) is an uncommon cerebrovascular disease which leads to progressive stenosis and occlusion of the bilateral internal carotid artery and main intracerebral arteries. Concerns are always on how the hemisphere with infarction affects cognitive function, while little attention is paid to the role that the non-infarcted hemisphere plays. Therefore, we aimed to detect cortical indexes, especially cortical complexity in the left or right hemisphere separately in patients with MMD after stroke.Methods28 patients with MMD (14 males, 14 females) and 14 healthy controls were included in this study. All participants underwent cognitive tests and magnetic resonance imaging (MRI) scan. The preprocessing of three-dimensional T1 weighted images were performed by standard surface-based morphometry. Surface-based morphometry statistical analysis was carried out with a threshold of False Discovery Rate (FDR) P < 0.05 and fractal dimension (FD) was used to provide a quantitative description of cerebral cortical complexity.ResultsWidespread cognitive dysfunctions were found in MMD patient with stroke. Extensive FD reduction in the left hemisphere with right-sided infarction, mainly in the superior temporal, inferior frontal, and insula, while the post central gyrus, superior parietal, and inferior parietal gyrus also showed a wide range of significant differences (FDR corrected P < 0.05). Meanwhile, FD changes in the right hemisphere with left-sided infarction are restricted to the precuneus and cingulate isthmus (FDR corrected P < 0.05).ConclusionsExtensive cognitive impairment was reconfirmed in Moyamoya disease with stroke, while wild and asymmetrical decrease of cortical complexity is observed on both sides. These differences could be relative to unbalanced cognitive dysfunction, and may be the result of a long-term chronic ischemia and compensatory of the contralateral hemisphere to the infarction.

Common Gene Expression Signature of B-Cells of Waldenström Macroglobulinemia (WM) and IgM Monoclonal Gammopathies of Undetermined Significance (IgM MGUS) Compared to Healthy Subjects

We performed a comparative gene expression profiling (GEP) study on B-cells and plasma cells of Waldenström Macroglobulinemia (WM), IgM monoclonal gammopathies of undetermined significance (IgMMGUS), and normal individuals (CTRLs) to identify GEP changes as reliable predictors of progression of IgMMGUS to WM.We analyzed bone marrow B-cells and plasma cells from 36 WM patients, 13 IgMMGUS subjects, and 7 CTRLs by Affymetrix microarray, respectively (Table 1). GEP experiments were performed on the CD19+ and CD138+ cells using GeneChip-HGU133 Plus 2.0. Data were preprocessed and normalized by Robust Multi-Array Average and ComBat. Selection of the different expressed genes was performed separately for CD19+ and CD138+ cells, using Significance Analysis of Microarrays (SAM) on the 3 groups and a false discovery rate threshold of 5%, followed, for significance comparisons, by a pair-wise SAM test corrected for multiple testing.We focused on the comparison of the CD19+ cells of WM vs. IgMMGUS vs. CTRLs which highlighted 2038 unique genes whereas the same comparison of the CD138+ cells determined 29 unique genes (Trojani et.al. Cancers 2021). Among the 2038 DEGs, 115 genes were grouped in KEGG pathways involved in Wnt-signaling, BCR-signaling, calcium signaling, hematopoietic cell antigens, cell adhesion, adherens junctions, coagulation cascade, platelet activation, cytokine receptor, and signaling pathways responsible for cell cycle, apoptosis, and survival.Interestingly, most of the 115 DEGs in B-cells were different expressed in WM vs. IgMMGUS and CTRLs. Only 9/115 DEGs were significantly different expressed in WM vs. CTRLs and in IgMMGUS vs. CTRLs, but no significant expression changes were noted between WM and IgMMGUS (Table 2).To further inspect the similarities and the differences among WM and IgMMGUS, we computed the Euclidean pair-wise distance between subjects and, using this distance as weight, constructed a minimum spanning tree (MST) (Figure 1).Considerably, four probesets identified ADRB2 (transmembrane Beta adrenergic receptor) which was up regulated in WM and IgMMGUS compared to CTRLs. The over expression of ADRB2 was also demonstrated in Mantle Cell Lymphoma cell lines and in Diffuse large B-cell lymphoma (DLBCL) lymphocytes compared to normal B-cells (doi10.1016/j.cellsig.2017.08.002), and in most malignancies (doi10.1007/s11033-021-06250-y) .As far as we know, ADAM23 (ADAM Metallopeptidase Domain23) has not been found in WM, whereas we suggest its possible role in WM patients with Sjogren's syndrome (SS). ADAM23 plays a role in the peripheral neuropathy by controlling the activity of potassium channels in SS (doi10.1007/s10067-016-3499-z). Some authors found that sensory/motor neuropathies were associated with MGUS patients (doi10.1017/s0317167100011483). We strongly believe that the down regulation of ADAM23 in WM and IgMMGUS has a good chance to be associated with clinical neuropathy in WM and IgMMGUS.RASGRP3 (RAS Guanyl Releasing Protein3) and PIK3AP1 (Phosphoinositide 3 Kinase Adaptor Protein1) play crucial roles in BCR signaling pathway: PIK3AP1 activates the PI3K-Akt signaling while RASGRP3 stimulates MAPK signaling pathway.The deregulation of LEF1 (Lymphoid Enhancer Binding Factor1) and genes of Wnt-pathway were previously demonstrated in B-cell disorders and multiple myeloma (doi10.1007/s00277-017-3207-3, doi10.1016/j.pathol.2019.09.009). According to these studies, we showed the under expression of LEF1 in WM and IgMMGUS compared to CTRLs.We identified the down regulation of EZH2 (Enhancer Of Zeste2 Polycomb Repressive Complex2Subunit) in WM and IgMMGUS compared to CTRLs. EZH2 is involved in Follicular lymphoma and DLBCL (doi10.1080/2162402X.2017.1321184).CDHR3 (Cadherin Related Family Member3), CHEK1 (Checkpoint Kinase1), and HIST1H1B (Histone-H1.5) were over expressed in CTRLs compared to IgMMGUS and WM.In conclusion, the common gene-set in WM and IgMMGUS could suggest two-hit hypothesis. First, the gene-set could play a role in the risk of progression of IgMMGUS to WM. Until now, all the IgMMGUS subjects have not been transformed in WM or other NHL, but they have been monitored every 6 months, and their possible transformation to lymphoma could highlight new insights. The second hypothesis suggests their involvement in the biological processes of leukemogenesis in WM and IgMMGUS which will be further investigated. [Display omitted] DisclosuresTedeschi: AbbVie: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

Patient-Reported Quality of Life Outcomes After Integrating Exclusive Liquid Meal Replacement in Patients With Head and Neck Cancer Undergoing Chemoradiation: Results From a Phase II Study

<h3>Purpose/Objective(s)</h3> Preventing malnutrition during chemoradiation (CRT) for head and neck cancer (HNC) is crucial for treatment adherence, minimizing treatment-related complications, and maximizing quality of life (QOL). We sought to assess patient-reported QOL outcomes after integrating exclusive liquid meal replacement with Soylent, a novel meal replacement agent, in patients with HNC undergoing CRT. <h3>Materials/Methods</h3> Patients undergoing definitive or adjuvant concurrent CRT for locally advanced HNC enrolled on our single-institution, prospective phase II protocol evaluating nutritional replacement with Soylent. Patients who reached 5% body weight loss during CRT were transitioned to Soylent meal replacement for all nutritional needs. Patients who reached 10% body weight loss were recommended for gastrostomy tube placement. The University of Washington QOL (UW-QOL) and the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) questionnaires were used to assess patient-reported QOL prior to the receipt of CRT (baseline), as well as at 1, 3, 6, 12, and 18 months following conclusion of CRT. Higher scores indicated better QOL for both assessments. Paired t-test or Wilcoxon signed-rank test was applied to assess whether differences between scores at each time point and baseline exist. Multiple testing was addressed via Benjamini-Hochberg procedure with a false discovery rate threshold of 0.2. <h3>Results</h3> Of the 41 patients who completed evaluable QOL surveys, 33/41 (80%) reached the 5% weight loss threshold and 32/33 (97%) were transitioned to Soylent. Subsequently, 11/33 (33%) on Soylent reached the 10% weight loss threshold, but only 1/11 (9%) received a gastrostomy tube. The nadirs for overall and health-related UW-QOL were reached at 1 month and rebounded to exceed baseline by 6 months. The mean overall UW-QOL score was 71 at baseline compared with 62, 69, 77, 73, and 80 at 1, 3, 6, 12, and 18 months, respectively. Comparing individual UW-QOL domains from baseline to 18 months, significant differences were found in only two domains. Saliva scores decreased from 91 to 73 (adjusted <i>P</i> = 0.02) whereas anxiety scores increased from 51 to 81 (adjusted <i>P</i> = 0.11). FACT-H&N survey scores were reduced from 32 at baseline to 20 at 1 month (adjusted <i>P</i> < 0.001) and 26 at 3 months (adjusted <i>P</i> < 0.001), but increased to 29, 30, and 27 at 6, 12, and 18 months, without significant differences as compared to baseline (adjusted <i>P</i> > 0.57 for all). <h3>Conclusion</h3> This study's results reveal encouraging QOL outcomes from exclusive liquid meal replacement with Soylent, which appear potentially comparable with QOL outcomes from contemporary de-escalation trials in HNC pending further direct comparison. Soylent liquid meal replacement with aggressive dietary monitoring appears to be a promising approach for maximizing patient-reported QOL after conventional, concurrent CRT.

Genetic dissection of grain architecture-related traits in a winter wheat population

BackgroundThe future productivity of wheat (T. aestivum L.) as the most grown crop worldwide is of utmost importance for global food security. Thousand kernel weight (TKW) in wheat is closely associated with grain architecture-related traits, e.g. kernel length (KL), kernel width (KW), kernel area (KA), kernel diameter ratio (KDR), and factor form density (FFD). Discovering the genetic architecture of natural variation in these traits, identifying QTL and candidate genes are the main aims of this study. Therefore, grain architecture-related traits in 261 worldwide winter accessions over three field-year experiments were evaluated.ResultsGenome-wide association analysis using 90K SNP array in FarmCPU model revealed several interesting genomic regions including 17 significant SNPs passing false discovery rate threshold and strongly associated with the studied traits. Four of associated SNPs were physically located inside candidate genes within LD interval e.g. BobWhite_c5872_589 (602,710,399 bp) found to be inside TraesCS6A01G383800 (602,699,767–602,711,726 bp). Further analysis reveals the four novel candidate genes potentially involved in more than one grain architecture-related traits with a pleiotropic effects e.g. TraesCS6A01G383800 gene on 6A encoding oxidoreductase activity was associated with TKW and KA. The allelic variation at the associated SNPs showed significant differences betweeen the accessions carying the wild and mutated alleles e.g. accessions carying C allele of BobWhite_c5872_589, TraesCS6A01G383800 had significantly higher TKW than the accessions carying T allele. Interestingly, these genes were highly expressed in the grain-tissues, demonstrating their pivotal role in controlling the grain architecture.ConclusionsThese results are valuable for identifying regions associated with kernel weight and dimensions and potentially help breeders in improving kernel weight and architecture-related traits in order to increase wheat yield potential and end-use quality.

Awareness, knowledge and trust in the Greek authorities towards COVID-19 pandemic: results from the Epirus Health Study cohort

BackgroundTo assess the level of knowledge and trust in the policy decisions taken regarding the coronavirus disease (COVID-19) pandemic among Epirus Health Study (EHS) participants.MethodsThe EHS is an ongoing and deeply-phenotyped prospective cohort study that has recruited 667 participants in northwest Greece until August 31st, 2020. Level of knowledge on coronavirus (SARS-CoV-2) transmission and COVID-19 severity was labeled as poor, moderate or good. Variables assessing knowledge and beliefs towards the pandemic were summarized overall and by sex, age group (25–39, 40–49, 50–59, ≥60 years) and period of report (before the lifting of lockdown measures in Greece: March 30th to May 3rd, and two post-lockdown time periods: May 4th to June 31st, July 1st to August 31st). A hypothesis generating exposure-wide association analysis was conducted to evaluate the associations between 153 agnostically-selected explanatory variables and participants’ knowledge. Correction for multiple comparisons was applied using a false discovery rate (FDR) threshold of 5%.ResultsA total of 563 participants (49 years mean age; 60% women) had available information on the standard EHS questionnaire, the clinical and biochemical measurements, and the COVID-19-related questionnaire. Percentages of poor, moderate and good knowledge status regarding COVID-19 were 4.5, 10.0 and 85.6%, respectively. The majority of participants showed absolute or moderate trust in the Greek health authorities for the management of the epidemic (90.1%), as well as in the Greek Government (84.7%) and the official national sources of information (87.4%). Trust in the authorities was weaker in younger participants and those who joined the study after the lifting of lockdown measures (p-value≤0.001). None of the factors examined was associated with participants’ level of knowledge after correction for multiple testing.ConclusionsHigh level of knowledge about the COVID-19 pandemic and trust in the Greek authorities was observed, possibly due to the plethora of good quality publicly available information and the timely management of the pandemic at its early stages in Greece. Information campaigns for the COVID-19 pandemic should be encouraged even after the lifting of lockdown measures to increase public awareness.

TP53 Targeted Deep Sequencing of Cell-Free DNA in Esophageal Squamous Cell Carcinoma Using Low-Quality Serum: Concordance with Tumor Mutation.

Circulating cell-free DNA (cfDNA) is emerging as a potential tumor biomarker. CfDNA-based biomarkers may be applicable in tumors without an available non-invasive screening method among at-risk populations. Esophageal squamous cell carcinoma (ESCC) and residents of the Asian cancer belt are examples of those malignancies and populations. Previous epidemiological studies using cfDNA have pointed to the need for high volumes of good quality plasma (i.e., >1 mL plasma with 0 or 1 cycles of freeze-thaw) rather than archival serum, which is often the main available source of cfDNA in retrospective studies. Here, we have investigated the concordance of TP53 mutations in tumor tissue and cfDNA extracted from archival serum left-over from 42 cases and 39 matched controls (age, gender, residence) in a high-risk area of Northern Iran (Golestan). Deep sequencing of TP53 coding regions was complemented with a specialized variant caller (Needlestack). Overall, 23% to 31% of mutations were concordantly detected in tumor and serum cfDNA (based on two false discovery rate thresholds). Concordance was positively correlated with high cfDNA concentration, smoking history (p-value = 0.02) and mutations with a high potential of neoantigen formation (OR; 95%CI = 1.9 (1.11–3.29)), suggesting that tumor DNA release in the bloodstream might reflect the effects of immune and inflammatory context on tumor cell turnover. We identified TP53 mutations in five controls, one of whom was subsequently diagnosed with ESCC. Overall, the results showed that cfDNA mutations can be reliably identified by deep sequencing of archival serum, with a rate of success comparable to plasma. Nonetheless, 70% non-identifiable mutations among cancer patients and 12% mutation detection in controls are the main challenges in applying cfDNA to detect tumor-related variants when blindly targeting whole coding regions of the TP53 gene in ESCC.

Single-cell co-expression analysis reveals that transcriptional modules are shared across cell types in the brain.

Gene-gene relationships are commonly measured via the co-variation of gene expression across samples, also known as gene co-expression. Because shared expression patterns are thought to reflect shared function, co-expression networks describe functional relationships between genes, including co-regulation. However, the heterogeneity of cell types in bulk RNA-seq samples creates connections in co-expression networks that potentially obscure co-regulatory modules. The brain initiative cell census network (BICCN) single-cell RNA sequencing (scRNA-seq) datasets provide an unparalleled opportunity to understand how gene-gene relationships shape cell identity. Comparison of the BICCN data (500,000 cells/nuclei across 7 BICCN datasets) with that of bulk RNA-seq networks (2,000 mouse brain samples across 52 studies) reveals a consistent topology reflecting a shared co-regulatory signal. Differential signals between broad cell classes persist in driving variation at finer levels, indicating that convergent regulatory processes affect cell phenotype at multiple scales.