Elevated exposures to persistent endocrine disrupting compounds impact the sperm methylome in regions associated with autism spectrum disorder.

Environmental exposures to endocrine disrupting compounds (EDCs) such as the organochlorines have been linked with various diseases including neurodevelopmental disorders. Autism spectrum disorder (ASD) is a highly complex neurodevelopmental disorder that is considered strongly genetic in origin due to its high heritability. However, the rapidly rising prevalence of ASD suggests that environmental factors may also influence risk for ASD. In the present study, whole genome bisulfite sequencing was used to identify genome-wide differentially methylated regions (DMRs) in a total of 52 sperm samples from a cohort of men from the Faroe Islands (Denmark) who were equally divided into high and low exposure groups based on their serum levels of the long-lived organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), a primary breakdown product of the now banned insecticide dichlorodiphenyltrichloroethane (DDT). Aside from being considered a genetic isolate, inhabitants of the Faroe Islands have a native diet that potentially exposes them to a wide range of seafood neurotoxicants in the form of persistent organic pollutants (POPs). The DMRs were mapped to the human genome using Bismark, a 3-letter aligner used for methyl-seq analyses. Gene ontology, functional, and pathway analyses of the DMR-associated genes showed significant enrichment for genes involved in neurological functions and neurodevelopmental processes frequently impacted by ASD. Notably, these genes also significantly overlap with autism risk genes as well as those previously identified in sperm from fathers of children with ASD in comparison to that of fathers of neurotypical children. These results collectively suggest a possible mechanism involving altered methylation of a significant number of neurologically relevant ASD risk genes for introducing epigenetic changes associated with environmental exposures into the sperm methylome. Such changes may provide the potential for transgenerational inheritance of ASD as well as other disorders.

Implementation of a pooled surveillance testing program for asymptomatic SARS-CoV-2 infections in K-12 schools and universities.

BACKGROUND: The negative impact of continued school closures during the height of the COVID-19 pandemic warrants the establishment of cost-effective strategies for surveillance and screening to safely reopen and monitor for potential in-school transmission. Here, we present a novel approach to increase the availability of repetitive and routine COVID-19 testing that may ultimately reduce the overall viral burden in the community. METHODS: We implemented a testing program using the SalivaClear࣪ pooled surveillance method that included students, faculty and staff from K-12 schools (student age range 5-18 years) and universities (student age range >18 years) across the country (Mirimus Clinical Labs, Brooklyn, NY). The data analysis was performed using descriptive statistics, kappa agreement, and outlier detection analysis. FINDINGS: From August 27, 2020 until January 13, 2021, 253,406 saliva specimens were self-collected from students, faculty and staff from 93 K-12 schools and 18 universities. Pool sizes of up to 24 samples were tested over a 20-week period. Pooled testing did not significantly alter the sensitivity of the molecular assay in terms of both qualitative (100% detection rate on both pooled and individual samples) and quantitative (comparable cycle threshold (Ct) values between pooled and individual samples) measures. The detection of SARS-CoV-2 in saliva was comparable to the nasopharyngeal swab. Pooling samples substantially reduced the costs associated with PCR testing and allowed schools to rapidly assess transmission and adjust prevention protocols as necessary. In one instance, in-school transmission of the virus was determined within the main office and led to review and revision of heating, ventilating and air-conditioning systems. INTERPRETATION: By establishing low-cost, weekly testing of students and faculty, pooled saliva analysis for the presence of SARS-CoV-2 enabled schools to determine whether transmission had occurred, make data-driven decisions, and adjust safety protocols. We provide strong evidence that pooled testing may be a fundamental component to the reopening of schools by minimizing the risk of in-school transmission among students and faculty. FUNDING: Skoll Foundation generously provided funding to Mobilizing Foundation and Mirimus for these studies.

Phenotypic Subtyping and Re-analyses of Existing Transcriptomic Data from Autistic Probands in Simplex Families Reveal Differentially Expressed and ASD Trait-Associated Genes.

Autism spectrum disorder (ASD) describes a collection of neurodevelopmental disorders characterized by core symptoms that include social communication deficits and repetitive, stereotyped behaviors often coupled with restricted interests. Primary challenges to understanding and treating ASD are the genetic and phenotypic heterogeneity of cases that complicates all omics analyses as well as a lack of information on relationships among genes, pathways, and autistic traits. In this study, we re-analyze existing transcriptomic data from simplex families by subtyping individuals with ASD according to multivariate cluster analyses of clinical ADI-R scores that encompass a broad range of behavioral symptoms. We also correlate multiple ASD traits, such as deficits in verbal and non-verbal communication, play and social skills, ritualistic behaviors, and savant skills, with expression profiles using Weighted Gene Correlation Network Analyses (WGCNA). Our results show that subtyping greatly enhances the ability to identify differentially expressed genes involved in specific canonical pathways and biological functions associated with ASD within each phenotypic subgroup. Moreover, using WGCNA, we identify gene modules that correlate significantly with specific ASD traits. Network prediction analyses of the genes in these modules reveal canonical pathways as well as neurological functions and disorders relevant to the pathobiology of ASD. Finally, we compare the WGCNA-derived data on autistic traits in simplex families with analogous data from multiplex families using transcriptomic data from our previous studies. The comparison reveals overlapping trait-associated pathways as well as upstream regulators of the module-associated genes that may serve as useful targets for a precision medicine approach to ASD.

Increased cerebrospinal fluid neurofilament light chain in central nervous system inflammatory demyelinating disease.

BACKGROUND: Central nervous system (CNS) inflammatory demyelinating disease (IDD) is an immune-mediated disease that is pathologically characterized by demyelination and inflammatory infiltration in the CNS and includes clinically isolated syndrome (CIS), multiple sclerosis (MS), and neuromyelitis optica spectrum disorders (NMOSD). IDD is usually characterized by variable symptoms, multivariate imaging, uncertain reactions to treatment, and a variable prognosis, which makes it difficult to diagnose early. In recent years, the role of the neurofilament light chain (NFL), an axonal injury biomarker, in IDD has become increasingly important. We will detect and analyse cerebrospinal fluid (CSF) NFL levels in IDD and normal control patients to determine the significance of NFL in the diagnosis and prognostic prediction of IDD. METHODS: A total of 41 CIS, 34 MS and 73 NMOSD patients and 40 other patients with conditions such as neurosis and migraine with lumbar puncture were enrolled as the patient groups and the normal control (NC) group from the population of in- and outpatients of the Department of Neurology of the Sixth Medical Centre of Chinese People's Liberation Army General Hospital from January 2014 to October 2016. Clinical and neuroimaging features of the patient groups as well as CSF samples from both types of groups were collected, and the NFL levels of CSF were measured by enzyme linked immunosorbent assay. RESULTS: CSF NFL levels in the CIS, MS and NMOSD groups were significantly higher than those in the NC group (P < 0.05, analysis of variance of NFL levels was performed after logarithmic transformation based on 10). There were no statistically significant differences in the CSF NFL levels among the CIS, MS and NMOSD groups (P > 0.05). The NFL levels of CSF in the CIS, MS and NMOSD groups were correlated with the expanded disability status scale score and enhancement in gadolinium-magnetic resonance imaging (all P < 0.05). Gender, oligoclonal band in CSF, aquaporin 4 antibody and 25­hydroxy vitamin D3 [25(OH)D3] in serum were not related to the NFL levels (P > 0.05). CONCLUSION: The NFL level of CSF is conducive to assessing the severity and probable progress of IDD but is not helpful in distinguishing IDD among Chinese.

PGC-1α or FNDC5 Is Involved in Modulating the Effects of Aß1-42 Oligomers on Suppressing the Expression of BDNF, a Beneficial Factor for Inhibiting Neuronal Apoptosis, Aß Deposition and Cognitive Decline of APP/PS1 Tg Mice.

Alzheimer's disease (AD) is generally defined as the aberrant production of ß-amyloid protein (Aß) and hyperphosphorylated tau protein, which are deposited in ß-amyloid plaques (APs) and neurofibrillary tangles (NFTs), respectively. Decreased levels of brain-derived neurotrophic factor (BDNF) have been detected in patients with AD compared to control subjects. However, the underlying molecular mechanisms driving the downregulation of the BDNF remain unknown. Therefore, we explored the mechanisms underlying the regulation of BDNF in the neurons of APP/PS1 transgenic (Tg) mice, an AD experimental model. Using the APP/PS1 Tg mice, we found that BDNF expression was markedly downregualted at the age of 3- and 9-month-old. After cerebroventricular injection (i.c.v) of Aß1-42 oligomers into the mice, BDNF was also found to be decreased, which demonstrated the critical roles of the Aß1-42 oligomers in regulating the expression of BDNF. In neuronal culture, peroxisome proliferators-activated receptor γ coactivator 1α (PGC-1α) and fibronectin type III domain-containing 5 (FNDC5) were found to be downregulated by treatment with the Aß1-42 oligomers. In addition, overexpression of either PGC-1α or FNDC5 reversed the suppressive effects of the Aß1-42 oligomers on the expression of BDNF in neuroblastoma 2a (n2a) cells. More importantly, elevating the levels of PGC-1α, FNDC5 or BDNF in the n2a cells counteracted the effects of the Aß1-42 oligomers on neuronal apoptosis. Additionally, intranasal administration BDNF in the APP/PS1 Tg mice decreased the Aß deposition and reduced the cognitive decline of the mice.

[Analysis of serum lipid level in patients with multiple system atrophy].

OBJECTIVE: To explore the serum levels of lipids and lipoproteins in patients with multiple system atrophy (MSA). METHODS: From July 2009 to June 2014, a total of 62 MSA patients from the neurology department of our hospital were enrolled as the case group and 63 healthy individuals were enrolled as control group. The serum levels of lipids and lipoproteins were compared between two groups and also analyzed according to gender, age and disease subtypes. RESULTS: Compared with the healthy controls, abnormal rates of high density lipoprotein cholesterol (HDL-C), apolipoproteins A (ApoA) and apolipoproteins B (ApoB) in MSA patients were decreased significantly (P<0.01), while there is no difference of abnormal rates in TC, TG and LDL-C. Compared with the healthy controls, the serum total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), LDL-C, ApoA and ApoB levels in MSA patients were decreased significantly (P<0.01). There was no significant difference in TG levels. Compared with female MSA patients, the serum TG and LDL-C in male MSA patients were decreased significantly (P<0.05). Compared with male controls, TC, LDL-C, HDL-C, ApoA and ApoB levels of male MSA patients were decreased significantly (P<0.05) whilst there was no significant difference in TG level (P>0.05). Compared with female controls, the serum TC,TG, HDL-C, ApoA and ApoB levels in female MSA patients were decreased significantly (P<0.05) whilst there was no significant difference in LDL-C (P>0.05). There was no significant difference in lipid levels between elder patients (age over 65) and younger patients (age under 65) (P>0.05). Also no significant difference existed between type C and type P of MSA (P>0.05). No significant relationship between course of disease and lipids was found (P>0.05). CONCLUSION: Serum levels of TC, HDL-C, LDL-C, ApoA and ApoB are decreased in MSA patients but all lipid levels are not related to either disease course or subtype, which may indicate that lipids levels are related to the pathogenesis of MSA.