Altered Immunoglobulin Repertoire and Decreased IgA Somatic Hypermutation in the Gut during Chronic HIV-1 Infection.

Humoral immune perturbations contribute to pathogenic outcomes in persons with HIV-1 infection (PWH). Gut barrier dysfunction in PWH is associated with microbial translocation and alterations in microbial communities (dysbiosis), and IgA, the most abundant immunoglobulin (Ig) isotype in the gut, is involved in gut homeostasis by interacting with the microbiome. We determined the impact of HIV-1 infection on the antibody repertoire in the gastrointestinal tract by comparing Ig gene utilization and somatic hypermutation (SHM) in colon biopsies from PWH (n = 19) versus age and sex-matched controls (n = 13). We correlated these Ig parameters with clinical, immunological, microbiome and virological data. Gene signatures of enhanced B cell activation were accompanied by skewed frequencies of multiple Ig Variable genes in PWH. PWH showed decreased frequencies of SHM in IgA and possibly IgG, with a substantial loss of highly mutated IgA sequences. The decline in IgA SHM in PWH correlated with gut CD4+ T cell loss and inversely correlated with mucosal inflammation and microbial translocation. Diminished gut IgA SHM in PWH was driven by transversion mutations at A or T deoxynucleotides, suggesting a defect not at the AID/APOBEC3 deamination step but at later stages of IgA SHM. These results expand our understanding of humoral immune perturbations in PWH that could have important implications in understanding mucosal immune defects in individuals with chronic HIV-1 infection. IMPORTANCE The gut is a major site of early HIV-1 replication and pathogenesis. Extensive CD4+ T cell depletion in this compartment results in a compromised epithelial barrier that facilitates the translocation of microbes into the underlying lamina propria and systemic circulation, resulting in chronic immune activation. To date, the consequences of microbial translocation on the mucosal humoral immune response (or vice versa) remains poorly integrated into the panoply of mucosal immune defects in PWH. We utilized next-generation sequencing approaches to profile the Ab repertoire and ascertain frequencies of somatic hypermutation in colon biopsies from antiretroviral therapy-naive PWH versus controls. Our findings identify perturbations in the Ab repertoire of PWH that could contribute to development or maintenance of dysbiosis. Moreover, IgA mutations significantly decreased in PWH and this was associated with adverse clinical outcomes. These data may provide insight into the mechanisms underlying impaired Ab-dependent gut homeostasis during chronic HIV-1 infection.

A comparison of resting-state eyes-closed and dark-room alpha-band activity in children.

In a relaxed and awake state with the eyes closed, 8-12 Hz neural oscillations are the dominant rhythm, most prominent in parietal-occipital regions. Resting-state (RS) alpha is associated with processing speed and is also thought to be central to how networks process information. Unfortunately, the RS eyes-closed (EC) exam can only be used with individuals who can remain awake with their eyes closed for an extended period. As such, infants, toddlers, and individuals with intellectual disabilities are usually excluded from RS alpha studies. Previous research suggests obtaining RS alpha measures in a dark room with the eyes open as a viable alternative to the traditional RS EC exam. To further explore this, RS EC and RS dark room (DR) eyes-open alpha activity was recorded using magnetoencephalography in children with typical development (TD; N = 37) and children with autism spectrum disorder (ASD; N = 30) 6.9-12.6 years old. Findings showed good reliability for the RS EC and DR peak alpha frequency (frequency with strongest alpha power; interclass correlation (ICC) = 0.83). ICCs for posterior alpha power were slightly lower (ICCs in the 0.70 s), with an ~ 5% reduction in posterior alpha power in the DR than EC condition. No differences in the EC and DR associations were observed between the TD and ASD groups. Finally, age was associated with both EC and DR peak alpha frequency. Findings thus indicate the DR exam as a viable way to obtain RS alpha measures in populations frequently excluded from electrophysiology RS studies.

Qualitative Differences Between the IFNα subtypes and IFNß Influence Chronic Mucosal HIV-1 Pathogenesis.

The Type I Interferons (IFN-Is) are innate antiviral cytokines that include 12 different IFNα subtypes and IFNß that signal through the IFN-I receptor (IFNAR), inducing hundreds of IFN-stimulated genes (ISGs) that comprise the 'interferome'. Quantitative differences in IFNAR binding correlate with antiviral activity, but whether IFN-Is exhibit qualitative differences remains controversial. Moreover, the IFN-I response is protective during acute HIV-1 infection, but likely pathogenic during the chronic stages. To gain a deeper understanding of the IFN-I response, we compared the interferomes of IFNα subtypes dominantly-expressed in HIV-1-exposed plasmacytoid dendritic cells (1, 2, 5, 8 and 14) and IFNß in the earliest cellular targets of HIV-1 infection. Primary gut CD4 T cells from 3 donors were treated for 18 hours ex vivo with individual IFN-Is normalized for IFNAR signaling strength. Of 1,969 IFN-regulated genes, 246 'core ISGs' were induced by all IFN-Is tested. However, many IFN-regulated genes were not shared between the IFNα subtypes despite similar induction of canonical antiviral ISGs such as ISG15, RSAD2 and MX1, formally demonstrating qualitative differences between the IFNα subtypes. Notably, IFNß induced a broader interferome than the individual IFNα subtypes. Since IFNß, and not IFNα, is upregulated during chronic HIV-1 infection in the gut, we compared core ISGs and IFNß-specific ISGs from colon pinch biopsies of HIV-1-uninfected (n = 13) versus age- and gender-matched, antiretroviral-therapy naïve persons with HIV-1 (PWH; n = 19). Core ISGs linked to inflammation, T cell activation and immune exhaustion were elevated in PWH, positively correlated with plasma lipopolysaccharide (LPS) levels and gut IFNß levels, and negatively correlated with gut CD4 T cell frequencies. In sharp contrast, IFNß-specific ISGs linked to protein translation and anti-inflammatory responses were significantly downregulated in PWH, negatively correlated with gut IFNß and LPS, and positively correlated with plasma IL6 and gut CD4 T cell frequencies. Our findings reveal qualitative differences in interferome induction by diverse IFN-Is and suggest potential mechanisms for how IFNß may drive HIV-1 pathogenesis in the gut.

Exploring developmental changes in infant anticipation and perceptual processing: EEG responses to tactile stimulation.

There is an increasing interest in alpha-range rhythms in the electroencephalogram (EEG) in relation to perceptual and attentional processes. The infant mu rhythm has been extensively studied in the context of linkages between action observation and action production in infancy, but less is known about the mu rhythm in relation to cross-modal processes involving somatosensation. We investigated differences in mu responses to cued vibrotactile stimulation of the hand in two age groups of infants: From 6 to 7 months and 13 to 14 months. We were also interested in anticipatory neural responses in the alpha frequency range prior to tactile stimulation. Tactile stimulation of infants' left or right hand was preceded by an audiovisual cue signaling which hand would be stimulated. In response to the tactile stimulus, infants demonstrated significant mu desynchronization over the central areas contralateral to the hand stimulated, with higher mu peak frequency and greater contralateral mu desynchronization for older infants. Prior to the tactile stimulus, both age groups showed significant bilateral alpha desynchronization over frontocentral sites, which may be indicative of generalized anticipation of an upcoming stimulus. The findings highlight the potential of examining the sensorimotor mu rhythm in the context of infant attentional development.

Neuropsychology of Human Body Parts: Exploring Categorical Boundaries of Tactile Perception Using Somatosensory Mismatch Responses.

The focus of the current study is on a particular aspect of tactile perception: categorical segmentation on the body surface into discrete body parts. The MMN has been shown to be sensitive to categorical boundaries and language experience in the auditory modality. Here we recorded the somatosensory MMN (sMMN) using two tactile oddball protocols and compared sMMN amplitudes elicited by within- and across-boundary oddball pairs. Both protocols employed the identity MMN method that controls for responsivity at each body location. In the first protocol, we investigated the categorical segmentation of tactile space at the wrist by presenting pairs of tactile oddball stimuli across equal spatial distances, either across the wrist or within the forearm. Amplitude of the sMMN elicited by stimuli presented across the wrist boundary was significantly greater than for stimuli presented within the forearm, suggesting a categorical effect at an early stage of somatosensory processing. The second protocol was designed to investigate the generality of this MMN effect, and involved three digits on one hand. Amplitude of the sMMN elicited by a contrast of the third digit and the thumb was significantly larger than a contrast between the third and fifth digits, suggesting a functional boundary effect that may derive from the way that objects are typically grasped. These findings demonstrate that the sMMN is a useful index of processing of somatosensory spatial discrimination that can be used to study body part categories.

Touching lips and hearing fingers: effector-specific congruency between tactile and auditory stimulation modulates N1 amplitude and alpha desynchronization.

Understanding the interactions between audition and sensorimotor processes is of theoretical importance, particularly in relation to speech processing. Although one current focus in this area is on interactions between auditory perception and the motor system, there has been less research on connections between the auditory and somatosensory modalities. The current study takes a novel approach to this omission by examining specific auditory-tactile interactions in the context of speech and non-speech sound production. Electroencephalography was used to examine brain responses when participants were presented with speech syllables (a bilabial sound /pa/ and a non-labial sound /ka/) or finger-snapping sounds that were simultaneously paired with tactile stimulation of either the lower lip or the right middle finger. Analyses focused on the sensory-evoked N1 in the event-related potential and the extent of alpha band desynchronization elicited by the stimuli. N1 amplitude over fronto-central sites was significantly enhanced when the bilabial /pa/ sound was paired with tactile lip stimulation and when the finger-snapping sound was paired with tactile stimulation of the finger. Post-stimulus alpha desynchronization at central sites was also enhanced when the /pa/ sound was accompanied by tactile stimulation of the lip. These novel findings indicate that neural aspects of somatosensory-auditory interactions are influenced by the congruency between the location of the bodily touch and the bodily origin of a perceived sound.

Acetylcholinesterase Biosensor Based On Mesoporous Hollow Carbon Spheres/Core-Shell Magnetic Nanoparticles-Modified Electrode for the Detection of Organophosphorus Pesticides.

The present study investigated the synthesis of mesoporous hollow carbon spheres (MHCS) and magnetic mesoporous hollow carbon spheres with core-shell structures (Fe3O4@MHCS). Two acetylcholinesterase sensors (acetylcholinesterase/mesoporous hollow carbon spheres/glassy carbon electrode (AChE/MHCS/GCE) and acetylcholinesterase/core-shell magnetic mesoporous hollow carbon spheres/glassy carbon electrode (AChE/Fe3O4@MHCS/GCE) based on mesoporous carbon materials were prepared. Under the optimum conditions, using Malathion as the model compound, the developed biosensors showed a wide detection range, low detection limit, good reproducibility, and high stability. The AChE/MHCS/GCE electrochemical sensor response exhibited two good linear ranges at the incubation time of 10 min at the Malathion concentration ranges of 0.01 to 100 ppb and 100 to 600 ppb, with a detection limit of 0.0148 ppb (S/N = 3). The AChE/Fe3O4@MHCS/GCE electrochemical sensor that was operated with an incubation time of 12 min at the malathion concentration ranges between 0.01⁻50 ppb and 50⁻600 ppb had a detection limit of 0.0182 ppb (S/N = 3). Moreover, the AChE/MHCS/GCE and AChE/Fe3O4@MHCS/GCE biosensors were effective for the detection of real samples, and were demonstrated to be suitable for the field-testing of organophosphorus pesticide (OP) residues.

IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages.

BACKGROUND & AIM: Alcohol consumption increases intestinal permeability and causes damage to hepatocytes, leading to the release of pathogen- and damage-associated molecular pattern molecules (PAMPs and DAMPs), stimulating hepatic macrophages and activating NF-κB. The resultant inflammation exacerbates alcoholic liver disease (ALD). However, much less is known about the mechanisms attenuating inflammation and preventing disease progression in most heavy drinkers. Interleukin (IL)-33 is a DAMP (alarmin) released from dead cells that acts through its receptor, IL-1 receptor like 1 (ST2). ST2 signaling has been reported to either stimulate or inhibit NF-κB activation. The role of IL-33/ST2 in ALD has not been studied. METHODS: Serum levels of IL-33 and its decoy receptor, soluble ST2 (sST2) were measured in ALD patients. Alcohol-induced liver injury, inflammation and hepatic macrophage activation were compared between wild-type, IL-33-/- and ST2-/- mice in several models. RESULTS: Elevation of serum IL-33 and sST2 were only observed in patients with severe decompensated ALD. Consistently, in mice with mild ALD without significant cell death and IL-33 release, IL-33 deletion did not affect alcohol-induced liver damage. However, ST2-deletion exacerbated ALD, through enhancing NF-κB activation in liver macrophages. In contrast, when extracellular IL-33 was markedly elevated, liver injury and inflammation were attenuated in both IL-33-/- and ST2-/- mice compared to wild-type mice. CONCLUSION: Our data revealed a dichotomous role of IL-33/ST2 signaling during ALD development. At early and mild stages, ST2 restrains the inflammatory activation of hepatic macrophages, through inhibiting NF-κB, and plays a protective function in an IL-33-independent fashion. During severe liver injury, significant cell death and marked IL-33 release occur, which triggers IL-33/ST2 signaling and exacerbates tissue damage. LAY SUMMARY: In mild ALD, ST2 negatively regulates the inflammatory activation of hepatic macrophages, thereby protecting against alcohol-induced liver damage, whereas in the case of severe liver injury, the release of extracellular IL-33 may exacerbate tissue inflammation by triggering the canonical IL-33/ST2L signaling in hepatic macrophages.

Categorical perception of lexical tones by English learners of Mandarin Chinese.

Whether native speakers of non-tonal languages can acquire categorical representations of lexical tones remains controversial. This study investigates the acquisition of lexical tone categories by native English speakers learning Mandarin Chinese as a foreign language by comparing the categorical perception (CP) of lexical tones between three groups of listeners: (1) native English speakers who had taken advanced Mandarin courses in colleges; (2) native English speakers with no knowledge of Mandarin Chinese; and (3) native Mandarin speakers. Two tonal continua derived from natural speech within carrier phrases were created through interpolation within two tonal contrasts (tone 1/tone 4, T1/T4; tone 2/tone 3, T2/T3). Results showed categorical-like perception of tones by native Mandarin speakers. The inexperienced English speakers performed near chance on discrimination tasks and showed significantly broader identification boundaries than the other two groups. The learners of Mandarin showed similar pattern of CP to native Mandarin speakers, but with higher overall discrimination scores. Findings suggest that CP of lexical tone may be available to advanced second language learners.

Ginsenoside Rb1 enhanced immunity and altered the gut microflora in mice immunized by H1N1 influenza vaccine.

Background: Influenza is an acute infectious respiratory disease caused by the influenza virus that seriously damages human health, and the essential way to prevent influenza is the influenza vaccine. Vaccines without adjuvants produce insufficient specific antibodies and therefore require adjuvants to boost antibody titers. Microbes and hosts are a community that needs to "promote bacteria," which could provide new value for the immune effect. Methods: (1) The H1N1 influenza vaccine, in combination with Ginsenoside Rb1, was co-injected into mice intraperitoneally (I.P.). Then, immunoglobulin G and antibody subtype levels were tested by enzyme-linked immunosorbent assay (ELISA). Moreover, mice were infected with a lethal dose of the H1N1 influenza virus (A/Michigan/45/2015), and survival status was recorded for 14 days. Lung tissues were stained by hematoxylin and eosin (H&E), and ELISA detected inflammatory factor expression levels. (2) Mice were immunized with Ginsenoside Rb1 combined with quadrivalent influenza inactivated vaccine(IIV4), and then IgG levels were measured by ELISA. (3) Fresh stool was collected for fecal 16S rDNA analysis. Results: Ginsenoside Rb1 boosted IgG and antibody subtypes in the H1N1 influenza vaccine, improved survival of mice after virus challenge, attenuated lung histopathological damage, and reduced inflammatory cytokines expression in IL-6 and TNF-α. The results of 16S rDNA showed that Rb1 decreased species diversity but increased species richness compared to the PBS group and increased the abundance of Akkermansiaceae and Murbaculaceae at the Family and Genus levels compared with the HA+Alum group. Conclusion: Ginsenoside Rb1 has a boosting effect on the immune efficacy of the H1N1 influenza vaccine and is promising as a novel adjuvant to regulate the microecological balance and achieve an anti-infective effect.

Resting-State Activity in Children: Replicating and Extending Findings of Early Maturation of Alpha Rhythms in Autism Spectrum Disorder.

Resting-state alpha brain rhythms provide a foundation for basic as well as higher-order brain processes. Research suggests atypical maturation of the peak frequency of resting-state alpha activity (= PAF) in autism spectrum disorder (ASD). The present study examined resting-state alpha activity in young school-aged children, obtaining magnetoencephalographic (MEG) eyes-closed resting-state data from 47 typically developing (TD) males and 45 ASD males 6.0 to 9.3 years old. Results confirmed a higher PAF in ASD versus TD, and demonstrated that alpha power differences between groups were linked to the shift of PAF in ASD. Additionally, a higher PAF was associated with better cognitive performance in TD but not ASD. Finding thus suggested functional consequences of group differences in resting-state alpha activity.

Differential Maturation of Auditory Cortex Activity in Young Children with Autism and Typical Development.

Maturation of auditory cortex neural encoding processes was assessed in children with typical development (TD) and autism. Children 6-9 years old were enrolled at Time 1 (T1), with follow-up data obtained ~ 18 months later at Time 2 (T2), and ~ 36 months later at Time 3 (T3). Findings suggested an initial period of rapid auditory cortex maturation in autism, earlier than TD (prior to and surrounding the T1 exam), followed by a period of faster maturation in TD than autism (T1-T3). As a result of group maturation differences, post-stimulus group differences were observed at T1 but not T3. In contrast, stronger pre-stimulus activity in autism than TD was found at all time points, indicating this brain measure is stable across time.

Bidialectal and monodialectal differences in morphosyntactic processing of AAE and MAE: Evidence from ERPs and acceptability judgments.

INTRODUCTION: African American English (AAE) has never been examined through neurophysiological methods in investigations of dual-language variety processing. This study examines whether contrastive and non-contrastive morphosyntactic features in sentences with and without AAE constructions elicit differing neural and/or behavioral responses in bidialectal speakers of AAE and Mainstream American English (MAE), compared to monodialectal MAE speakers. We compared electroencephalographic (EEG) and behavioral (grammatical acceptability judgment) data to determine whether two dialects are processed similarly to distinct languages, as seen in studies of bilingual codeswitching where the P600 event related potential (ERP) has been elicited when processing a switch between language varieties. METHODS: Bidialectal AAE-MAE speakers (n = 15) and monodialectal MAE speakers (n = 12) listened to sentences in four conditions, while EEG was recorded to evaluate time-locked brain responses to grammatical differences between sentence types. The maintained verb form in the present progressive tense sentences (e.g., The black cat lap/s the milk) was the morphosyntactic feature of interest for comparing P600 responses as an indicator of error detection. Following each trial, responses and reaction times to a grammatical acceptability judgment task were collected and compared. RESULTS: Findings indicate distinct neurophysiological profiles between bidialectal and monodialectal speakers. Monodialectal speakers demonstrated a P600 response within 500-800ms following presentation of an AAE morphosyntax feature, indicating error detection; this response was not seen in the bidialectal group. Control sentences with non-contrasting grammar revealed no differences in ERP responses between groups. Behaviorally, bidialectal speakers showed greater acceptance of known dialectal variation and error (non-contrastive) sentence types compared to the monodialectal group. CONCLUSIONS: ERP and behavioral responses are presented as preliminary evidence of dual-language representation in bidialectal speakers. Increased consideration of AAE language processing would enhance equity in the study of language at large, improving the work of clinicians, researchers, educators and policymakers alike.

Effects of storage temperature and time on enzymatic digestibility and fermentability of Densifying lignocellulosic biomass with chemicals pretreated corn stover.

A novel pretreatment, Densifying Lignocellulosic biomass with acidic/alkali Chemicals (DLC), was recently invented and owns unique advantages for biomass logistics and fermentation. The pretreatment was largely completed during biomass storage, which renders the storage conditions critical. In this study, the effects of storage temperature (-80 °C to 60 °C) and storage time (up to half a year) on the enzymatic digestibility and fermentability of DLC corn stover (CS) were investigated. DLC-CS containing calcium hydroxide(ch) showed increased enzymatic digestibility with increased storage temperature and time. High glucan conversions (>90%) and ethanol titers (e.g. 73.1 g/L) were achieved after regular steam autoclave of DLC(ch)-CS, without washing or detoxification. DLC-CS containing sulfuric acid(sa) was sensitive to storage conditions, and autoclaved DLC(sa)-CS reached the highest ethanol titer (66.6 g/L) when DLC(sa)-CS was stored at room temperature for 14 days. Results indicated that different ambient temperatures in different regions and seasons have a far-reaching impact on DLC-CS for bioconversion.

Body representation in infants: Categorical boundaries of body parts as assessed by somatosensory mismatch negativity.

There is growing interest in developing and using novel measures to assess how the body is represented in human infancy. Various lines of evidence with adults and older children show that tactile perception is modulated by a high-level representation of the body. For instance, the distance between two points of tactile stimulation is perceived as being greater when these points cross a joint boundary than when they are within a body part, suggesting that the representation of the body is structured with joints acting as categorical boundaries between body parts. Investigating the developmental origins of this categorical effect has been constrained by infants' inability to verbally report on the properties of tactile stimulation. Here we made novel use of an infant brain measure, the somatosensory mismatch negativity (sMMN), to explore categorical aspects of tactile body processing in infants aged 6-7 months. Amplitude of the sMMN elicited by tactile stimuli across the wrist boundary was significantly greater than for stimuli of equal distance that were within the boundary, suggesting a categorical effect in body processing in infants. We suggest that an early-appearing, structured representation of the body into 'parts' may play a role in mapping correspondences between self and other.

Evaluation of mismatch negativity as a marker for language impairment in autism spectrum disorder.

BACKGROUND: The identification of an early and objective marker of language impairment in autism spectrum disorder (ASD) has the potential to lead to earlier language intervention for affected children. The mismatch negativity (MMN), a passive auditory evoked potential, offers insight into the brain's ability to direct attention to novel sounds. Since exposure to speech is necessary for learning to map meaning onto phonemes, we predicted slower MMN responses to speech sounds would indicate presence of language impairment in ASD. METHODS: We explored the relationship between MMN latency in children ages 5-10 with ASD plus language impairment (ASD + LI), ASD minus language impairment (ASD-LI), and typically developing children (TD) during an auditory oddball experiment presenting speech and pure tone sounds. RESULTS: Contrary to our prediction, children with ASD + LI demonstrated decreased MMN latency in the left hemisphere in response to novel vowel sounds compared to children with ASD-LI and TD controls. Parent responses to the Sensory Experiences Questionnaire revealed that all participating individuals with ASD were hypersensitive to sounds. CONCLUSIONS: Our results lend support to the theory that some children with ASD + LI have increased connectivity in primary sensory cortices at the expense of connectivity to association areas of the brain. This may account for faster speech sound processing despite low language scores in these children. Future studies should focus on individuals with language impairment and hyper-or hyposensitivity to sounds.

Maturation of Auditory Cortex Neural Activity in Children and Implications for Auditory Clinical Markers in Diagnosis.

Functional brain markers that can inform research on brain abnormalities, and especially those ready to facilitate clinical work on such abnormalities, will need to show not only considerable sensitivity and specificity but enough consistency with respect to developmental course that their validity in individual cases can be trusted. A challenge to establishing such markers may be individual differences in developmental course. The present study examined auditory cortex activity in children at an age when developmental changes to the auditory cortex 50 ms (M50) and 100 ms (M100) components are prominent to better understand the use of auditory markers in pediatric clinical research. MEG auditory encoding measures (auditory evoked fields in response to pure tone stimuli) were obtained from 15 typically developing children 6-8 years old, with measures repeated 18 and 36 months after the initial exam. MEG analyses were conducted in source space (i.e., brain location), with M50 and M100 sources identified in left and right primary/secondary auditory cortex (Heschl's gyrus). A left and right M50 response was observed at all times (Time 1, Time 2, Time 3), with M50 latency (collapsing across hemisphere) at Time 3 (77 ms) 10 ms earlier than Time 1 (87 ms; p < 0.001) and with M50 responses on average (collapsing across time) 5 ms earlier in the right (80 ms) than left hemisphere (85 ms; p < 0.05). In the majority of children, however, M50 latency changes were not constant across the three-year period; for example, whereas in some children a ~10 ms latency reduction was observed from Time 1 to Time 2, in other children a ~10 ms latency reduction was observed from Time 2 to Time 3. M100 responses were defined by a significant "peak" of detected power with magnetic field topography opposite M50 and occurring 50-100 ms later than the M50. Although M100s were observed in a few children at Time 1 and Time 2 (and more often in the right than left hemisphere), M100s were not observed in the majority of children except in the right hemisphere at Time 3. In sum, longitudinal findings showed large between- and within-subject variability in rate of change as well as time to reach neural developmental milestones (e.g., presence of a detectable M100 response). Findings also demonstrated the need to examine whole-brain activity, given hemisphere differences in the rate of auditory cortex maturation. Pediatric research will need to take such normal variability into account when seeking clinical auditory markers.

Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in women of reproductive age. Prenatal PFAS exposure is associated with adverse health outcomes in children. We hypothesized that DNA methylation changes may result from prenatal PFAS exposure and may be linked to offspring cardio-metabolic phenotype. OBJECTIVES: We estimated associations of prenatal PFAS with DNA methylation in umbilical cord blood. We evaluated associations of methylation at selected sites with neonatal cardio-metabolic indicators. METHODS: Among 583 mother-infant pairs in a prospective cohort, five PFAS were quantified in maternal serum (median 27 wk of gestation). Umbilical cord blood DNA methylation was evaluated using the Illumina HumanMethylation450 array. Differentially methylated positions (DMPs) were evaluated at a false discovery rate (FDR)<0.05 and differentially methylated regions (DMRs) were identified using comb-p (Sidák-adjusted p<0.05). We estimated associations between methylation at candidate DMPs and DMR sites and the following outcomes: newborn weight, adiposity, and cord blood glucose, insulin, lipids, and leptin. RESULTS: Maternal serum PFAS concentrations were below the median for females in the U.S. general population. Moderate to high pairwise correlations were observed between PFAS concentrations (ρ=0.28-0.76). Methylation at one DMP (cg18587484), annotated to the gene TJAP1, was associated with perfluorooctanoate (PFOA) at FDR< 0.05. Comb-p detected between 4 and 15 DMRs for each PFAS. Associated genes, some common across multiple PFAS, were implicated in growth (RPTOR), lipid homeostasis (PON1, PON3, CIDEB, NR1H2), inflammation and immune activity (RASL11B, RNF39), among other functions. There was suggestive evidence that two PFAS-associated loci (cg09093485, cg09637273) were associated with cord blood triglycerides and birth weight, respectively (FDR< 0.1). DISCUSSION: DNA methylation in umbilical cord blood was associated with maternal serum PFAS concentrations during pregnancy, suggesting potential associations with offspring growth, metabolism, and immune function. Future research should explore whether DNA methylation changes mediate associations between prenatal PFAS exposures and child health outcomes. https://doi.org/10.1289/EHP6888.

Body representations as indexed by oscillatory EEG activities in the context of tactile novelty processing.

Neural oscillatory activities in different frequency bands are known to reflect different cognitive functions. The current study investigates neural oscillations involved in tactile novelty processing, in particular how physically different digits of the hand may be categorized as being more or less similar to one another. Time-frequency analyses were conducted on EEG responses recorded from a somatosensory mismatch protocol involving stimulation of the 1st, 3rd, and 5th digits. The pattern of tactile stimulation leveraged a functional category boundary between the 1st digit (thumb) and the other fingers. This functional category has been hypothesized to derive, in part, from the way that the hand is used to grasp and haptically explore objects. EEG responses to standard stimuli (the 3rd digit, probability of 80%) and two deviant stimuli (1st digit as across-boundary deviant and 5th digit as within-boundary deviant, probability of 10% each) were examined. Analyses of EEG responses examined changes in power as well as phase information. Deviant tactile stimuli evoked significantly greater theta event-related synchronization and greater phase-locking values compared to the corresponding control stimuli. The increase in theta power evoked by the contrast of the 3rd digit and the 1st digit was significantly larger than for the contrast between the 3rd and 5th digits. Desynchronization in the alpha and beta bands was greater for deviant than control stimuli, which may reflect increased local cortical excitation to novel stimuli, modulated by top-down feedback processes as part of a hierarchical novelty detection mechanism. The results are discussed in the context of the growing literature on neural processes involved in the generation and maintenance of body representations.

The somatosensory mismatch negativity as a window into body representations in infancy.

How the body is represented in the developing brain is a topic of growing interest. The current study takes a novel approach to investigating neural body representations in infants by recording somatosensory mismatch negativity (sMMN) responses elicited by tactile stimulation of different body locations. Recent research in adults has suggested that sMMN amplitude may be influenced by the relative distance between representations of the stimulated body parts in somatosensory cortex. The current study uses a similar paradigm to explore whether the sMMN can be elicited in infants, and to test whether the infant sMMN response is sensitive to the somatotopic organization of somatosensory cortex. Participants were healthy infants (n = 31) aged 6 and 7 months. The protocol leveraged a discontinuity in cortical somatotopic organization, whereby the representations of the neck and the face are separated by representations of the arms, the hands and the shoulder. In a double-deviant oddball protocol, stimulation of the hand (100 trials, 10% probability) and neck (100 trials, 10% probability) was interspersed among repeated stimulation of the face (800 trials, 80% probability). Waveforms showed evidence of an infant sMMN response that was significantly larger for the face/neck contrast than for the face/hand contrast. These results suggest that, for certain combinations of body parts, early pre-attentive tactile discrimination in infants may be influenced by distance between the corresponding cortical representations. The results provide the first evidence that the sMMN can be elicited in infants, and pave the way for further applications of the sMMN in studying body representations in preverbal infants.