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BACKGROUND: Human infants develop IgG responses to dietary antigens during the first 2 years of life. Yet, the source of these antibodies is unclear. In previous studies we reported on the thymus as a unique functional niche for plasma cells (PCs) specific to environmental antigens. OBJECTIVE: We sought to examine whether PCs specific to dietary antigens are detected in the infant thymus. METHODS: We tested IgG reactivity to 112 food antigens and allergens in the serum of 20 neonates and infants using microarrays. The presence of PC-secreting IgG specific to the most prominent antigens was then assessed among thymocytes in the same cohort. Using an LC-MS proteomics approach, we looked for traces of these antigens in the thymus. RESULTS: Our studies first confirmed that cow's milk proteins are prevalent targets of serum IgG in early life. Subjects with the highest serum IgG titers to cow's milk proteins also harbored IgG-producing PCs specific to the same antigens in the thymic niche. Furthermore, we detected multiple peptide fragments of cow's milk antigens in the thymus. Lastly, we verified that both serum IgG and IgG secreted by thymic PCs recognized the peptide epitopes found in the thymus. CONCLUSIONS: Our studies reveal the presence of antibody-secreting PCs specific to common dietary antigens in the infant thymus. The presence of these antigens in the thymus suggested that activation and differentiation of specific PCs occurred in this organ. Further studies are now warranted to evaluate the possible implication of these cells in tolerance to dietary antigens.

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Electrophysiology recordings are frequently affected by artifacts (e.g., subject motion or eye movements), which reduces the number of available trials and affects the statistical power. When artifacts are unavoidable and data are scarce, signal reconstruction algorithms that allow for the retention of sufficient trials become crucial. Here, we present one such algorithm that makes use of large spatiotemporal correlations in neural signals and solves the low-rank matrix completion problem, to fix artifactual entries. The method uses a gradient descent algorithm in lower dimensions to learn the missing entries and provide faithful reconstruction of signals. We carried out numerical simulations to benchmark the method and estimate optimal hyperparameters for actual EEG data. The fidelity of reconstruction was assessed by detecting event-related potentials (ERP) from a highly artifacted EEG time series from human infants. The proposed method significantly improved the standardized error of the mean in ERP group analysis and a between-trial variability analysis compared to a state-of-the-art interpolation technique. This improvement increased the statistical power and revealed significant effects that would have been deemed insignificant without reconstruction. The method can be applied to any time-continuous neural signal where artifacts are sparse and spread out across epochs and channels, increasing data retention and statistical power.

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Introduction: Factors influencing vaccine immune priming in the first year of life involve both innate and adaptive immunity but there are gaps in understanding how these factors sustain vaccine antibody levels in healthy infants. The hypothesis was that bioprofiles associated with B cell survival best predict sustained vaccine IgG levels at one year. Methods: Longitudinal study of plasma bioprofiles in 82 term, healthy infants, who received standard recommended immunizations in the United States, with changes in 15 plasma biomarker concentrations and B cell subsets associated with germinal center development monitored at birth, soon after completion of the initial vaccine series at 6 months, and prior to the 12-month vaccinations. Post vaccination antibody IgG levels to Bordetella pertussis, tetanus toxoid, and conjugated Haemophilus influenzae type B (HiB) were outcome measures. Results: Using a least absolute shrinkage and selection operator (lasso) regression model, cord blood (CB) plasma IL-2, IL-17A, IL-31, and soluble CD14 (sCD14) were positively associated with pertussis IgG levels at 12 months, while CB plasma concentrations of APRIL and IL-33 were negatively associated. In contrast, CB concentrations of sCD14 and APRIL were positively associated with sustained tetanus IgG levels. A separate cross-sectional analysis of 18 mother/newborn pairs indicated that CB biomarkers were not due to transplacental transfer, but rather due to immune activation at the fetal/maternal interface. Elevated percentages of cord blood switched memory B cells were positively associated with 12-month HiB IgG levels. BAFF concentrations at 6 and 12 months were positively associated with pertussis and HiB IgG levels respectively. Discussion: Sustained B cell immunity is highly influenced by early life immune dynamics beginning prior to birth. The findings provide important insights into how germinal center development shapes vaccine responses in healthy infants and provide a foundation for studies of conditions that impair infant immune development.

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Little is known empirically about connectivity and communication between the two hemispheres of the brain in the first year of life, and what theoretical opinion exists appears to be at variance with the meager extant anatomical evidence. To shed initial light on the question of interhemispheric connectivity and communication, this study investigated brain correlates of interhemispheric transmission of information in young human infants. We analyzed EEG data from 12 4-month-olds undergoing a face-related oddball ERP protocol. The activity in the contralateral hemisphere differed between odd-same and odd-difference trials, with the odd-different response being weaker than the response during odd-same trials. The infants' contralateral hemisphere "recognized" the odd familiar stimulus and "discriminated" the odd-different one. These findings demonstrate connectivity and communication between the two hemispheres of the brain in the first year of life and lead to a better understanding of the functional integrity of the developing human infant brain.

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Lactobacilli (n = 24), isolated from human infants and yogurt, showed variable in vitro activity against Salmonella enteritidis (8.0 ± 1.0 to 16.6 ± 0.5 mm) and other gut pathogens (9.0 ± 1.0 to 15.3 ± 0.5 mm), as determined by a well diffusion assay. The isolates were identified as Limosilactobacillus fermentum (FY1, FY3, FY4, IL2, and IL5), Lactobacillus delbrueckii (FY6 and FY7), Lactobacillus sp. (IL7), and Lactobacillus gasseri (IL12). All isolates showed variable in vitro tolerance to acidic pH for 3 h and visible growth at pH 4 and in the presence of 0.3% ox-bile. The antibiotic susceptibility profile of Lactobacillus isolates indicated resistance against vancomycin, ciprofloxacin, streptomycin, and lincomycin. Isolates had variable auto-aggregation and showed variable capabilities to co-aggregate with S. enteritidis. Based on all tested parameters, L. fermentum IL2, L. fermentum IL5, and L. gasseri IL12 were selected for co-culture experiments, followed by in vivo evaluation in Balb/c mice. All the selected isolates resulted in a 100% reduction in S. enteritidis in broth. Lactobacillus isolates efficiently colonized mouse guts and inhibited S. enteritidis colonization. Overall, there was ≥99.06% and ≤4.32 Mean log10 reduction in Salmonella counts in mice feces within 7 days. The study, thus, provided characterized lactobacilli that could be considered as potential ingredients for probiotic formulations intended to prevent S. enteritidis infection in humans.

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Geometrically arranged spots and crosshatched incised lines are frequently portrayed in prehistoric cave and mobiliary art. Two experiments examined the saliency of snake scales and leopard rosettes to infants that are perceptually analogous to these patterns. Experiment 1 examined the investigative behavior of 23 infants at three daycare facilities. Four plastic jars (15×14.5cm) with snake scales, leopard rosettes, geometric plaid, and plain patterns printed on yellowish-orange paper inside were placed individually on the floor on separate days during playtime. Fourteen 7-15-month-old infants approached each jar hesitantly and poked it before handling it for five times, the criterion selected for statistical analyses of poking frequency. The jars with snake scales and leopard rosettes yielded reliably higher poking frequencies than the geometric plaid and plain jars. The second experiment examined the gaze and grasping behavior of 15 infants (spanning 5months of age) seated on the laps of their mothers in front of a table. For paired comparisons, the experimenter pushed two of four upright plastic cylinders (13.5×5.5cm) with virtually the same colored patterns simultaneously toward each infant for 6s. Video recordings indicated that infants gazed significantly longer at the cylinders with snake scales and leopard rosettes than the geometric plaid and plain cylinders prior to grasping them. Logistic regression of gaze duration predicting cylinder choice for grasping indicated that seven of 24 paired comparisons were not significant, all of which involved choices of cylinders with snake scales and leopard rosettes that diverted attention before reaching. Evidence that these biological patterns are salient to infants during an early period of brain development might characterize the integration of subcortical and neocortical visual processes known to be involved in snake recognition. In older individuals, memorable encounters with snakes and leopards coupled with the saliency of snake scales and leopard rosettes possibly biased artistic renditions of similar patterns during prehistoric times.

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Human cytomegalovirus (HCMV) infection rates approach 100% by the first year of life in low-income countries. It is not known if this drives changes to innate immunity in early life and thereby altered immune reactivity to infections and vaccines. Given the panoply of sex differences in immunity, it is feasible that any immunological effects of HCMV would differ in males and females. We analysed ex vivo innate cytokine responses to a panel of toll-like receptor (TLR) ligands in 108 nine-month-old Gambian males and females participating in a vaccine trial. We found evidence that HCMV suppressed reactivity to TLR2 and TLR7/8 stimulation in females but not males. This is likely to contribute to sex differences in responses to infections and vaccines in early life and has implications for the development of TLR ligands as vaccine adjuvants. Development of an effective HCMV vaccine would be able to circumvent some of these potentially negative effects of HCMV infection in childhood.

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Human cytomegalovirus (HCMV) infection has a profound effect on the human immune system, causing massive clonal expansion of CD8, and to a lesser extend CD4 T cells. The few human trials that have explored the effect of HCMV infection on responses to vaccination are conflicting, with some studies suggesting no effect whilst others suggest decreased or increased immune responses. Recent studies indicate substantial differences in overall immune system reactivity to vaccines based on age and sex, particularly cellular immunity. 225 nine-month old Gambian infants were immunized with diphtheria-tetanus-whole cell pertussis and/or measles vaccines. HCMV infection status was determined by the presence of CMV DNA by PCR of urine samples prior to vaccination. The effect of HCMV infection on either protective antibody immunity or vaccine-specific and overall cellular immune responses 4 weeks post-vaccination was determined, further stratified by sex. Tetanus toxoid-specific antibody responses were significantly lower in HCMV+ infants compared to their HCMV- counterparts, while pertussis, diphtheria and measles antibody responses were generally comparable between the groups. Responses to general T cell stimulation with anti-CD3/anti-CD28 as well as antigen-specific cytokine responses to purified protein derivative (PPD) were broadly suppressed in infants infected with HCMV but, perhaps surprisingly, there was only a minimal impact on antigen-specific cellular responses to vaccine antigens. There was evidence for subtle sex differences in the effects of HCMV infection, in keeping with the emerging evidence suggesting sex differences in homeostatic immunity and in responses to vaccines. This study reassuringly suggests that the high rates of HCMV infection in low income settings have little clinically significant impact on antibody and cellular responses to early life vaccines, while confirming the importance of sex stratification in such studies.

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BACKGROUND: DL-2-hydroxy-4-methylthiobutyric acid (DL-HMTBA), an L-methionine (L-Met) hydroxyl analogue, has been suggested to be a dietary L-Met source. How dietary DL-HMTBA compared with L-Met affects whole-body L-Met kinetics in growing individuals is unknown. OBJECTIVES: We determined to what extent DL-HMTBA supplementation of an L-Met-deficient diet affects whole-body L-Met and L-cysteine (L-Cys) kinetics, protein synthesis (PS), and the L-Met incorporation rate in liver protein (L-MetInc) compared with L-Met and DL-Met supplementation in a piglet model. METHODS: Forty-five, 28-d-old weaned piglets (male, German Landrace) were allocated to 4 dietary groups: L-Met-deficient diet [Control: 69% of recommended L-Met plus L-Cys supply; 0.22% standardized ileal digestible (SID) L-Met; 0.27% SID L-Cys; n = 12] and Control diet supplemented equimolarly to 100% of recommended intake with either L-Met (n = 12; LMET), DL-Met (n = 11; DLMET), or DL-HMTBA (n = 10; DLHMTBA). At 47 d of age, the piglets were infused with L-[1-13C; methyl-2H3]-Met and [3,3-2H2]-Cys to determine the kinetics and PS rates. Plasma amino acid (AA) concentrations, hepatic mRNA abundances of L-Met cycle and transsulfuration (TS) enzymes, and L-MetInc were measured. RESULTS: During feed deprivation, L-Met kinetics did not differ between groups, and were ≤3 times higher in the fed state (P < 0.01). Remethylation (RM) was 31% and 45% higher in DLHMTBA than in DLMET and Control pigs, respectively, and the RM:transmethylation (TM) ratio was 50% higher in DLHMTBA than in LMET (P < 0.05). Furthermore, TS and the TS:TM ratio were 32% lower in DLHMTBA than in LMET (P < 0.05). L-MetInc was 42% lower in DLMET and DLHMTBA than in L-Met-deficient Control pigs, whereas plasma AA and hepatic mRNA abundances were similar among DL-HMTBA-, L-Met-, and DL-Met-supplemented pigs. CONCLUSIONS: In piglets, DL-HMTBA compared with L-Met and DL-Met supplementation increases RM and reduces the TS rate to conserve L-Met, but all 3 Met isomers support growth at a comparable rate.

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In this article, we review recent empirical and theoretical work on infant memory development, highlighting future directions for the field. We consider the state of the field since Carolyn Rovee-Collier's call for developmental scientists to "shift the focus from what to why," emphasizing the function of infant behavior and the value of integrating fractionized, highly specialized subfields. We discuss functional approaches of early learning and memory, including ecological models of memory development and relevant empirical work in human and non-human organisms. Ontogenetic changes in learning and memory occur in developing biological systems, which are embedded in broader socio-cultural contexts with shifting ecological demands that are in part determined by the infants themselves. We incorporate biopsychosocial and dynamical systems perspectives as we analyze the state of the field's integration of multiple areas of specialization to provide more holistic understanding of the contributing factors and underlying mechanisms of the development of memory.

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There is growing evidence that activation of the motor system during observation of actions, a phenomenon first observed in non-human primates, underlies action understanding and even communication. This review (a) examines the evidence on motor system activity as an underlying neural correlate of action understanding; (b) reviews the theoretical and empirical work linking action understanding and the development of communication, with a specific focus on the role that gestures play as an intermediary; and (c) discusses the research on and existing opportunities for understanding the link between the motor system and communication in both humans and non-human primates, through the lens of action perception. Bringing together findings and perspectives from developmental social cognition in both humans and non-human primates and applying recent neuroscientific perspectives will help to elucidate the processes underlying the ability to understand and communicate with others.

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Recursive, hierarchically organized serial patterns provide the underlying structure in many cognitive and motor domains including speech, language, music, social interaction, and motor action. We investigated whether learning of hierarchical patterns emerges in infancy by habituating 204 infants to different hierarchical serial patterns and then testing for discrimination and generalization of such patterns. Results indicated that 8- to 10-month-old and 12- to 14-month-old infants exhibited sensitivity to the difference between hierarchical and non-hierarchical structure but that 4- to 6-month-old infants did not. These findings demonstrate that the ability to perceive, learn, and generalize recursive, hierarchical, pattern rules emerges in infancy and add to growing evidence that general-purpose pattern learning mechanisms emerge during the first year of life.

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A central assumption in the perceptual attunement literature holds that exposure to a speech sound contrast leads to improvement in native speech sound processing. However, whether the amount of exposure matters for this process has not been put to a direct test. We elucidated indicators of frequency-dependent perceptual attunement by comparing 5-8-month-old Dutch infants' discrimination of tokens containing a highly frequent [hɪt-he:t] and a highly infrequent [hʏt-hø:t] native vowel contrast as well as a non-native [hɛt-haet] vowel contrast in a behavioral visual habituation paradigm (Experiment 1). Infants discriminated both native contrasts similarly well, but did not discriminate the non-native contrast. We sought further evidence for subtle differences in the processing of the two native contrasts using near-infrared spectroscopy and a within-participant design (Experiment 2). The neuroimaging data did not provide additional evidence that responses to native contrasts are modulated by frequency of exposure. These results suggest that even large differences in exposure to a native contrast may not directly translate to behavioral and neural indicators of perceptual attunement, raising the possibility that frequency of exposure does not influence improvements in discriminating native contrasts.

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Differences in vocal fundamental (F0) and average formant (Fn) frequencies covary with body size in most terrestrial mammals, such that larger organisms tend to produce lower frequency sounds than smaller organisms, both between species and also across different sex and life-stage morphs within species. Here we examined whether three-month-old human infants are sensitive to the relationship between body size and sound frequencies. Using a violation-of-expectation paradigm, we found that infants looked longer at stimuli inconsistent with the relationship-that is, a smaller organism producing lower frequency sounds, and a larger organism producing higher frequency sounds-than at stimuli that were consistent with it. This effect was stronger for fundamental frequency than it was for average formant frequency. These results suggest that by three months of age, human infants are already sensitive to the biologically relevant covariation between vocalization frequencies and visual cues to body size. This ability may be a consequence of developmental adaptations for building a phenotype capable of identifying and representing an organism's size, sex and life-stage.

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Sensory preconditioning (SPC) is a form of latent learning in which preexposure to co-occurring neutral stimuli (S1 -S2 ) permits subsequent learning to be transferred from one stimulus (S1 ) to the other (S2 ). We examined whether human infants exhibit developmental transitions in the temporal parameters of SPC by manipulating the preexposure regimen. Infants received simultaneous or sequential preexposure to puppets S1 and S2 (Days 1-2); saw target actions modeled on S1 (Day 3); and were tested for deferred imitation with S2 (Day 4). Although 6-, 9-, and 12-month-olds associated the puppets, there was a shift in the effective regimen from simultaneous to sequential preexposure-similar to prior findings with rat pups (Experiment 1). Experiment 2 revealed that human infants potentially exhibit another transition in SPC at 15 and 18 months of age. We consider the roles of ontogenetic shifts in infants' ecological niche, selective attention, and unitization in developmental transitions in SPC.

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BACKGROUND: Home fortification using sachets of micronutrient powder (e.g. "Sprinkles") is a food-based approach offering an alternative to high dose vitamin A (VA) supplements for infants. The primary objective was to investigate the impact of VA-home fortification on infant VA pool size. The secondary objective was to compare VA status of infants assessed by the modified relative dose response (MRDR) test before and the (13)C-retinol isotope dilution ((13)C-RID) test in the same infants after vitamin A supplementation. METHODS: A randomized-controlled trial was conducted in 7-9 month old infants in Ghana. Eligible children were randomly allocated to receive a daily sachet of "Sprinkles" with or without VA for 5 months added to complementary foods. The MRDR test indirectly determined VA liver reserves at baseline and the (13)C-RID determined VA body pool at follow-up in the same cohort of children. RESULTS: At baseline, the MRDR values (95 % CI) for infants were comparable in the intervention and control groups: normal at 0·032 (SD 0·018) (0·025-0·038) and 0·031 (SD 0·018) (0·024-0·038), respectively. After intervention, total body stores (TBS) and liver retinol concentrations did not differ between intervention and control groups; TBS were 436 (SD 303) and 434 (SD 186) µmol, respectively, and estimated liver concentrations were 0·82 (SD 0·53) and 0·79 (SD 0·36) µmol/g liver, indicating adequate reserves in all children. CONCLUSIONS: Both the MRDR and (3)C-RID tests confirmed that the infants had adequate VA status before and after home fortification of their complementary foods. These tests offered more information than serum retinol concentrations alone, which predicted VA deficiency using current suggested cutoffs not corrected for inflammation status.

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Extinction allows organisms to adapt to an ever-changing environment. Despite its theoretical and applied significance, extinction has never been systematically studied with human infants. Using the operant mobile task, we examined whether 3-month-olds would exhibit evidence of original learning following extinction. In a recognition paradigm, infants exhibited renewal when tested in the acquisition context (ABA renewal) or a neutral context (ABC and AAB renewal) 1 day following extinction (Experiment 1a) and spontaneous recovery 3 days following extinction (Experiment 1b). In Experiments 2a-2b, we used a reminder paradigm to examine whether the extinguished response could be reinstated after the operant response had been forgotten. We failed, however, to find reinstatement of extinguished responding after spontaneous forgetting, regardless of the reminder and test contexts. We attributed this retention failure to competing responses at test. Although extinguished responding is recovered during infancy, this effect is elusive after the response has been forgotten.

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Infants growing up in bilingual environments succeed at learning two languages. What adaptive processes enable them to master the more complex nature of bilingual input? One possibility is that bilingual infants take greater advantage of the redundancy of the audiovisual speech that they usually experience during social interactions. Thus, we investigated whether bilingual infants' need to keep languages apart increases their attention to the mouth as a source of redundant and reliable speech cues. We measured selective attention to talking faces in 4-, 8-, and 12-month-old Catalan and Spanish monolingual and bilingual infants. Monolinguals looked more at the eyes than the mouth at 4 months and more at the mouth than the eyes at 8 months in response to both native and nonnative speech, but they looked more at the mouth than the eyes at 12 months only in response to nonnative speech. In contrast, bilinguals looked equally at the eyes and mouth at 4 months, more at the mouth than the eyes at 8 months, and more at the mouth than the eyes at 12 months, and these patterns of responses were found for both native and nonnative speech at all ages. Thus, to support their dual-language acquisition processes, bilingual infants exploit the greater perceptual salience of redundant audiovisual speech cues at an earlier age and for a longer time than monolingual infants.

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Ethical issues and their optimal solutions in longitudinal infant studies have not received adequate attention in the literature. To address this gap, this manuscript pulls from universal research ethics, ethical guidelines for infant and child research, and ethical guidelines for longitudinal research and combines them in the context of infant longitudinal research with typically-developing infants. Topics explored relate to participant consent to research studies, the participant-observer relationship, and closure of developmental studies in this targeted population. Additionally, this manuscript highlights the importance and need for new and more relevant considerations of ethical procedures that concern infants involved in longitudinal research.

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Human adults can process emotional information both with and without conscious awareness, and it has been suggested that the two processes rely on partly distinct brain mechanisms. However, the developmental origins of these brain processes are unknown. In the present event-related brain potential (ERP) study, we examined the brain responses of 7-month-old infants in response to subliminally (50 and 100 msec) and supraliminally (500 msec) presented happy and fearful facial expressions. Our results revealed that infants' brain responses (Pb and Nc) over central electrodes distinguished between emotions irrespective of stimulus duration, whereas the discrimination between emotions at occipital electrodes (N290 and P400) only occurred when faces were presented supraliminally (above threshold). This suggests that early in development the human brain not only discriminates between happy and fearful facial expressions irrespective of conscious perception, but also that, similar to adults, supraliminal and subliminal emotion processing relies on distinct neural processes. Our data further suggest that the processing of emotional facial expressions differs across infants depending on their behaviorally shown perceptual sensitivity. The current ERP findings suggest that distinct brain processes underpinning conscious and unconscious emotion perception emerge early in ontogeny and can therefore be seen as a key feature of human social functioning.

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