Brain intrinsic connection patterns underlying tool processing in human adults are present in neonates and not in macaques

Tool understanding and use are supported by a dedicated left-lateralized, intrinsically connected network in the human adult brain. To examine this network's phylogenic and ontogenetic origins, we compared resting-state functional connectivity (rsFC) among regions subserving tool processing in human adults to rsFC among homologous regions in human neonates and macaque monkeys (adolescent and mature). These homologous regions formed an intrinsic network in human neonates, but not in macaques. Network topological patterns were highly similar between human adults and neonates, and significantly less so between humans and macaques. The premotor-parietal rsFC had most significant contribution to the formation of the neonate tool network. These results suggest that an intrinsic brain network potentially supporting tool processing exists in the human brain prior to individual tool use experiences, and that the premotor-parietal functional connection in particular offers a brain basis for complex tool behaviors specific to humans.

Intrathymic differentiation of natural antibody-producing plasma cells in human neonates

The thymus is a central lymphoid organ primarily responsible for the development of T cells. A small proportion of B cells, however, also reside in the thymus to assist negative selection of self-reactive T cells. Here we show that the thymus of human neonates contains a consistent contingent of CD138+ plasma cells, producing all classes and subclasses of immunoglobulins with the exception of IgD. These antibody-secreting cells are part of a larger subset of B cells that share the expression of signature genes defining mouse B1 cells, yet lack the expression of complement receptors CD21 and CD35. Data from single-cell transcriptomic, clonal correspondence and in vitro differentiation assays support the notion of intrathymic CD138+ plasma cell differentiation, alongside other B cell subsets with distinctive molecular phenotypes. Lastly, neonatal thymic plasma cells also include clones reactive to commensal and pathogenic bacteria that commonly infect children born with antibody deficiency. Thus, our findings point to the thymus as a source of innate humoral immunity in human neonates.

The genetic basis of tail-loss evolution in humans and apes

The loss of the tail is one of the main anatomical evolutionary changes to have occurred along the lineage leading to humans and to the “anthropomorphous apes”1,2. This morphological reprogramming in the ancestral hominoids has been long considered to have accommodated a characteristic style of locomotion and contributed to the evolution of bipedalism in humans3–5. Yet, the precise genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Primate genome sequencing projects have made possible the identification of causal links between genotypic and phenotypic changes6–8, and enable the search for hominoid-specific genetic elements controlling tail development9. Here, we present evidence that tail-loss evolution was mediated by the insertion of an individual Alu element into the genome of the hominoid ancestor. We demonstrate that this Alu element – inserted into an intron of the TBXT gene (also called T or Brachyury10–12) – pairs with a neighboring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated a mouse model that mimics the expression of human TBXT products by expressing both full-length and exon-skipped isoforms of the mouse TBXT ortholog. We found that mice with this genotype exhibit the complete absence of a tail or a shortened tail, supporting the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype, albeit with incomplete penetrance. We further noted that mice homozygous for the exon-skipped isoforms exhibited embryonic spinal cord malformations, resembling a neural tube defect condition, which affects ~1/1000 human neonates13. We propose that selection for the loss of the tail along the hominoid lineage was associated with an adaptive cost of potential neural tube defects and that this ancient evolutionary trade-off may thus continue to affect human health today.

The genetic basis of tail-loss evolution in humans and apes

The loss of the tail is one of the main anatomical evolutionary changes to have occurred along the lineage leading to humans and to the "anthropomorphous apes"1,2. This morphological reprogramming in the ancestral hominoids has been long considered to have accommodated a characteristic style of locomotion and contributed to the evolution of bipedalism in humans3-5. Yet, the precise genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Primate genome sequencing projects have made possible the identification of causal links between genotypic and phenotypic changes6-8, and enable the search for hominoid-specific genetic elements controlling tail development9. Here, we present evidence that tail-loss evolution was mediated by the insertion of an individual Alu element into the genome of the hominoid ancestor. We demonstrate that this Alu element - inserted into an intron of the TBXT gene (also called T or Brachyury10-12) - pairs with a neighboring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated a mouse model that mimics the expression of human TBXT products by expressing both full-length and exon-skipped isoforms of the mouse TBXT ortholog. We found that mice with this genotype exhibit the complete absence of a tail or a shortened tail, supporting the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype, albeit with incomplete penetrance. We further noted that mice homozygous for the exon-skipped isoforms exhibited embryonic spinal cord malformations, resembling a neural tube defect condition, which affects ~1/1000 human neonates13. We propose that selection for the loss of the tail along the hominoid lineage was associated with an adaptive cost of potential neural tube defects and that this ancient evolutionary trade-off may thus continue to affect human health today.

Lung ultrasound features and relationships with respiratory mechanics of evolving BPD in preterm rabbits and human neonates

Evolving broncho-pulmonary dysplasia (BPD) is a regionally heterogeneous disorder characterized by impaired alveolarization leading to lung aeration inhomogeneities. Hyperoxia-exposed preterm rabbits have been proposed to mimic evolving BPD and we aim to verify if this model has the same lung ultrasound and mechanical features of evolving BPD in human neonates. Twenty-five preterm rabbits and twenty-five neonates with evolving BPD were enrolled and subjected to semi-quantitative lung ultrasound and lung mechanics measurement. A modified rabbit lung ultrasound score (rLUS), the previously validated neonatal lung ultrasound score (LUS) and classical mechanics measurements were obtained. Lung ultrasound images were also recorded and evaluated by two independent observers with different expertise blinded to each other's evaluation. Lung ultrasound findings were equally heterogeneous both in rabbits as in human neonates: images were very similar and encompassed all the classical lung ultrasound semiology. The inter-rater absolute agreement for the evaluation of lung ultrasound images in rabbits was very high (ICC: 0.989 (95%CI: 0.975-0.995); p<0.0001) and there was no difference between the two observers. Lung mechanics parameters were similarly altered both in rabbits and human neonates. There were significant correlations between airway resistances and lung ultrasound scores both in rabbits (r=0.519; p=0.008) and in neonates (r=0.409; p=0.042). No significant correlation between rLUS, LUS and any other mechanics parameter. Lung ultrasound was easy to be performed and accurate even in these small animals and with a short training. In conclusion, the preterm rabbit model fairly reproduces the lung ultrasound and mechanical characteristics of preterm neonates with evolving BPD.

Resurgence of an Inborn Attraction for Animate Objects via Thyroid Hormone T3

For inexperienced brains, some stimuli are more attractive than others. Human neonates and newly hatched chicks preferentially orient towards face-like stimuli, biological motion, and objects changing speed. In chicks, this enhances exposure to social partners, and subsequent attachment trough filial imprinting. Early preferences are not steady. For instance, preference for stimuli changing speed fades away after 2 days in chicks. To understand the physiological mechanisms underlying these transient responses, we tested whether early preferences for objects changing speed can be promoted by thyroid hormone 3,5,3′-triiodothyronine (T3). This hormone determines the start of imprinting’s sensitive period. We found that the preference for objects changing speed can be re-established in female chicks treated with T3. Moreover, day-1 chicks treated with an inhibitor of endogenous T3 did not show any preference. These results suggest that the time windows of early predispositions and of sensitive period for imprinting are controlled by the same molecular mechanisms.

Bedside functional monitoring of the dynamic brain connectivity in human neonates

Clinicians have long been interested in functional brain monitoring, as reversible functional losses often precedes observable irreversible structural insults. By characterizing neonatal functional cerebral networks, resting-state functional connectivity is envisioned to provide early markers of cognitive impairments. Here we present a pioneering bedside deep brain resting-state functional connectivity imaging at 250-μm resolution on human neonates using functional ultrasound. Signal correlations between cerebral regions unveil interhemispheric connectivity in very preterm newborns. Furthermore, fine-grain correlations between homologous pixels are consistent with white/grey matter organization. Finally, dynamic resting-state connectivity reveals a significant occurrence decrease of thalamo-cortical networks for very preterm neonates as compared to control term newborns. The same method also shows abnormal patterns in a congenital seizure disorder case compared with the control group. These results pave the way to infants’ brain continuous monitoring and may enable the identification of abnormal brain development at the bedside.