Early Disruption Research Articles

A Little Girl’s Recovery: An Analysis of a Six-Year-Old Girl Who Experienced Loss

ABSTRACT This paper will focus on the process of recovery during the analysis of a latency girl referred after the death of her mother, having been expelled from several schools due to aggressive outbursts and early attachment disruptions in her relationship with the father. The intent of this paper is to illustrate the internal conflicts and difficulty with aggression surrounding early traumatic loss of her mother. The inner work on a trauma never ceases and through the transferential process this child was able to reexperience her early relationship with her mother leading to more mature ego development. The analytic work with Katie shows how her integrative capacity allowed for her to mourn.

Association of Postpartum Maternal Mood With Infant Speech Perception at 2 and 6.5 Months of Age

Language development builds on speech perception, with early disruptions increasing the risk for later language difficulties. Although a major postpartum depressive episode is associated with language development, this association has not been investigated among infants of mothers experiencing a depressed mood at subclinical levels after birth, even though such a mood is frequently present in the first weeks after birth. Understanding whether subclinical depressed maternal mood after birth is associated with early language development is important given opportunities of coping strategies for subclinical depressed mood. To examine whether depressed maternal mood at subclinical levels 2 months after birth is associated with infant speech perception trajectories from ages 2 to 6.5 months. In this longitudinal cohort study conducted between January 1, 2018, and October 31, 2019, 46 healthy, monolingual German mother-infant dyads were tested. The sample was recruited from the infants database of the Max Planck Institute for Human Cognitive and Brain Sciences. Initial statistical analysis was performed between January 1 and March 31, 2021; the moderation analysis (results reported herein) was conducted between July 1 and July 31, 2022. Mothers reported postpartum mood via the German version of the Edinburgh Postnatal Depression Scale (higher scores indicated higher levels of depressed mood, with a cutoff of 13 points indicating a high probability of clinical depression) when their infants were 2 months old. Electrophysiological correlates of infant speech perception (mismatch response to speech stimuli) were tested when the infants were aged 2 months (initial assessment) and 6.5 months (follow-up). A total of 46 mothers (mean [SD] age, 32.1 [3.8] years) and their 2-month-old children (mean [SD] age, 9.6 [1.2] weeks; 23 girls and 23 boys) participated at the initial assessment, and 36 mothers (mean [SD] age, 32.2 [4.1] years) and their then 6.5-month-old children (mean [SD] age, 28.4 [1.5 weeks; 18 girls and 18 boys) participated at follow-up. Moderation analyses revealed that more depressed maternal subclinical postpartum mood (mean [SD] Edinburgh Postnatal Depression Scale score, 4.8 [3.6]) was associated with weaker longitudinal changes of infants' electrophysiological brain responses to syllable pitch speech information from ages 2 to 6.5 months (coefficient: 0.68; 95% CI, 0.03-1.33; P = .04). The results of this cohort study suggest that infant speech perception trajectories are correlated with subclinical depressed mood in postpartum mothers. This finding lays the groundwork for future research on early support for caregivers experiencing depressed mood to have a positive association with children's language development.

Abstract 007: Hypertension-induced Neurovascular Dysfunction At Single-cell Resolution

Hypertension (HTN) disrupts vital neurovascular control mechanisms, thereby increasing the brain’s susceptibility to vascular insufficiency, white matter lesions, and cognitive impairment. Yet, the distinct vascular, neuronal, and glial cell types targeted by HTN, as well as the ensuing cellular network disruption driving the neurovascular and cognitive deficits remain undefined. Here we sought to uncover transcriptomic changes in neurons and vascular cells using unbiased, single-cell RNA sequencing on the neocortex of 10-week old C57BL/6 male mice with angiotensin II (AngII) HTN. Vehicle or AngII (600ng/kg/min s.c.) were administered for 3 days, when blood-brain barrier (BBB) permeability start to increase, or 42 days, when neurovascular and cognitive dysfunction are fully developed (n=3/group). We analyzed 39,451 single-cell transcriptomes comprising 26 cell types. Surprisingly, 3 days of AngII induced significantly greater transcriptional changes in venular ECs compared to arteriolar ECs (EdgeR; pval< 0.05, logFC> 2), supporting the notion that venular ECs are uniquely sensitive to the early effects of HTN (Hypertension 76:795, 2020). Gene ontology analysis of differentially expressed genes prominently implicated altered venular immune signaling, BBB dysfunction, and, notably, a secretory phenotype characteristic of senescence (pval <0.05). Moreover, unbiased ligand-receptor interaction analysis (CellChat) demonstrated that senescent venular ECs strongly communicate with oligodendrocyte precursors, and NPY-expressing interneurons, pointing to a previously unrecognized early disruption in the oligo-vascular niche, essential for maintaining white matter integrity, and neuronal network stability. Furthermore, at 42 days of AngII we observed an overrepresentation of aging and neurodegeneration-linked genes in oligos and NPY interneurons, relating to myelin disruption, synaptic dysfunction, and metabolic dysregulation. The data reveal a novel endothelial-oligo-interneuron crosstalk and transcriptomic alterations underlying the impact of HTN on the brain. Future studies will establish how these transcriptomic changes are linked to neurovascular dysfunction, white matter damage and cognitive impairment.

A "multi-omics" analysis of blood-brain barrier and synaptic dysfunction in APOE4 mice.

Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer's disease, leads to blood-brain barrier (BBB) breakdown in humans and mice. Remarkably, BBB dysfunction predicts cognitive decline and precedes synaptic deficits in APOE4 human carriers. How APOE4 affects BBB and synaptic function at a molecular level, however, remains elusive. Using single-nucleus RNA-sequencing and phosphoproteome and proteome analysis, we show that APOE4 compared with APOE3 leads to an early disruption of the BBB transcriptome in 2-3-mo-old APOE4 knock-in mice, followed by dysregulation in protein signaling networks controlling cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, as well as transcription and RNA splicing suggestive of DNA damage in pericytes. Changes in BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes, which preceded postsynaptic interactome disruption and behavioral deficits that developed 2-5 mo later. Thus, dysregulated signaling mechanisms in endothelium and pericytes in APOE4 mice reflect a molecular signature of a progressive BBB failure preceding changes in synaptic function and behavior.

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

BackgroundPatients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3WT/ΔC mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption.MethodsWe recorded sleep behavior in developing Shank3ΔC/ΔC, Shank3WT/ΔC, and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3WT/ΔC and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults.ResultsMale and female Shank3ΔC/ΔC mice slept significantly less than wild-type and Shank3WT/ΔC siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3WT/ΔC mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3WT/ΔC subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3WT/ΔC subjects had a significant reduction in risk aversion. CON Shank3WT/ΔC mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests.LimitationsThis study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities.ConclusionOur study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility.

The location of the t(4;14) translocation breakpoint within the NSD2 gene identifies a subset of patients with high-risk NDMM

AbstractAlthough translocation events between chromosome 4 (NSD2 gene) and chromosome 14 (immunoglobulin heavy chain [IgH] locus) (t(4;14)) is considered high risk in newly diagnosed multiple myeloma (NDMM), only ∼30% to 40% of t(4;14) patients are clinically high risk. We generated and compared a large whole genome sequencing (WGS) and transcriptome (RNA sequencing) from 258 t(4;14) (n = 153 discovery, n = 105 replication) and 183 non-t(4;14) NDMM patients with associated clinical data. A landmark survival analysis indicated only ∼25% of t(4;14) patients had an overall survival (OS) <24 months, and a comparative analysis of the patient subgroups identified biomarkers associated with this poor outcome, including translocation breakpoints located in the NSD2 gene and expression of IgH-NSD2 fusion transcripts. Three breakpoints were identified and are designated as: “no-disruption” (upstream of NSD2), “early-disruption” (in the 5' UTR), and “late-disruption” (within the NSD2 gene). Our results show a significant difference in OS based on the location of DNA breakpoints (median OS 28.6 “late-disruption” vs 59.2 “early disruption” vs 75.1 months “no disruption”). These findings have been replicated in an independent replication dataset. Also, univariate and multivariate analysis suggest high-risk markers such as del17p, 1p independently contribute to poor outcome in t(4;14) MM patients.

Mid-Cretaceous drainage reorganization and exorheic to endorheic transition in Southeast Tibet

To understand the early topographic growth of the Tibetan Plateau and the causes and effects of climate change in this region, it is important to reconstruct the drainage evolution across Southeast Tibet. Based on age constraints provided by detrital zircons in the fluvial sandstones in the Khorat Plateau Basin, we identified a major Early Cretaceous drainage disruption and reorganization event. The ages and Hf isotope compositions of the detrital zircons in the Upper Jurassic-Lower Cretaceous Phu Kradung to Phu Phan formations (166–122 Ma) suggest the existence of an exorheic continental-scale paleo-Mekong River with headwaters in the Songpan-Garze and Qiangtang terranes. This paleo-river flowed southwards across the Khorat Plateau to what is presently the offshore Phuquoc Basin, which was then part of the Neo-Tethys Ocean. In contrast, the U-Pb-Hf compositions of the detrital zircons in the Lower Cretaceous Khok Kruat Formation (122–113 Ma) indicate that a prominent detrital supply from the Sibumasu magmatic rocks was transported by the paleo-Salween River. This major change reflects the occurrence of ancestral transcontinental river disruption at around 122 Ma, which was driven by the final collision between the Lhasa and Qiangtang and Woyla Arc and Sibumasu terranes. The tectonic uplift and ensuing arid climate corresponded to the reorganization of the ancestral Mekong drainage system during the Mid-Cretaceous (113–94 Ma).

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

SummaryDysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder.

Three-dimensional chromatin interactions regulate gene expressions. The significance of de novo mutations (DNMs) in chromatin interactions remains poorly understood for autism spectrum disorder (ASD). We generated 813 whole-genome sequences from 242 Korean simplex families to detect DNMs, and identified target genes which were putatively affected by non-coding DNMs in chromatin interactions. Non-coding DNMs in chromatin interactions were significantly involved in transcriptional dysregulations related to ASD risk. Correspondingly, target genes showed spatiotemporal expressions relevant to ASD in developing brains and enrichment in biological pathways implicated in ASD, such as histone modification. Regarding clinical features of ASD, non-coding DNMs in chromatin interactions particularly contributed to low intelligence quotient levels in ASD probands. We further validated our findings using two replication cohorts, Simons Simplex Collection (SSC) and MSSNG, and showed the consistent enrichment of non-coding DNM-disrupted chromatin interactions in ASD probands. Generating human induced pluripotent stem cells in two ASD families, we were able to demonstrate that non-coding DNMs in chromatin interactions alter the expression of target genes at the stage of early neural development. Taken together, our findings indicate that non-coding DNMs in ASD probands lead to early neurodevelopmental disruption implicated in ASD risk via chromatin interactions.

Cysteine string protein alpha accumulates with early pre-synaptic dysfunction in Alzheimer's disease.

In Alzheimer’s disease, synapse loss causes memory and cognitive impairment. However, the mechanisms underlying synaptic degeneration in Alzheimer’s disease are not well understood. In the hippocampus, alterations in the level of cysteine string protein alpha, a molecular co-chaperone at the pre-synaptic terminal, occur prior to reductions in synaptophysin, suggesting that it is a very sensitive marker of synapse degeneration in Alzheimer’s. Here, we identify putative extracellular accumulations of cysteine string alpha protein, which are proximal to beta-amyloid deposits in post-mortem human Alzheimer’s brain and in the brain of a transgenic mouse model of Alzheimer’s disease. Cysteine string protein alpha, at least some of which is phosphorylated at serine 10, accumulates near the core of beta-amyloid deposits and does not co-localize with hyperphosphorylated tau, dystrophic neurites or glial cells. Using super-resolution microscopy and array tomography, cysteine string protein alpha was found to accumulate to a greater extent than other pre-synaptic proteins and at a comparatively great distance from the plaque core. This indicates that cysteine string protein alpha is most sensitive to being released from pre-synapses at low concentrations of beta-amyloid oligomers. Cysteine string protein alpha accumulations were also evident in other neurodegenerative diseases, including some fronto-temporal lobar dementias and Lewy body diseases, but only in the presence of amyloid plaques. Our findings are consistent with suggestions that pre-synapses are affected early in Alzheimer’s disease, and they demonstrate that cysteine string protein alpha is a more sensitive marker for early pre-synaptic dysfunction than traditional synaptic markers. We suggest that cysteine string protein alpha should be used as a pathological marker for early synaptic disruption caused by beta-amyloid.

Retinoic acid signaling regulates late stages of semicircular canal morphogenesis and otolith maintenance in the zebrafish inner ear

The vitamin A derivative all-trans retinoic acid (RA) regulates early stages of inner ear development. As the early disruption of the RA pathway results in profound mispatterning of the developing inner ear, this confounds analyses of specific roles in later stages. Therefore, we used the temporal-specific exposure of all-trans RA or diethylaminobenzaldehyde to evaluate RA functions in late otic development. Perturbing late RA signaling causes behavioral defects analogous to those expected in larvae suffering from vestibular dysfunction. These larvae also demonstrate malformations of the semi-circular canals, as visualized through (a) use of the transgenic strain nkhspdmc12a, a fluorescent reporter expressed in otic epithelium; and (b) injection of the fluorescent lipophilic dye DiI. We also noted the altered expression of genes encoding ECM proteins or modifying enzymes. Other malformations of the inner ear observed in our work include the loss or reduced size of the utricular and saccular otoliths, suggesting a role for RA in otolith maintenance. Our work has identified a previously undescribed late phase of RA activity in otic development, demonstrating that vestibular defects observed in human patients in relation to perturbed RA signaling are not solely due to its early disruption in otic development.

Fluoxetine exposure throughout neurodevelopment differentially influences basilar dendritic morphology in the motor and prefrontal cortices

The significance of serotonin (5HT) in mental health is underscored by the serotonergic action of many classes of psychiatric medication. 5HT is known to have a significant role in neurodevelopment, thus 5HT disruption during development may have a long term impact on brain structure and circuits. We previously generated a model of 5HT alteration throughout neurodevelopment by maternal administration of the selective serotonin reuptake inhibitor fluoxetine. We found resulting social behavior alterations in the offspring during both postnatal and adult ages. Previous work by others has indicated that early 5HT disruption influences neuronal morphology. Therefore, in the current study we sought to determine if dendritic morphological changes occur in areas involved in the social behavior deficits we previously observed, specifically the primary motor (M1) and medial prefrontal (mPFC) cortices. We quantified dendritic morphology of projection neurons in M1 and mPFC at postnatal day (P)10 and P79 in mice exposed to fluoxetine. Basilar dendritic complexity and spine density were persistently decreased in M1 fluoxetine-exposed neurons while in the mPFC, similar reductions were observed at P79 but were not present at P10. Our findings underscore that the developing brain, specifically the projection cortex, is vulnerable to 5HT system perturbation, which may be related to later behavioral disruptions.

Early life circadian rhythm disruption in mice alters brain and behavior in adulthood.

Healthy sleep supports robust development of the brain and behavior. Modern society presents a host of challenges that can impair and disrupt critical circadian rhythms that reinforce optimal physiological functioning, including the proper timing and consolidation of sleep. While the acute effects of inadequate sleep and disrupted circadian rhythms are being defined, the adverse developmental consequences of disrupted sleep and circadian rhythms are understudied. Here, we exposed mice to disrupting light–dark cycles from birth until weaning and demonstrate that such exposure has adverse impacts on brain and behavior as adults. Mice that experience early-life circadian disruption exhibit more anxiety-like behavior in the elevated plus maze, poorer spatial memory in the Morris Water Maze, and impaired working memory in a delayed match-to-sample task. Additionally, neuron morphology in the amygdala, hippocampus and prefrontal cortex is adversely impacted. Pyramidal cells in these areas had smaller dendritic fields, and pyramidal cells in the prefrontal cortex and hippocampus also exhibited diminished branching orders. Disrupted mice were also hyperactive as adults, but otherwise exhibited no alteration in adult circadian locomotor rhythms. These results highlight that circadian disruption early in life may have long lasting and far-reaching consequences for the development of behavior and the brain.

Childhood Disruptions in Caregiving, Adult Parental Attachment, and Borderline Features in Emerging Adulthood: Rejection Sensitivity as a Mechanism of Influence.

Borderline personality disorder (BPD) is a severe psychiatric disorder first diagnosed in adolescence or emerging adulthood, which develops in part in the context of early attachment relationships. We tested a cross-sectional model linking caregiver disruptions during childhood, current parental attachment, and rejection sensitivity, to borderline features in 2,546 emerging adult college students. A structural equation model revealed that childhood caregiver disruptions were associated with lower quality adult parental attachment. Moreover, rejection sensitivity mediated the relationship between adult parental attachment and borderline features. Results suggest a representational model of others as rejecting links early disruptions in caregiving relationships and attachment insecurity, to borderline features in emerging adulthood. Implications for practice are discussed, including for means of targeting cognitive schemas related to rejection sensitivity, which could lead to reductions in BPD symptoms.

Early disturbance of dynamic synchronization and neurovascular coupling in cognitively normal Parkinson’s disease

Pathological process in Parkinson’s disease (PD) is accompanied with functional and metabolic alterations. The time-varying properties of functional coherence and their coupling to regional perfusion are still rarely elucidated. To investigate early disruption of dynamic regional homogeneity (dReho) and neurovascular coupling in cognitively normal PD patients, dynamic neuronal synchronization and regional perfusion were measured using dReho and cerebral blood flow (CBF), respectively. Neurovascular coupling was assessed by CBF-ReHo correlation coefficient and CBF/ReHo ratio. Multivariate pattern analysis was conducted for the differentiating ability of each feature. Relative to healthy controls (HC) subjects, PD patients demonstrated increased dReho in middle temporal gyrus (MTG), rectus gyrus, middle occipital gyrus, and precuneus, whereas reduced dReho in putamen and supplementary motor area (SMA); while higher CBF/dReho ratio was located in putamen, SMA, paracentral lobule, and postcentral gyrus, whereas lower CBF/dReho ratio in superior temporal gyrus, MTG, precuneus, and angular gyrus (AG). Global and regional CBF-Reho decoupling were both observed in PD groups. The CBF/Reho ratio features achieved more powerful classification performance than other features. From the view of dynamic neural synchronization and neurovascular coupling, this study reinforced the insights into neural basis underlying PD and the potential role in the disease diagnosis and differentiation.

A systematic search for galaxy protocluster cores at the transition epoch of their star formation activity

ABSTRACT The redshift of z ∼ 1.5 is the transition epoch of protoclusters (PCs) from the star-forming phase into the quenching phase, and hence an appropriate era to investigate the build up of the quenched population. We define a ‘core’ as the most massive halo in a given PC, where environmental effects are likely to work most effectively, and search for cores at 1 &amp;lt; z &amp;lt; 1.5. We use a photometric redshift catalogue of a wide (effective area of ${\sim}22.2\, \mathrm{deg}^{2}$) and deep ($i\sim 26.8\, \mathrm{mag}$) optical survey with Subaru Hyper-Suprime Cam. Regarding galaxies with log (M*/M⊙) &amp;gt; 11.3 as the central galaxies of PC cores, we estimate their average halo mass by clustering analysis and find it to be log (Mh/M⊙) ∼ 13.7. An expected mass growth by the IllustrisTNG simulation and the observed overdensities around them suggest that the PC cores we find are progenitors of present-day clusters. Classifying our galaxy sample into red and blue galaxies, we calculate the stellar mass function (SMF) and the red galaxy fraction. The SMFs in the PC cores are more-top heavy than field, implying early high-mass galaxy formation and disruption of low-mass galaxies. We also find that the red fraction increases with stellar mass, consistent with stellar mass dependent environmental quenching recently found at z &amp;gt; 1. Interestingly, although the cores with red and blue centrals have similar halo masses, only those with red centrals show a significant red fraction excess compared to the field, suggesting a conformity effect. Some observational features of PC cores may imply that the conformity is caused by assembly bias.

Altered excitatory and decreased inhibitory transmission in the prefrontal cortex of male mice with early developmental disruption to the ventral hippocampus.

Ventral hippocampal (vHPC)-prefrontal cortical (PFC) pathway dysfunction is a core neuroimaging feature of schizophrenia. However, mechanisms underlying impaired connectivity within this pathway remain poorly understood. The vHPC has direct projections to the PFC that help shape its maturation. Here, we wanted to investigate the effects of early developmental vHPC perturbations on long-term functional PFC organization. Using whole-cell recordings to assess PFC cellular activity in transgenic male mouse lines, we show early developmental disconnection of vHPC inputs, by excitotoxic lesion or cell-specific ablations, impairs pyramidal cell firing output and produces a persistent increase in excitatory and decrease in inhibitory synaptic inputs onto pyramidal cells. We show this effect is specific to excitatory vHPC projection cell ablation. We further identify PV-interneurons as a source of deficit in inhibitory transmission. We find PV-interneurons are reduced in density, show a reduced ability to sustain high-frequency firing, and show deficits in excitatory inputs that emerge over time. We additionally show differences in vulnerabilities to early developmental vHPC disconnection, wherein PFC PV-interneurons but not pyramidal cells show deficits in NMDA receptor-mediated current. Our results highlight mechanisms by which the PFC adapts to early developmental vHPC perturbations, providing insights into schizophrenia circuit pathology.

Tungsten and molybdenum isotopic evidence for an impact origin of pallasites

The origin of pallasites—stony-iron meteorites mainly composed of olivine and Fe-Ni metal—is debated and proposed formation scenarios broadly range from models that explain pallasite formation by internal processes in the mantle of a differentiated planetesimal to those that involve impact–induced mixing of core and mantle materials. Here, the origin of pallasites is examined by studying the nebular source regions of their precursor material using Mo isotopes and their history of metal-silicate segregation using Hf-W chronometry. We report new Mo and W isotopic data for a large suite of pallasite metal samples, alongside Pt isotope data to quantify superimposed cosmic ray exposure effects. Most main-group pallasites exhibit uniform pre-exposure 182W and Mo isotopic compositions that bear an excellent similarity to those of IIIAB iron meteorites. Four main-group pallasites and the IIIAB iron Thunda have more radiogenic pre-exposure 182W compositions, but display the same Mo isotopic composition as other main-group pallasites and IIIAB irons. This strong chronological and genetic link strongly suggests that main-group pallasite metal originated in the IIIAB parent body core. This, combined with prior Pd-Ag chronometric evidence for an early collisional disruption of the IIIAB parent body, implies that main-group pallasites formed by impact–induced mixing of metal and silicates rather than by an internal process on the IIIAB parent body. This mixing led to elevated 182W compositions in some pallasites, which are best accounted for by partial re-equilibration of IIIAB metal with radiogenic 182W from the colliding body. Collectively, our results support models that explain main-group pallasite formation by injection of pallasite metal into the mantle of another differentiated body, implying that pallasite silicates did not primarily derive from the IIIAB mantle, but instead from that of the colliding body.

Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes

Usher syndrome (USH) is the most common form of monogenic deaf‐blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin‐encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis, and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Fibroblasts from USH1C pigs or USH1C patients showed significantly elongated primary cilia, confirming USH as a true and general ciliopathy. Primary cells also proved their capacity for assessing the therapeutic potential of CRISPR/Cas‐mediated gene repair or gene therapy in vitro. AAV‐based delivery of harmonin into the eye of USH1C pigs indicated therapeutic efficacy in vivo.

Advanced Brain Imaging in Preterm Infants: A Narrative Review of Microstructural and Connectomic Disruption.

Preterm birth disrupts the in utero environment, preventing the brain from fully developing, thereby causing later cognitive and behavioral disorders. Such cerebral alteration occurs beneath an anatomical scale, and is therefore undetectable by conventional imagery. Prematurity impairs the microstructure and thus the histological process responsible for the maturation, including the myelination. Cerebral MRI diffusion tensor imaging sequences, based on water’s motion into the brain, allows a representation of this maturation process. Similarly, the brain’s connections become disorganized. The connectome gathers structural and anatomical white matter fibers, as well as functional networks referring to remote brain regions connected one over another. Structural and functional connectivity is illustrated by tractography and functional MRI, respectively. Their organizations consist of core nodes connected by edges. This basic distribution is already established in the fetal brain. It evolves greatly over time but is compromised by prematurity. Finally, cerebral plasticity is nurtured by a lifetime experience at microstructural and macrostructural scales. A preterm birth causes a negative and early disruption, though it can be partly mitigated by positive stimuli based on developmental neonatal care.