Predominantly antibody deficiency (PAD) is the most prevalent form of human inborn errors of immunity (IEI). PAD is characterized by recurrent bacterial infections, immune dysregulation, and impaired immunoglobulin production. A monogenic cause of PAD can be identified in about 20% of cases. Approximately 10% of patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 13B gene (TNFRSF13B), encoding the B cell surface protein TACI. Heterozygous variants in TNFRSF13B are not sufficient to cause PAD, as approximately 1% of the healthy population carries one of these variants. To identify additional genetic contributors to the immune defect in these individuals, we examined the exomes of 161 PAD patients with rare-damaging variants in TNFRSF13B. We identified (i) biallelic mutations in TNFRSF13B, (ii) the HLA-class II marker (DPA1*03), and (iii) multiple single nucleotide polymorphisms in known B-cell related genes, as additional genetic risk factors. Moreover, pathogenic mutations in other known IEI genes were presented in 16% of patients with heterozygous TNFRSF13B variants.

Early studies on orientation selectivity in the visual cortex have suggested that sensory systems generate new feature representations at specific processing stages. Many observations challenge this view, but in the absence of systematic, multistage measurements, the logic of how feature tuning emerges remains elusive. Here, using a generic approach based on representational similarity analysis with a noise-corrected population metric, we demonstrate in the mouse auditory system that feature representations evolve gradually with, in some cases, major, feature-specific improvements at particular stages. We observe that single frequency tuning is already fully developed in the cochlear nucleus, the first stage of processing, while tuning to higher-order features improves up to the auditory cortex, with major steps in the inferior colliculus for amplitude modulation frequency or noise bandwidth tuning and in the cortex for frequency modulation direction and for complex sound identity or direction. Moreover, we observe that intensity tuning is established in a feature-dependent manner, earlier for pure frequencies than for more complex sounds. This indicates that auditory feature computations are a mix of stepwise and gradual processes which together contribute to decorrelate sound representations.

Signatures of consciousness are found in spectral and temporal properties of neuronal activity. Among these, spatiotemporal complexity after a perturbation has recently emerged as a robust metric to infer levels of consciousness. Perturbation paradigms remain, however, difficult to perform routinely. To discover alternative paradigms and metrics, we systematically explore brain stimulation and resting-state activity in a whole-brain model. We find that perturbational complexity only occurs when the brain model operates within a specific dynamical regime, in which spontaneous activity produces a large degree of functional network reorganizations referred to as being fluid. The regime of high brain fluidity is characterized by a small battery of metrics drawn from dynamical systems theory and predicts the impact of consciousness-altering drugs (Xenon, Propofol, and Ketamine). We validate the predictions in a cohort of 15 subjects at various stages of consciousness and demonstrate their agreement with previously reported perturbational complexity, but in a more accessible paradigm. Beyond the facilitation in clinical use, the metrics highlight complexity properties of brain dynamics in support of the emergence of consciousness.

During cortical development, oligodendrocyte precursor (OPC) attachment and detachment to microvessels play a crucial role in their positioning and differentiation. In the developing brain, endothelial cells are regionally diverse, and previous studies showed a peak in cortical endothelial NMDA receptor (eNMDAR) expression during perinatal life, coinciding with OPC migration along microvessels. This raises the hypothesis that eNMDAR might influence the fate of vessel-associated OPC. In this study, a Grin1lox/lox/VeCadCre mouse model was used to investigate in females and males the effects of endothelial GluN1 invalidation (eNMDAR-/-) on (1) positioning and differentiation of cortical oligodendrocytes and myelination, (2) OPC/microvessel association and endothelial MMP9-like activity, and (3) motor activity. Results showed that, from postnatal days (P) 2 to P15, PDGFRα expression was increased in eNMDAR-/- mice and returned to wild-type levels by P45. CNPase and MBP expression was reduced at P15 and remained low in adult eNMDAR-/- mice. Histological analysis revealed no change in OPC-microvessel association, but positioning was altered with increased density in layers VI and V at P15. Myelination was impaired, as evidenced by thinner corpus callosum, reduced myelin sheath thickness, and higher g-ratio. Axonal mitochondria density was significantly increased. Functional tests revealed that glutamate could not stimulate endothelial MMP9-like activity in eNMDAR-/- mice. Molecular, histological and functional changes were linked to sensorimotor disabilities. At P45, despite the absence of observable myelination defects, locomotor impairments persisted, suggesting that early OPC differentiation disruption contributes to lasting motor dysfunction. These findings offer new insights into OPC vulnerability in human preterm infants.

In cancer cells, ATR signaling is crucial to tolerate the intrinsically high damage levels that normally block replication fork progression. Assembly of TopBP1, a multifunctional scaffolding protein, into condensates is required to amplify ATR kinase activity to the levels needed to coordinate the DNA damage response and manage DNA replication stress. Many ATR inhibitors are tested for cancer treatment in clinical trials, but their overall effectiveness is often compromised by the emergence of resistance and toxicities. In this proof-of-concept study, we propose to disrupt the ATR pathway by targeting TopBP1 condensation. First, we screened a molecule-based library using a previously developed optogenetic approach and identified several TopBP1 condensation inhibitors. Among them, AZD2858 disrupted TopBP1 assembly induced by the clinically relevant topoisomerase I inhibitor SN-38, thereby inhibiting the ATR/Chk1 signaling pathway. We found that AZD2858 exerted its effects by disrupting TopBP1 self-interaction and binding to ATR in mammalian cells, and by increasing its chromatin recruitment in cell-free Xenopus laevis egg extracts. Moreover, AZD2858 prevented S-phase checkpoint induction by SN-38, leading to increased DNA damage and apoptosis in a colorectal cancer cell line. Lastly, AZD2858 showed a synergistic effect in combination with the FOLFIRI chemotherapy regimen in a spheroid model of colorectal cancer.