Maternal immune activation (MIA) and poor maternal nutritional habits are risk factors for the occurrence of neurodevelopmental disorders (NDD). Human studies show the deleterious impact of prenatal ...inflammation and low n-3 polyunsaturated fatty acid (PUFA) intake on neurodevelopment with long-lasting consequences on behavior. However, the mechanisms linking maternal nutritional status to MIA are still unclear, despite their relevance to the etiology of NDD. We demonstrate here that low maternal n-3 PUFA intake worsens MIA-induced early gut dysfunction, including modification of gut microbiota composition and higher local inflammatory reactivity. These deficits correlate with alterations of microglia-neuron crosstalk pathways and have long-lasting effects, both at transcriptional and behavioral levels. This work highlights the perinatal period as a critical time window, especially regarding the role of the gut-brain axis in neurodevelopment, elucidating the link between MIA, poor nutritional habits, and NDD.
Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an ...attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7-12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
Quantum-correlated ψ(3770)→DD‾ decays collected by the CLEO-c experiment are used to perform a first measurement of F+4π, the fractional CP-even content of the self-conjugate decay D→π+π−π+π−, ...obtaining a value of 0.737±0.028. An important input to the measurement comes from the use of D→KS0π+π− and D→KL0π+π− decays to tag the signal mode. This same technique is applied to the channels D→π+π−π0 and D→K+K−π0, yielding F+πππ0=1.014±0.045±0.022 and F+KKπ0=0.734±0.106±0.054, where the first uncertainty is statistical and the second systematic. These measurements are consistent with those of an earlier analysis, based on CP-eigenstate tags, and can be combined to give values of F+πππ0=0.973±0.017 and F+KKπ0=0.732±0.055. The results will enable the three modes to be included in a model-independent manner in measurements of the unitarity triangle angle γ using B∓→DK∓ decays, and in time-dependent studies of CP violation and mixing in the D0D‾0 system.
SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal ...striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl−/− murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl−/− zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.
X chromosome-linked immunodeficiency with hyper-IgM (HIGM1, MIM number 308230) is a rare disorder characterized by recurrent bacterial infections, very low or absent IgG, IgA and IgE, and normal to ...increased IgM and IgD serum levels. HIGM1 has been suggested to result from ineffective T-cell help for B cells. We and others have identified a novel, TNF-related activation protein (TRAP) that is exclusively expressed on the surface of stimulated T cells. TRAP, a type II transmembrane protein of M(r) 33,000, is the physiological ligand for CD40 (refs 5-8). Crosslinking of CD40 on B cells induces, in the presence of lymphokines, immunoglobulin class switching from IgM to IgG, IgA or IgE. Mapping of the TRAP gene to the X-chromosomal location q26.3-q27.1 (ref. 6) suggested a causal relationship to HIGM1, which had previously been assigned to Xq26 (refs 12-14). Here we present evidence that point mutations in the TRAP gene give rise to nonfunctional or defective expression of TRAP on the surface of T cells in patients with HIGM1. The resultant failure of TRAP to interact with CD40 on functionally intact B cells is responsible for the observed immunoglobulin isotype defect in HIGM1.
Measurements of the coherence factors (RKππ0 and RK3π) and the average strong-phase differences (δDKππ0 and δDK3π) for the decays D0→K−π+π0 and D0→K−π+π+π− are presented. These parameters are ...important inputs to the determination of the unitarity triangle angle γ in B∓→DK∓ decays, where D designates a D0 or D¯0 meson decaying to a common final state. The measurements are made using quantum correlated DD¯ decays collected by the CLEO-c experiment at the ψ(3770) resonance, and augment a previously published analysis by the inclusion of new events in which the signal decay is tagged by the mode D→KS0π+π−. The measurements also benefit from improved knowledge of external inputs, namely the D0D¯0 mixing parameters, rDKπ and several D-meson branching fractions. The measured values are RKππ0=0.82±0.07, δDKππ0=(164−14+20)°, RK3π=0.32−0.28+0.20 and δDK3π=(225−78+21)°. Consideration is given to how these measurements can be improved further by using the larger quantum-correlated data set collected by BESIII.
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