The rockefeller university

Purpose CTLA4 deficiency is an inborn error of immunity (IEI) due to heterozygosity for germline loss-of-function variants of the CTLA4 gene located on chromosome 2q33.2. CTLA4 deficiency underlies pleiotropic immune and lymphoproliferation-mediated features with incomplete penetrance. It has been identified in hundreds of patients but copy number variants (CNVs) have been reported in only 12 kindreds, including nine which displayed large 2q33.1-2q33.2 deletions encompassing CTLA4. Methods We conducted a nationwide study in France to identify patients with 2q33 deletions encompassing CTLA4. We investigated the clinical and immunological phenotypes and genotypes of these patients. Results We identified 12 patients across six unrelated kindreds with clinical immunodeficiency. Neurological features were recorded in three patients, including one with syndromic neurodevelopmental disorder. Single- nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) array analysis, and targeted high-throughput sequencing revealed five different heterozygous 2q33 deletions of 26 kilobases to 7.12 megabases in size and encompassing one to 41 genes. We identified a contiguous gene syndrome (CGS) due to associated KLF7 deficiency in a kindred with a neurodevelopmental phenotype. Conclusion Deletions within the 2q33 region encompassing CTLA4 are rare and not extensively explored, and are probably underdiagnosed in cytogenetic practice. A literature review identified 14 different CGS loci including at least one gene responsible for an IEI. The deletions involved in IEIs should be systematically delimited, to facilitate screening for CGS.

The alpha V beta 3 receptor is a member of the integrin family of receptors, which includes 24 members involved in a variety of key biological processes. It is widely expressed in multiple cell types and is involved in cell adhesion and migration, angiogenesis and immune cell regulation. These processes play important roles in both normal placentation and placental progression through pregnancy. This review describes the potential roles of alpha V beta 3 integrin receptor throughout gestation in normal and abnormal conditions, and the need for additional studies to better define its precise contributions.

Dystocia, a common murine reproductive condition, is classified as either obstructive, a result of fetal factors such as an oversized fetus, or functional, a result of dam factors such as advanced age. Treatment is based on the dam's clinical condition and the underlying etiology, but usually requires euthanasia. A prospective study was conducted to characterize the etiology of murine dystocia to determine if treatment is warranted. The signalment and experimental, clinical, and breeding histories were obtained, and a targeted serum chemistry panel, radiographs, and a gross necropsy were conducted on mice presenting with clinical signs consistent with dystocia. Obstructive dystocia was diagnosed if the pelvic canal width was less than the diameter of the fetal head closest to the cervix or a fetus was lodged in the pelvic canal. Functional dystocia was diagnosed based on clinicopathologic abnormalities. A total of 54 mice were evaluated over 7 mo with 45/54 (83%) confirmed to have dystocia with the remaining 9 (17%) having other reproductive abnormalities. Of the confirmed cases, 27/45 (60%) were C57BL/6 or on a C57BL/6 background, and the average age at presentation was 181 +/- 85 d. The number of mice categorized as having an obstructive (n = 16) compared with a functional (n = 11) dystocia was not significantly different than those in which the definitive category could not be ascertained (n = 18). Neither clinical signs nor clinical pathology were significantly different between mice categorized as having an obstructive compared with a functional dystocia. Hunched posture, lethargy, and vaginal discharge were the most common presentation. Azotemia (BUN: 66.6 +/- 10.2 mg/dL, mean +/- SE), hypoglycemia (96.11 +/- 8.5 mg/dL), and hyperglobulinemia (3.13 +/- 0.14 mg/dL) were common. Differentiating obstructive from functional dystocia could not be determined cageside with strong confidence.

Across species, a major axis of variation in social behaviour relates to how offspring are reared. Parental care behaviours have independently evolved in hundreds of animal lineages. Care is usually limited to one or both parents, but in some lineages parenting is a highly cooperative endeavour. In social insects, for example, entire societies have evolved around parenting, complete with distinct adult morphs that specialize in reproduction, nursing, foraging and defence. Recent advances in omic technologies have enabled data collection across diverse taxa, revealing broad patterns in the molecular regulation of parental behaviour. These studies indicate that evolution has systematically co-opted molecular machinery that pleiotropically regulates three deeply interlinked biological processes: feeding, growth and reproduction. Where more sophisticated social systems have evolved, the same factors have been further co-opted to additionally regulate the developmental differentiation of distinct morphs, division of labour between adults and behavioural changes associated with ageing. These findings suggest that complex behaviours evolve through repeated and predictable co-option of ancient molecular systems.

Transcription elongation by RNA polymerase II (Pol II) is an integral step in eukaryotic gene expression. The speed of Pol II is controlled by a multitude of elongation factors, but the exact regulatory mechanisms remain incompletely understood, especially for higher eukaryotes. Here we develop a single-molecule platform to visualize the dynamics of individual mammalian transcription elongation complexes (ECs) reconstituted from purified proteins. This platform allows us to follow the elongation and pausing behavior of EC in real time and unambiguously determine the role of each elongation factor in the kinetic control of Pol II. We find that the mammalian EC harbors multiple speed gears dictated by its associated factors and phosphorylation status. Moreover, the elongation factors are not functionally redundant but act hierarchically and synergistically to achieve optimal elongation activity. We propose that such elaborate kinetic regulation underlies the major speed-changing events during the transcription cycle and enables cells to adapt to a changing environment.

ObjectiveSystemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. Although previous studies have highlighted the presence of functional autoantibodies targeting the angiotensin II receptor type 1 (AT1) and endothelin-1 type A receptor (ETAR), leading to autoantibody-mediated receptor stimulation and subsequent activation of endothelial cells (ECs), a comprehensive understanding of the direct interaction between these autoantibodies and their receptors is currently lacking. Moreover, existing data confirming the presence of these autoantibodies in SSc often rely on similar methodologies and assays. Our aim was to replicate previous findings and to investigate the functional effects of IgG derived from patients with SSc (SSc IgG) on AT1 and ETAR signaling, the downstream EC response, and the presence of AT1-binding autoantibodies in circulation.MethodsQuantitative polymerase chain reaction and cytokine enzyme-linked immunosorbent assay, alongside a real-time cell analyzer, were used to assess receptor-specific functional characteristics of purified SSc IgG (n = 18). Additionally, a novel protein capture assay using solubilized epitope-tagged AT1 was developed to detect AT1-binding autoantibodies in plasma samples from patients with SSc (n = 28) and healthy donors (n = 14).ResultsNo evidence for EC activation in an AT1- or ETAR-dependent manner was revealed. Furthermore, stimulation with SSc IgG did not induce receptor activation or alter G protein-coupled receptor signaling on agonist stimulation in a model with receptor overexpression. Lastly, no AT1-binding autoantibodies were detected in plasma samples from patients with SSc when using epitope-tagged solubilized AT1.ConclusionOverall, our study did not provide evidence to support the presence of AT1- or ETAR-activating autoantibodies in purified SSc IgG or AT1-binding autoantibodies in the circulation of patients with SSc.

In the arboviral vector Aedes aegypti, adaptation to anthropogenic environments has led to a major evolutionary shift separating the domestic Aedes aegypti aegypti (Aaa) ecotype from the wild Aedes aegypti formosus (Aaf) ecotype. Aaa mosquitoes are distributed globally and have higher vectorial capacity than Aaf, which remained in Africa. Despite the evolutionary and epidemiological relevance of this separation, inconsistent morphological data and a complex population structure have hindered the identification of genomic signals distinguishing the two ecotypes. Here we assessed the correspondence between the geographic distribution, population structure and genome-wide selection of 511 Aaf and 123 Aaa specimens and report adaptive signals in 186 genes that we call Aaa molecular signatures. Our results indicate that Aaa molecular signatures arose from standing variation associated with extensive ancestral polymorphisms in Aaf populations and have been co-opted for self-domestication through genomic and functional redundancy and local adaptation. Overall, we show that the behavioural shift of Ae. aegypti mosquitoes to live in association with humans relied on the fine regulation of chemosensory, neuronal and metabolic functions, as seen in the domestication processes of rabbits and silkworms. Our results also provide a foundation for the investigation of new genic targets for the control of Ae. aegypti populations.

Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.

Background A thorough analysis of genome evolution is fundamental for biodiversity understanding. The iconic monotremes (platypus and echidna) feature extraordinary biology. However, they also exhibit rearrangements in several chromosomes, especially in the sex chromosome chain. Therefore, the lack of a chromosome-level echidna genome has limited insights into genome evolution in monotremes, in particular the multiple sex chromosomes complex.Results Here, we present a new long reads-based chromosome-level short-beaked echidna (Tachyglossus aculeatus) genome, which allowed the inference of chromosomal rearrangements in the monotreme ancestor (2n = 64) and each extant species. Analysis of the more complete sex chromosomes uncovered homology between 1 Y chromosome and multiple X chromosomes, suggesting that it is the ancestral X that has undergone reciprocal translocation with ancestral autosomes to form the complex. We also identified dozens of ampliconic genes on the sex chromosomes, with several ancestral ones expressed during male meiosis, suggesting selective constraints in pairing the multiple sex chromosomes.Conclusion The new echidna genome provides an important basis for further study of the unique biology and conservation of this species.

We studied a family with three male individuals across two generations affected by common variable immune deficiency (CVID). We identified a novel missense heterozygous variant (c.2602T>A:p.Y868N) of NFKB2 in all patients and not in healthy relatives. Functional studies of the mutant allele in an overexpression system and of the patients' cells confirmed the deleteriousness of the NFKB2 variant and genotype, respectively, on the activation of the non-canonical NF-kappa B signaling pathway. Impaired processing of p100 into p52 underlies p100 accumulation, which results in gain-of-function (GOF) of I kappa B delta inhibitory activity and loss-of-function (LOF) of p52 transcriptional activity. The three patients' plasma contained autoantibodies that neutralized IFN-alpha 2 and/or IFN-omega, accounting for the severe or recurrent viral diseases of the patients, including influenza pneumonia in one sibling, and severe COVID-19 and recurrent herpes labialis in another. Our results confirm that NFKB2 alleles that are I kappa B delta GOF and p52 LOF can underlie CVID and drive the production of autoantibodies neutralizing type I IFNs, thereby predisposing to severe viral diseases.