The rockefeller university

Oxytocin, an evolutionarily conserved neuropeptide, plays a crucial role in various physiological and behavioural processes, offering potential therapeutic benefits for several psychiatric and neurodevelopmental conditions. Despite its promise, oxytocin research has been marked by inconsistent results concerning its therapeutic applications and underlying mechanisms. Performing a systematic review and meta-analysis is a popular approach to shed light on mixed findings in a body of literature; however, they can become quickly outdated as new evidence becomes available. Given these challenges, research on the links between oxytocin and biobehavioural outcomes is ideally positioned for the adoption of 'living' meta-analyses, which allow for the continuous integration of new data and updated conclusions. Here we introduce the Active Monitoring of Oxytocin Research Evidence (AMORE) platform (https://amore-project.org), which is a hub that aggregates articles and materials associated with living meta-analyses for biobehavioural oxytocin research in humans. Developed through consensus among 24 expert researchers, a standardized framework was established that either requires or recommends practices ensuring transparency and rigor in living meta-analyses featured on the AMORE platform. Overall, AMORE has been designed to advance human oxytocin biobehavioural research by the timely integration of emerging evidence through transparent living meta-analyses. To date, two living meta-analysis projects at different stages of publication are hosted on AMORE, demonstrating the platform's practical application.

The complement system is a central component of innate and shaping adaptive responses. Deficiencies in complement proteins, whether inherited or acquired, predispose to severe infections, particularly with encapsulated bacteria such as Neisseria meningitidis and Streptococcus pneumoniae. Although rare, inherited defects affect different pathways and may also present with autoimmune or renal diseases. Diagnosis relies on functional and quantitative assays, especially in patients with earlyonset or recurrent infections. Complement inhibition, introduced with eculizumab and expanded to agents targeting C3, Factor B, or Factor D, has transformed the management of complement-mediated disorders but unmasked novel infectious risks, including meningococcal disease and invasive fungal infections.

Immunodeficient mice, particularly the NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) strain and other non-obese diabetic (NOD)-derived lines are widely used in biomedical research due to their profound immunosuppression, which enables stable engraftment of human cells and tissues with minimal rejection. Despite their broad utility, these models exhibit unique immunologic and anatomic features and are predisposed to infectious and noninfectious diseases that may confound experimental outcomes and limit translational relevance. This review summarizes current knowledge on spontaneous, infectious, and experimentally induced lesions in NSG and related strains. These mice characteristically display hypoplastic lymphoid organs, including the spleen, thymus, and lymph nodes, due to a near-complete absence of lymphocytes. Spontaneous background lesions include splenic osseous metaplasia, neurodegeneration, pancreatic mastocytosis, cochlear degeneration, intervertebral disk disease, skull hyperostosis, and pancreatic duct cysts, among others. Common spontaneous neoplasms include lymphomas, osteosarcomas, and mammary gland tumors. Due to their immunodeficient status, NSG and NOD-derived mice are also highly susceptible to opportunistic infections, such as Corynebacterium bovis, Chlamydia muridarum, Clostridioides difficile, and mouse kidney parvovirus. In humanized models, engraftment of human immune cells can result in distinctive syndromes, including xenogeneic graft-versus-host disease, post-transplant lymphoproliferative disorders, and chimeric myeloid cell hyperactivation syndrome, which can impact study outcomes and lead to mortality and morbidity. This review is intended as a resource for comparative pathologists to become familiar with these widely used immunodeficient mice, so they can interpret strain-specific lesions and recognize experimental confounders in these mouse models.

Eukaryotic ribosomal small subunit (SSU) assembly requires the SSU processome, a nucleolar precursor containing the RNA chaperone U3 small nucleolar RNA (snoRNA). The underlying molecular mechanisms of SSU processome maturation, remodelling, disassembly and RNA quality control, and the transitions between states remain unknown owing to a paucity of intermediates1, 2-3. Here we report 16 native SSU processome structures alongside genetic data, revealing how two helicases, the Mtr4-exosome and Dhr1, are controlled for accurate and unidirectional ribosome biogenesis. Our data show how irreversible pre-ribosomal RNA degradation by the redundantly tethered RNA exosome couples the transformation of the SSU processome into a pre-40S particle, during which Utp14 can probe evolving surfaces, ultimately positioning and activating Dhr1 to unwind the U3 snoRNA and initiate nucleolar pre-40S release. This study highlights a paradigm for large dynamic RNA-protein complexes in which irreversible RNA degradation drives compositional changes and communicates these changes to govern enzyme activity while maintaining overall quality control.

Antibodies play a crucial role in adaptive immunity. They develop as B cell receptors (BCRs): membrane-bound forms of antibodies that are expressed on the surfaces of B cells. BCRs are refined through affinity maturation, a process of somatic hypermutation (SHM) and natural selection, to improve binding to an antigen. Computational models of affinity maturation have developed from two main perspectives: molecular evolution and language modeling. The molecular evolution perspective focuses on nucleotide sequence context to describe mutation and selection; the language modeling perspective involves learning patterns from large data sets of protein sequences. In this paper, we compared models from both perspectives on their ability to predict the course of antibody affinity maturation along phylogenetic trees of BCR sequences. This included models of SHM, models of SHM combined with an estimate of selection, and protein language models. We evaluated these models for large human BCR repertoire data sets, as well as an antigen-specific mouse experiment with a pre-rearranged cognate naive antibody. We demonstrated that precise modeling of SHM, which requires the nucleotide context, provides a substantial amount of predictive power for predicting the course of affinity maturation. Notably, a simple nucleotide-based convolutional neural network modeling SHM outperformed state-of-the-art protein language models, including one trained exclusively on antibody sequences. Furthermore, incorporating estimates of selection based on a custom deep mutational scanning experiment brought only modest improvement in predictive power. To support further research, we introduce EPAM (Evaluating Predictions of Affinity Maturation), a benchmarking framework to integrate evolutionary principles with advances in language modeling, offering a road map for understanding antibody evolution and improving predictive models.

Avian influenza A virus (IAV) H5N1 is an emerging threat of human pandemic. We describe a 71-year-old man who died of H5N1 pneumonia in Louisiana and whose blood contained autoantibodies neutralizing type I IFNs (AAN-I-IFNs), including the 12 IFN-alpha subtypes (1-10 ng/ml) and IFN-omega (100 pg/ml). Causality between these AAN-I-IFN and lethal outcome of avian influenza in this patient is based on (1) our previous report that AA-I-IFN underlie about 5% of cases of critical pneumonia triggered by seasonal influenza viruses in three cohorts, (2) the rarity of this combination of AAN-I-FNs in individuals over 70 years old (<1%), and (3) the rarity of lethal avian influenza among infected individuals (<1%). AAN-I-IFNs underlie a growing number of severe viral diseases, from arboviral encephalitis to viral pneumonia, particularly in the elderly. This case suggests they can also underlie life-threatening avian H5N1 influenza. The presence of AAN-I-IFN may facilitate infection, replication, and adaptation of zoonotic IAVs to humans and, therefore, human-to-human transmission.

The dominant approach to the study of living systems in the 20th century into today has been that of a reductionist approach focused on genetics and biochemistry. The hunt for genes and the elucidation of their biochemical outputs has organized funding in research, educational curricula, academic promotion, and the distribution of prestige through awards. Such reductionism has gone hand in hand with an ontology of the machine. We will discuss how viewing life as if it emanated from a set of molecular machines is the main bottleneck in addressing key questions in biology. We will discuss how moving beyond it is not contingent on new technologies but rather a refreshed perspective of life that can be termed "organic". Furthermore, we suggest that the study of how form arises, morphogenesis, is the key to an organic renewal of biology and biomedicine. Although morphogenesis is currently seen as a subsidiary branch of developmental biology as well as the consequence of molecular patterning processes at the subcellular scale, we will argue that morphology and its self-organizing capacity at the supracellular scale is the fundamental nexus in embryonic development as well as disease. We see the inability to appreciate form through an organic supracellular perspective as the principal bottleneck for making inroads into health issues such as cancer and the chronic disease epidemic.

The autosomal recessive form of hyperimmunoglobulin E syndrome (AR-HIES), caused by mutations in the DOCK8 (Dedicator of Cytokinesis 8) gene, presents a wide range of clinical manifestations and phenotypically overlaps with several types of combined immunodeficiency disorders characterized by elevated serum IgE levels. Due to the high rates of morbidity and mortality, as well as the potential curability through hematopoietic stem cell transplantation (HSCT), early and accurate differential diagnosis of this syndrome is crucial for optimal management and improved prognosis. Flow cytometry tests can be beneficial for early diagnosis of many inborn errors of immunity (IEIs), including this syndrome. This study, conducted for the first time on Iranian patients, investigated the expression of the DOCK8 protein. DOCK8 expression was assessed by flow cytometry in 14 patients (6 males and 8 females) with a clinical diagnosis of DOCK8 deficiency. The diagnosis was ultimately confirmed through genetic testing. The results showed that DOCK8 expression in patients was significantly lower compared to the healthy control group.Flow cytometric evaluation of DOCK8 protein expression offers a rapid and efficient diagnostic method with a sensitive detection range suitable for many cases. This approach can facilitate the diagnosis of DOCK8 deficiency, thereby enabling timely and effective disease management.

Nuclear pore complexes (NPCs) mediate selective exchange of macromolecules between the nucleus and cytoplasm, but the organization of their transport barrier has been a matter of debate. Here we used high-speed atomic force microscopy, complemented with orthogonal in vitro and in vivo approaches, to probe the dynamic behaviour of the NPC central channel at millisecond resolution. We found that nuclear transport factors dynamically remodel intrinsically disordered phenylalanine-glycine (FG) domains tethered within the NPC channel, partitioning the barrier into two zones: a rapidly fluctuating annular region and a highly mobile central plug. Increased FG-repeat density in mutant NPCs dampened barrier dynamics and impaired transport. Notably, NPC-like behaviour was recapitulated in DNA origami nanopores bearing transport factors and correctly tethered FG domains but not in in vitro FG hydrogels. Thus, the rotationally symmetric architecture of NPCs supports a nanoscopic barrier organization that contrasts with many of the bulk properties of in vitro FG-domain assemblies.