The rockefeller university

Ervin Bauer (1890-1938) outlined the paradigm of theoretical biology in his monograph "Fundamental Principles of Biology as Pure Natural Science and their Applications in Physiology and Pathology" (1920) and further developed these ideas in his book "Theoretical Biology" (1935). In these works, he defined the foundations of theoretical biology from the perspective of biophysics and bioenergetics, formulated the principle of a sustainable non-equilibrium state, which is continuously maintained by all biological systems throughout their life, and developed original views on cell differentiation, adaptation, and evolution. In 1938, Ervin Bauer and his wife Stefania became the victims of Stalin's Great Terror. The book of 1920 was published in German. It outlines the main principles of Bauer's concept. Bauer's magnum opus "Theoretical Biology" (1935) was published in Russian and republished in 1967 in Hungarian (together with the monograph of 1920) and several times in Russian. Immediately after the Russian edition appeared, two chapters were also published in German translation. Only small excerpts of the book were published in English translation. Here we present a complete English translation of both books. The books contain many important ideas that remain actual today and have great potential for further development in modern concepts of the foundations of life, the structure of living matter, and evolution.

Fanconi anemia (FA) is a rare genetic disease characterized by loss-of-function variants in any of the 22 previously identified genes (FANCA-FANCW) that encode proteins participating in the repair of DNA interstrand crosslinks (ICLs). Patient phenotypes are variable but may include developmental abnormalities, early-onset pancytopenia, and a predisposition to hematologic and solid tumors. Here, we describe 2 unrelated families with multiple pregnancy losses and offspring presenting with severe developmental and hematologic abnormalities leading to death in utero or in early life. Homozygous loss-of-function variants in FAAP100 were identified in affected children of both families. The FAAP100 protein associates with FANCB and FANCL, the E3 ubiquitin ligase responsible for the monoubiquitination of FANCD2 and FANCI, which is necessary for FA pathway function. Patient-derived cells exhibited phenotypes consistent with FA. Expression of the WT FAAP100 cDNA, but not the patient-derived variants, rescued the observed cellular phenotypes. This establishes FAAP100 deficiency as a cause of FA, with FAAP100 gaining an alias as FANCX. The extensive developmental malformations of individuals with FAAP100 loss-of-function variants are among the most severe across previously described FA phenotypes, indicating that the FA pathway is essential for human development.

Nanodiscs, small discoidal membrane patches stabilized by membrane-scaffold proteins (MSPs), are popular tools to stabilize integral membrane proteins (IMPs) for structural studies by cryogenic electron microscopy (cryo-EM). While nanodiscs provide a near-native membrane environment for the incorporated IMPs, they do not reproduce all characteristics of a native membrane. Also, IMPs must first be purified in detergent before they can be reconstituted into MSP-based nanodiscs, a problem that has been overcome by newer approaches, such as copolymer-based native nanodiscs and cell-derived vesicles. In this review, we argue that despite these advances, MSP-based nanodiscs remain a unique tool for the structural interrogation of IMPs.

Despite waning of virus-neutralizing antibodies, protection against severe SARS-CoV-2 in the majority of immune individuals remains high, but the underlying immune mechanisms are incompletely understood. Here, rhesus macaques with pre-existing immunity from Novavax WA-1 and/or P.1 vaccines and WA-1 or P.1 infection are immunized with a bivalent WA-1/Omicron BA.5 Novavax vaccine ten months after the last exposure. The boost vaccination primarily increases the frequency of cross-reactive spike (S)-specific antibodies and B cells instead of inducing de novo BA.5-specific responses. Reinfection with heterologous Omicron XBB.1.5 six months after the boost vaccination results in low levels of virus replication in the respiratory tract compared with virus-na & iuml;ve results from other studies. Whereas systemic S-specific immunity remains largely unchanged in all animals, the animals with complete protection from infection exhibit a stronger influx of S-specific IgG, monocytes, B cells and T cells into the bronchioalveolar space combined with expansion of CD69+CD103+ lung tissue-resident, S-specific CD8 T cells compared to actively infected animals. Our results underscore the importance of localized respiratory immune responses in mediating protection from Omicron reinfection and provide guidance for future vaccine development.

Defining viral proteomes is crucial to understanding viral life cycles and immune recognition but the landscape of translated regions remains unknown for most viruses. We have developed massively parallel ribosome profiling (MPRP) to determine open reading frames (ORFs) across tens of thousands of designed oligonucleotides. MPRP identified 4208 unannotated ORFs in 679 human-associated viral genomes. We found viral peptides originating from detected noncanonical ORFs presented on class-I human leukocyte antigen in infected cells and hundreds of upstream ORFs that likely modulate translation initiation of viral proteins. The discovery of viral ORFs across a wide range of viral families-including highly pathogenic viruses-expands the repertoire of vaccine targets and reveals potential cis-regulatory sequences.

Tauopathies are characterized by the aggregation and accumulation of hyperphosphorylated tau proteins that correlates with cognitive impairment in affected individuals. The presence of tauopathy follows a temporospatial spreading pattern in which certain neuronal cell types in specific brain regions are more vulnerable to tau accumulation and atrophy. However, the mechanisms underlying the selective vulnerability of these neurons and regions to pathological tau accumulation are not fully understood. Here, we characterized the presence of phosphorylated tau in excitatory and inhibitory neurons in post-mortem prefrontal cortex of tauopathy patients, including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal lobar dementia due to a MAPT mutation. We observed that neuronal tau accumulation across these tauopathies occurs predominantly in excitatory neurons compared to inhibitory neurons. Next, we performed viral translating ribosome affinity purification (vTRAP) from vulnerable and resistant brain regions on vGLUT1CRE+ and GAD2CRE+ PS19 mice to understand molecular signatures of tau vulnerability. We observed that both vulnerable regions and vulnerable neurons are characterized by alterations in synaptic transmission and neuronal excitability. Transcription factor Mef2c (myocyte enhancer factor 2c) was identified as an upstream regulator affecting myelination and synaptic organization in vulnerable brain regions in PS19 mice. The relevance of these findings was validated in human tauopathies via coexpression network analysis. Concordantly, we observed tau-induced changes in spontaneous postsynaptic currents of excitatory neurons in mice especially in the prefrontal cortex. Taken together, we conclude that selective vulnerability to tau could arise from changes in neurotransmission and synaptic compositions, potentially due to an altered Mef2c transcriptional network.

The mammalian cochlea benefits from an active process characterized by amplification of mechanical inputs, sharp frequency selectivity, compressive nonlinearity, and spontaneous otoacoustic emission. Similar traits are observed in individual hair cells of nonmammalian tetrapods, in which they emerge from the critical dynamical regime of hair cells operating near a Hopf bifurcation. It remains unclear whether a similar critical regime also underpins the active process of the mammalian cochlea. Efforts to address this question have been limited in part by the absence of an ex vivo preparation that both preserves the physiological integrity of the sensory epithelium and grants direct experimental access to it. To overcome these problems, we improved a two-compartment cochlear preparation (Chan and Hudspeth, 2005a, 2005b) to more closely simulate in vivo conditions and used it to conduct electrophysiological recordings of microphonic signals in isolated cochlear segments of the Mongolian gerbil. Our methodological advances included refining the dissection protocol to reduce the size of the exposed cochlear segment and altering the ionic compositions of the solutions to better control the Ca2+ concentration. We also maintained a constant temperature in order to stabilize the experimental conditions. Most critically, by introducing a mechanism to adjust the pressure in the endolymphatic compartment, we were able to explore how variations in transepithelial pressure influence the electrical response. These changes enabled us to reliably measure compressive nonlinearities with a one-third power law similar to that observed from cochleas in vivo and consistent with the behavior of a dynamical system operating near a Hopf bifurcation.

Bacteria have evolved a wide range of defence strategies to protect themselves against bacterial viruses (phages). Most known bacterial antiphage defence systems target phages with DNA genomes, which raises the question of how bacteria defend against phages with RNA genomes. Bacterial toxin-antitoxin systems that cleave intracellular RNA could potentially protect bacteria against RNA phages, but this has not been explored experimentally. In this study, we investigated the role of a model toxin-antitoxin system, MazEF, in protecting Escherichia coli against two RNA phage species. When challenged with these phages, the native presence of mazEF moderately reduced population susceptibility and increased the survival of individual E. coli cells. Genomic analysis further revealed an underrepresentation of the MazF cleavage site in genomes of RNA phages infecting E. coli, indicating selection against cleavage. These results show that, in addition to other physiological roles, RNA-degrading toxin-antitoxin systems may also help defend against RNA phages.

Background Suppressor of cytokine signalling 1 (SOCS1) insufficiency is an inborn error of immunity affecting the negative regulation of cytokine and growth factor signalling. We aimed to enhance the understanding of clinical manifestations, disease trajectories, disease penetrance, and the effect of Janus kinase (JAK) inhibition in individuals with SOCS1 insufficiency. Methods This study used data from two independent cohorts: the European Society for Immunodeficiencies (ESID) registry and the UK Biobank. Participants from the ESID registry were from nine European countries (Austria, Belgium, France, Germany, Ireland, Italy, Portugal, Sweden, and Ukraine), China, Taiwan, and the USA. Participants from the ESID registry were eligible if they had heterozygous, functionally validated SOCS1 variants; participants from the UK Biobank were included if they had any SOCS1 variant detected in the ESID registry cohort or any other SOCS1 variant that was classed as high-impact. Clinical manifestations of the underlying SOCS1 insufficiency were documented and summarised into nine subgroups, with ICD-10 diagnosis codes collected for participants from the UK Biobank. Participants from the ESID registry were tested for relevant autoantibodies in their local laboratory. Responses to JAK inhibitor treatment in participants from the ESID registry were assessed by the treating physician using a visual analogue scale. Descriptive statistics were used for analysis. People with lived experience were not involved in the study design. Findings We included 119 participants with SOCS1 insufficiency: 67 from the ESID registry, enrolled between Feb 15, 2021, and Dec 31, 2023, and 52 from the UK Biobank. Of the 67 participants from the ESID registry, 39 (58%) were female, 28 (42%) were male, and the median age was 28 years (IQR 15-44, range 2-85). 27 different monoallelic SOCS1 variants were identified in these participants. 62 (93%) of the 67 participants in the ESID registry cohort were symptomatic and five (7%) were asymptomatic family members; of the 62 participants with symptoms, allergy (33 [50%]), inflammatory gastrointestinal (22 [36%]) and skin (18 [29%]) manifestations, autoimmune cytopenia (24 [39%]), and lymphoproliferation (23 [37%]) were most frequent. Rheumatological manifestations (23 [37%]) included systemic lupus erythematosus, Sj & ouml;gren's disease, and rheumatoid arthritis, with typical autoantibody profiles. 42 (68%) of the 62 symptomatic participants had at least three different manifestations. In the UK Biobank we found 52 participants carrying high-impact SOCS1 variants; 29 (56%) were female, 23 (44%) were male, and the median age was 72 years (65-78, 57-86). Only 30 (58%) of these participants had developed manifestations that were potentially related to SOCS1 insufficiency. Allergy and rheumatological manifestations were more common in participants from the UK Biobank than the ESID registry. Female predominance (21 [70%] of 30 participants were female and nine [30%] were male) was also found among symptomatic participants from the UK Biobank. Treatment with JAK inhibitors showed promising results in 12 (92%) of 13 participants in the ESID registry. Interpretation SOCS1 insufficiency differs from other genetic autoimmune lymphoproliferative disorders by the presence of frequent atopic and rheumatological manifestations. Penetrance is incomplete and is higher in females than in males. JAK inhibition is a promising targeted therapy for patients with SOCS1 insufficiency. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.