The rockefeller university

Ervin Bauer (1890-1938) made historical contributions to contemporary biology, provided a new definition of life, defined the contents of theoretical biology. He worked in different countries, perturbed by deep historical events. These historical events necessarily impacted his fate and finally led to the violent loss of his life and the life of his wife. His work and with it his theory of life had a no less complicated history than the history of his personal life. Bauer's main work "Theoretical Biology" was published in 1935 in Russian. The author and his wife Stefania became victims of the Great Purge. They were executed in 1938, all their publications were banned and most copies of "Theoretical Biology" destroyed. Ervin and Stefania Bauer were rehabilitated in 1956 but renewed publication of Bauer's works was delayed. The first reprint edition of "Theoretical Biology" of 1967 was not in Russian, but was a translation into Hungarian, the native language of Bauer. The first Russian reprint of "Theoretical Biology", in which the original Russian chapters are followed by short English summaries, was published in Hungary in 1982. This edition was prepared by Hungarian and Russian scientists. The best-known Russian edition of "Theoretical Biology" was published in 2002 in St. Petersburg. A complete English translation of Bauer's main work "Theoretical Biology" is still outstanding.

There have been substantial advances in vascular protein disulfide isomerases (PDIs) in platelet function and thrombosis in recent years. There are 4 known prothrombotic thiol isomerases; PDI, endoplasmic reticulum protein (ERp)57, ERp72, and ERp46, and 1 antithrombotic PDI; transmembrane protein 1. A sixth PDI, ERp5, may exhibit either prothrombotic or antithrombotic properties in platelets. Studies on ERp46 in platelet function and thrombosis provide insight into the mechanisms by which these enzymes function. ERp46-catalyzed disulfide cleavage in the xIIbP3 platelet integrin occurs prior to PDI-catalyzed events to maximally support platelet aggregation. The transmembrane PDI transmembrane protein 1 counterbalances the effect of ERp46 by inhibiting activation of xIIbP3. Recent work on the prototypic PDI found that oxidized PDI supports platelet aggregation. The a ' domain of PDI is constitutively oxidized, possibly by endoplasmic reticulum oxidoreductase-1x. However, the a domain is normally reduced but becomes oxidized under conditions of oxidative stress. In contrast to the role of oxidized PDI in platelet function, reduced PDI downregulates activation of the neutrophil integrin xMP2. Intracellular platelet PDI cooperates with Nox1 and contributes to thromboxane A2 production to support platelet function. Finally, xIIb and von Willebrand factor contain free thiols, which alter the functions of these proteins, although the extent to which the PDIs regulate these functions is unclear. We are beginning to understand the substrates and functions of vascular thiol isomerases and the redox network they form that supports hemostasis and thrombosis. Moreover, the disulfide bonds these enzymes target are being defined. The clinical implications of the knowledge gained are wide-ranging.

The past 20 years have seen the definition of human monogenic disorders and their autoimmune phenocopies underlying either defective or enhanced type I interferon (IFN) activity. These disorders delineate the impact of type I IFNs in natural conditions and demonstrate that only a narrow window of type I IFN activity is beneficial. Insufficient type I IFN predisposes humans to life-threatening viral diseases (albeit unexpectedly few) with a central role in immunity to respiratory and cerebral viral infection. Excessive type I IFN, perhaps counterintuitively, appears to underlie a greater number of autoinflammatory and/or autoimmune conditions known as type I interferonopathies, whose study has revealed multiple molecular programs involved in the induction of type I IFN signaling. These observations suggest that the manipulation of type I IFN activity to within a physiological range may be clinically relevant for the prevention and treatment of viral and inflammatory diseases.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here, we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify CFTR modulators. We docked-155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered mid-nanomolar potentiators, as well as inhibitors, that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.

Locating sound sources such as prey or predators is critical for survival in many vertebrates. Terrestrial vertebrates locate sources by measuring the time delay and intensity difference of sound pressure at each ear 1-5 . Underwater, however, the physics of sound makes interaural cues very small, suggesting that directional hearing in fish should be nearly impossible 6 . Yet, directional hearing has been confirmed behaviourally, although the mechanisms have remained unknown for decades. Several hypotheses have been proposed to explain this remarkable ability, including the possibility that fish evolved an extreme sensitivity to minute interaural differences or that fish might compare sound pressure with particle motion signals 7,8 . However, experimental challenges have long hindered a definitive explanation. Here we empirically test these models in the transparent teleost Danionella cerebrum, one of the smallest vertebrates 9,10 . By selectively controlling pressure and particle motion, we dissect the sensory algorithm underlying directional acoustic startles. We find that both cues are indispensable for this behaviour and that their relative phase controls its direction. Using micro-computed tomography and optical vibrometry, we further show that D. cerebrum has the sensory structures to implement this mechanism. D. cerebrum shares these structures with more than 15% of living vertebrate species, suggesting a widespread mechanism for inferring sound direction. A study demonstrates that the fish Danionella cerebrum is able to discriminate the direction of sound by comparing the relative phase of pressure and particle motion.

The first observation of the decay Xi(-)(b) -> psi(2S)Xi(-) and measurement of the branching ratio of Xi(-)(b) -> psi(2S)Xi(-) to Xi(-)(b) -> J/psi Xi(-) are presented. The J/psi and psi(2S) mesons are reconstructed using their dimuon decay modes. The results are based on proton-proton colliding beam data from the LHC collected by the CMS experiment at root s = 13 TeV in 2016-2018, corresponding to an integrated luminosity of 140 fb(-1). The branching fraction ratio is measured to be B(Xi(-)(b) -> psi(2S)Xi(-))/B(Xi(-)(b) -> J/psi Xi(-)) = 0.84(-0.19)(+0.21)(stat) +/- 0.10(syst) +/- 0.02(B), where the last uncertainty comes from the uncertainties in the branching fractions of the charmonium states. New measurements of the Xi(b)(5945)(0) baryon mass and natural width are also presented, using the Xi(-)(b)pi(+) final state, where the Xi(-)(b) baryon is reconstructed through the decays J/psi Xi(-), psi(2S)Xi(-), J/psi Lambda K-, and J/psi Sigma K-0(-). Finally, the fraction of Xi(-)(b) baryons produced from Xi(b)(5945)(0) decays is determined.

The ecological success of social insects makes their colony organization fascinating to scientists studying collective systems. In recent years, the combination of automated behavioural tracking and social network analysis has deepened our understanding of many aspects of colony organization. However, because studies have typically worked with single species, we know little about interspecific variation in network structure. Here, we conduct a comparative network analysis across five ant species from five subfamilies, separated by more than 100 Myr of evolution. We find that social network structure is highly conserved across subfamilies. All species studied form modular networks, with two social communities, a similar distribution of individuals between the two communities, and equivalent mapping of task performance onto the communities. Against this backdrop of organizational similarity, queens of the different species occupied qualitatively distinct network positions. The deep conservation of the two community structure implies that the most fundamental behavioural division of labour in social insects is between workers that stay in the nest to rear brood, and those that leave the nest to forage. This division has parallels across the animal kingdom in systems of biparental care and probably represents the most readily evolvable form of behavioural division of labour.

A search for heavy neutral leptons (HNLs) decaying in the CMS muon system is presented. A data sample is used corresponding to an integrated luminosity of 138 fb(-1) of proton-proton collisions at root s = 13 TeV, recorded at the CERN LHC in 2016-2018. Decay products of long-lived HNLs could interact with the shielding materials in the CMS muon system and create hadronic and electromagnetic showers detected in the muon chambers. This distinctive signature provides a unique handle to search for HNLs with masses below 4 GeV and proper decay lengths of the order of meters. The signature is sensitive to HNL couplings to all three generations of leptons. Candidate events are required to contain a prompt electron or muon originating from a vertex on the beam axis and a displaced shower in the muon chambers. No significant deviations from the standard model background expectation are observed. In the electron (muon) channel, the most stringent limits to date are set for HNLs in the mass range of 2.1-3.0 (1.9-3.3) GeV, reaching mixing matrix element squared values as low as 8.6(4.6) x 10(-6).

How does the brain process the faces of familiar people? Neuropsychological studies have argued for an area of the temporal pole (TP) linking faces with person identities, but magnetic susceptibility artifacts in this region have hampered its study with fMRI. Using data acquisition and analysis methods optimized to overcome this artifact, we identify a familiar face response in TP, reliably observed in individual brains. This area responds strongly to visual images of familiar faces over unfamiliar faces, objects, and scenes. However, TP did not just respond to images of faces, but also to a variety of high- level social cognitive tasks, including semantic, episodic, and theory of mind tasks. The response profile of TP contrasted with a nearby region of the perirhinal cortex that responded specifically to faces, but not to social cognition tasks. TP was functionally connected with a distributed network in the association cortex associated with social cognition, while PR was functionally connected with face- preferring areas of the ventral visual cortex. This work identifies a missing link in the human face processing system that specifically processes familiar faces, and is well placed to integrate visual information about faces with higher- order conceptual information about other people. The results suggest that separate streams for person and face processing reach anterior temporal areas positioned at the top of the cortical hierarchy.

Re-exposure to an antigen generates abundant antibody responses and drives the formation of secondary germinal centers (GCs). Recall GCs in mice consist almost entirely of na & imath;ve B cells, whereas recall antibodies derive overwhelmingly from memory B cells. Here, we examine this division between cellular and serum compartments. After repeated immunization with the same antigen, tetramer analyses of recall GCs revealed a marked decrease in the ability of B cells in these structures to bind the antigen. Boosting with viral variant proteins restored antigen binding in recall GCs, as did genetic ablation of primary-derived antibody-secreting cells through conditional deletion of Prdm1, demonstrating suppression of GC recall responses by pre-existing antibodies. In hapten-carrier experiments in which B and T cell specificities were uncoupled, memory T cell help allowed B cells with undetectable antigen binding to access GCs. Thus, antibody-mediated feedback steers recall GC B cells away from previously targeted epitopes and enables specific targeting of variant epitopes, with implications for vaccination protocols.