Sequence–function–stability relationships in proteins from datasets of functionally annotated variants: The case of TEM β-lactamases

AbstractA dataset of TEM lactamase variants with different substrate and inhibition profiles was compiled and analyzed. Trends show that loops are the main evolvable regions in these enzymes, gradually accumulating mutations to generate increasingly complex functions. Notably, many mutations present in evolved enzymes are also found in simpler variants, probably originating functional promiscuity. Following a function-stability tradeoff, the increase in functional complexity driven by accumulation of mutations fosters the incorporation of other stability-restoring substitutions, although our analysis suggests they might not be as “global” as generally accepted and seem instead specific to different networks of protein sites. Finally, we show how this dataset can be used to model functional changes in TEMs based on the physicochemical properties of the amino acids

Thermodynamics of an ideal generalized gas:II Means of order α\alpha

The property that power means are monotonically increasing functions of their order is shown to be the basis of the second laws not only for processes involving heat conduction but also for processes involving deformations. In an $L$-potentail equilibration the final state will be one of maximum entropy, while in an entropy equilibrium the final state will be one of minimum $L$. A metric space is connected with the power means, and the distance between means of different order is related to the Carnot efficiency. In the ideal classical gas limit, the average change in the entropy is shown to be proportional to the difference between the Shannon and R\'enyi entropies for nonextensive systems that are multifractal in nature. The $L$-potential, like the internal energy, is a Schur convex function of the empirical temperature, which satisfies Jensen's inequality, and serves as a measure of the tendency to uniformity in processes involving pure thermal conduction.Comment: 8 page

Impact of vaccination against Haemophilus influenzae type b with and without a booster dose on meningitis in four South American countries

Fil: García, Salvador. Pan American Health Organization, Washington DC; Estados Unidos.Fil: Lagos, Rosanna. Centro para Vacunas en Desarrollo (CVD-Chile), Santiago; Chile.Fil: Muñoz, Alma. Centro para Vacunas en Desarrollo (CVD-Chile), Santiago; Chile.Fil: Picón, Teresa. National Immunization Program and Department of Epidemiologic Surveillance, Ministry of Health, Montevideo; Uruguay.Fil: Rosa, Raquel. National Immunization Program and Department of Epidemiologic Surveillance, Ministry of Health, Montevideo; Uruguay.Fil: Alfonso, Adriana. National Immunization Program and Department of Epidemiologic Surveillance, Ministry of Health, Montevideo; Uruguay.Fil: Abriata, Graciela. Instituto Nacional del Cáncer, Ministerio de Salud de la Nación, Buenos Aires; Argentina.Fil: Gentile, Angela. Hospital de Niños Ricardo Gutierrez, Epidemiología, Buenos Aires; Argentina.Fil: Romanin, Viviana. Hospital de Niños Ricardo Gutierrez, Epidemiología, Buenos Aires; Argentina.Fil: Regueira, Mabel. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Chiavetta, Laura. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Agudelo, Clara Inés. Instituto Nacional de Salud, Bogotá; Colombia.Fil: Castañeda, Elizabeth. Instituto Nacional de Salud, Bogotá; Colombia.Fil: De la Hoz, Fernando. Facultad de Medicina, Departamento de Salud Pública, Universidad Nacional de Colombia, Bogotá; Colombia.Fil: Higuera, Ana Betty. Secretaria de Salud de Bogotá, Bogotá; Colombia.Fil: Arce, Patricia. Secretaria de Salud de Bogotá, Bogotá; Colombia.Fil: Cohen, Adam L.. National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA; Estados Unidos.Fil: Verani, Jennifer. National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA; Estados Unidos.Fil: Zuber, Patrick. Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva; Suiza.Fil: Gabastou, Jean-Marc. Pan American Health Organization, Washington DC; Estados Unidos.Fil: Pastor, Desiree. Pan American Health Organization, Washington DC; Estados Unidos.Fil: Flannery, Brendan. Pan American Health Organization, Washington DC; Estados Unidos.Fil: Andrus, Jon. Pan American Health Organization, Washington DC; Estados Unidos.To inform World Health Organization recommendations regarding use of Haemophilus influenzae type b (Hib) vaccines in national immunization programs, a multi-country evaluation of trends in Hib meningitis incidence and prevalence of nasopharyngeal Hib carriage was conducted in four South American countries using either a primary, three-dose immunization schedule without a booster dose or with a booster dose in the second year of life. Surveillance data suggest that high coverage of Hib conjugate vaccine sustained low incidence of Hib meningitis and low prevalence of Hib carriage whether or not a booster dose was used

Impact of vaccination against Haemophilus influenzae type b with and without a booster dose on meningitis in four South American countries

Fil: García, Salvador. Pan American Health Organization, Washington DC; Estados Unidos.Fil: Lagos, Rosanna. Centro para Vacunas en Desarrollo (CVD-Chile), Santiago; Chile.Fil: Muñoz, Alma. Centro para Vacunas en Desarrollo (CVD-Chile), Santiago; Chile.Fil: Picón, Teresa. National Immunization Program and Department of Epidemiologic Surveillance, Ministry of Health, Montevideo; Uruguay.Fil: Rosa, Raquel. National Immunization Program and Department of Epidemiologic Surveillance, Ministry of Health, Montevideo; Uruguay.Fil: Alfonso, Adriana. National Immunization Program and Department of Epidemiologic Surveillance, Ministry of Health, Montevideo; Uruguay.Fil: Abriata, Graciela. Instituto Nacional del Cáncer, Ministerio de Salud de la Nación, Buenos Aires; Argentina.Fil: Gentile, Angela. Hospital de Niños Ricardo Gutierrez, Epidemiología, Buenos Aires; Argentina.Fil: Romanin, Viviana. Hospital de Niños Ricardo Gutierrez, Epidemiología, Buenos Aires; Argentina.Fil: Regueira, Mabel. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Chiavetta, Laura. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Agudelo, Clara Inés. Instituto Nacional de Salud, Bogotá; Colombia.Fil: Castañeda, Elizabeth. Instituto Nacional de Salud, Bogotá; Colombia.Fil: De la Hoz, Fernando. Facultad de Medicina, Departamento de Salud Pública, Universidad Nacional de Colombia, Bogotá; Colombia.Fil: Higuera, Ana Betty. Secretaria de Salud de Bogotá, Bogotá; Colombia.Fil: Arce, Patricia. Secretaria de Salud de Bogotá, Bogotá; Colombia.Fil: Cohen, Adam L.. National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA; Estados Unidos.Fil: Verani, Jennifer. National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA; Estados Unidos.Fil: Zuber, Patrick. Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva; Suiza.Fil: Gabastou, Jean-Marc. Pan American Health Organization, Washington DC; Estados Unidos.Fil: Pastor, Desiree. Pan American Health Organization, Washington DC; Estados Unidos.Fil: Flannery, Brendan. Pan American Health Organization, Washington DC; Estados Unidos.Fil: Andrus, Jon. Pan American Health Organization, Washington DC; Estados Unidos.To inform World Health Organization recommendations regarding use of Haemophilus influenzae type b (Hib) vaccines in national immunization programs, a multi-country evaluation of trends in Hib meningitis incidence and prevalence of nasopharyngeal Hib carriage was conducted in four South American countries using either a primary, three-dose immunization schedule without a booster dose or with a booster dose in the second year of life. Surveillance data suggest that high coverage of Hib conjugate vaccine sustained low incidence of Hib meningitis and low prevalence of Hib carriage whether or not a booster dose was used

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R01NS109858, to VAG); the Paul A. Marks Scholar Program at the Columbia University Vagelos College of Physicians and Surgeons (to VAG); a TIGER grant from the TAUB Institute at the Columbia Vagelos College of Physicians and Scientists (to VAG); the Swiss National Science Foundation (SNF 31003A-179371, to TH); the European Joint Program on Rare Diseases (EJP RD+SNF 32ER30-187505, to TH); the Swiss Cancer League (KFS-4999-02-2020, to GD); the EPFL institutional fund (to GD); the Kristian Gerhard Jebsen Foundation (to GD); the Swiss National Science Foundation (SNSF) (310030_184926, to GD); the Swiss Foundation for Research on Muscle Disease (FSRMM, to MAL); the Natural Science and Engineering Research Council of Canada (Discovery Grant 2020-04241, to JEB); the Italian Ministry of Health Young Investigator Grant (GR-2011-02347754, to EL); the Fondazione Istituto di Ricerca Pediatrica – Città della Speranza (18-04, to EL); the Wroclaw Medical University (SUB.E160.21.004, to RS); the National Science Centre, Poland (2017/27/B/NZ5/0222, to RS); Telethon Undiagnosed Diseases Program (TUDP) (GSP15001); the Temple Street Foundation/Children’s Health Foundation Ireland (RPAC 19-02, to IK); the Deutsche Forschungsgemeinschaft (DFG) (PO2366/2–1, to BP); the Instituto de Salud Carlos III, Spain (to ELM, EBS, and BMD); the National Natural Science Foundation of China (81871079 and 81730036, to HG and KX); and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R01 DK115574, to SSC).The DEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. The funders were not involved in the study design, data acquisition, analysis, or writing of the manuscript. Funding for the DECIPHER project was provided by Wellcome. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.S

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome