CTCF orchestrates the germinal centre transcriptional program and prevents premature plasma cell differentiation

In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). GC B-cell-to-PC transition involves a major transcriptional switch that promotes a halt in cell proliferation and the production of secreted immunoglobulins. Here we show that the CCCTC-binding factor (CTCF) is required for the GC reaction in vivo, whereas in vitro the requirement for CTCF is not universal and instead depends on the pathways used for B-cell activation. CTCF maintains the GC transcriptional programme, allows a high proliferation rate, and represses the expression of Blimp-1, the master regulator of PC differentiation. Restoration of Blimp-1 levels partially rescues the proliferation defect of CTCF-deficient B cells. Thus, our data reveal an essential function of CTCF in maintaining the GC transcriptional programme and preventing premature PC differentiation

Influence of Surface Chemistry on the Electrochemical Performance of Biomass-Derived Carbon Electrodes for its Use as Supercapacitors

The following are available online at https://www.mdpi.com/1996-1944/12/15/2458/s1, Figure S1. N2 adsorption and desorption isotherms at 77K of CK-series samples. Figure S2: High resolution XPS deconvoluted spectra in the corresponding regions: (a) C1s, (b) O1s, (c) N1s and (d) S2p3/2 for the activated carbons prepared from Custard apple tree wood (CK-Serie). Figure S3: High resolution XPS deconvoluted spectra in the corresponding regions: (a) C1s, (b) O1s, (c) N1s and (d) S2p3/2 for the activated carbons prepared from Fig tree wood (FK-Serie). Figure S4: High resolution XPS deconvoluted spectra in the corresponding regions: (a) C1s, (b) O1s, (c) N1s and (d) S2p3/2 for the activated carbons prepared from Olive tree wood (OK-Serie).first_page settings Open AccessFeature PaperArticle Influence of Surface Chemistry on the Electrochemical Performance of Biomass-Derived Carbon Electrodes for its Use as Supercapacitors by Abdelhakim Elmouwahidi 1 [OrcID] , Esther Bailón-García 1, Luis A. Romero-Cano 2 [OrcID] , Ana I. Zárate-Guzmán 3, Agustín F. Pérez-Cadenas 1,* [OrcID] and Francisco Carrasco-Marín 1 [OrcID] 1 Research Group in Carbon Materials, Inorganic Chemistry Department, Faculty of Sciences, University of Granada, Campus Fuente Nueva s/n. 18071 Granada, Spain 2 Facultad de Ciencias Químicas, Universidad Autónoma de Guadalajara, Av. Patria 1201, Zapopan, Jalisco C. P. 45129, Mexico 3 Centro de Investigación y Desarrollo Tecnológico en Electroquímica (CIDETEQ) S.C., Parque Tecnológico Sanfandila, Pedro Escobedo, Querétaro 760703, Mexico * Author to whom correspondence should be addressed. Materials 2019, 12(15), 2458; https://doi.org/10.3390/ma12152458 Received: 28 June 2019 / Revised: 31 July 2019 / Accepted: 1 August 2019 / Published: 2 August 2019 (This article belongs to the Special Issue Element-Doped Functional Carbon-based Materials) Download PDF Browse Figures Cite This Paper Abstract Activated carbons prepared by chemical activation from three different types of waste woods were treated with four agents: melamine, ammonium carbamate, nitric acid, and ammonium persulfate, for the introduction of nitrogen and oxygen groups on the surface of materials. The results indicate that the presence of the heteroatoms enhances the capacitance, energy density, and power density of all samples. The samples treated with ammonium persulfate show the maximum of capacitance of 290 F g−1 while for the melamine, ammonium carbamate, and nitric acid treatments, the samples reached the maximum capacitances values of 283, 280, and 455 F g−1 respectively. This remarkable electro-chemical performance, as the high specific capacitances can be due to several reasons: i) The excellent and adequate textural characteristics makes possible a large adsorption interface for electrolyte to form the electrical double layer, leading to a great electrochemical double layer capacitance. ii) The doping with hetero-atoms enhances the surface interaction of these materials with the aqueous electrolyte, increasing the accessibility of electrolyte ions. iii) The hetero-atoms groups can also provide considerable pseudo-capacitance improving the overall capacitance.This work was supported by FEDER and Spanish MINECO (grant number CTQ-2013-44789-R); and Junta de Andalucía (grant numbers P12-RNM-2892, RNM172)

CTCF orchestrates the germinal centre transcriptional program and prevents premature plasma cell differentiation

In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). GC B-cell-to-PC transition involves a major transcriptional switch that promotes a halt in cell proliferation and the production of secreted immunoglobulins. Here we show that the CCCTC-binding factor (CTCF) is required for the GC reaction in vivo, whereas in vitro the requirement for CTCF is not universal and instead depends on the pathways used for B-cell activation. CTCF maintains the GC transcriptional programme, allows a high proliferation rate, and represses the expression of Blimp-1, the master regulator of PC differentiation. Restoration of Blimp-1 levels partially rescues the proliferation defect of CTCF-deficient B cells. Thus, our data reveal an essential function of CTCF in maintaining the GC transcriptional programme and preventing premature PC differentiation

Lesión ulcerocostrosa en cara: una forma inususal de presentación de linfoma

ResumenSe presenta el caso de una paciente con una lesión facial ulcerada y costrosa que corresponde a un linfoma. Apartir de este se hace una revisión extensa del cuadro clínico y su diagnóstico diferencial.[Vásquez AJ, Ávila MY, Rojas RF, Uribe CJ. Lesión ulcerocostrosa en cara: una forma inususal de presentación de linfoma. MedUNAB 2002;5(14):146-153].Palabras clave: Linfoma, enfermedad de Hodgkin, leishmaniasis

Melanoma nodular amelatónico

ResumenSe informa un caso de una mujer de 36 años de edad con tumor nodular en lóbulo de oreja de dos años de evolución, el cual clínicamente simulaba ser un queloide o un tumor benigno. Al estudio histopatológico se diagnosticó melanoma nodular amelanótico con diferenciación neuroendocrina.[Uribe CJ, Ávila MY, Zárate M, Rueda DF. Melanoma nodular amelatónico. MedUNAB 2002; 5(14):133-135].Palabras clave: Melanoma, amelanosis, neoplasia de piel

COVID-19 outbreaks in a transmission control scenario: challenges posed by social and leisure activities, and for workers in vulnerable conditions, Spain, early summer 2020

Severe acute respiratory syndrome coronavirus 2 community-wide transmission declined in Spain by early May 2020, being replaced by outbreaks and sporadic cases. From mid-June to 2 August, excluding single household outbreaks, 673 outbreaks were notified nationally, 551 active (>6,200 cases) at the time. More than half of these outbreaks and cases coincided with: (i) social (family/friends’ gatherings or leisure venues) and (ii) occupational (mainly involving workers in vulnerable conditions) settings. Control measures were accordingly applied

Exchange of functional domains between a bacterial conjugative relaxase and the integrase of the human adeno-associated virus

Endonucleases of the HUH family are specialized in processing single-stranded DNA in a variety of evolutionarily highly conserved biological processes related to mobile genetic elements. They share a structurally defined catalytic domain for site-specific nicking and strand-transfer reactions, which is often linked to the activities of additional functional domains, contributing to their overall versatility. To assess if these HUH domains could be interchanged, we created a chimeric protein from two distantly related HUH endonucleases, containing the N-terminal HUH domain of the bacterial conjugative relaxase TrwC and the C-terminal DNA helicase domain of the human adeno-associated virus (AAV) replicase and site-specific integrase. The purified chimeric protein retained oligomerization properties and DNA helicase activities similar to Rep68, while its DNA binding specificity and cleaving-joining activity at oriT was similar to TrwC. Interestingly, the chimeric protein could catalyse site-specific integration in bacteria with an efficiency comparable to that of TrwC, while the HUH domain of TrwC alone was unable to catalyze this reaction, implying that the Rep68 C-terminal helicase domain is complementing the TrwC HUH domain to achieve site-specific integration into TrwC targets in bacteria. Our results illustrate how HUH domains could have acquired through evolution other domains in order to attain new roles, contributing to the functional flexibility observed in this protein superfamily.This work was supported by the Medical Research Council (MRC) grant MR/N022890/1 to EH and grant 1001764 to RML; National Institutes of Health (NIH) grant RO1-GM09285 to CRE; Spanish Ministry of Economy and competitiveness (MINECO) grant BIO2013-46414-P to ML and AFM is supported by a Doc.Mobility fellowship from the Swiss National Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Mapping the human genetic architecture of COVID-19

Matters Arising to this article was published on 03 August 2022, available online at: https://doi.org/10.1038/s41586-022-04826-7 . A second Matters Arising to this article was published on 06 September 2023, available online at: https://doi.org/10.1038/s41586-023-06355-3 .Data availability: Summary statistics generated by the COVID-19 HGI are available at https://www.covid19hg.org/results/r5/ and are available in the GWAS Catalog (study code GCST011074). The analyses described here include the freeze-5 data. COVID-19 HGI continues to regularly release new data freezes. Summary statistics for non-European ancestry samples are not currently available due to the small individual sample sizes of these groups, but results for lead variants of 13 loci are reported in Supplementary Table 3. Individual level data can be requested directly from contributing studies, listed in Supplementary Table 1. We used publicly available data from GTEx (https://gtexportal.org/home/), the Neale lab (https://www.nealelab.is/uk-biobank/), Finucane lab (https://www.finucanelab.org), the FinnGen Freeze 4 cohort (https://www.finngen.fi/en/access_results) and the eQTL catalogue release 3 (https://www.ebi.ac.uk/eqtl/).Code availability: The code for summary statistics lift-over, the projection PCA pipeline including precomputed loadings and meta-analyses are available on GitHub (https://github.com/covid19-hg/) and the code for the Mendelian randomization and genetic correlation pipeline is available on GitHub at https://github.com/marcoralab/MRcovid.Reporting summary: Further information on research design is available in the Nature Research Reporting Summary linked to this paper online at: https://www.nature.com/articles/s41586-021-03767-x#MOESM2 .Supplementary information is available onlne at: https://www.nature.com/articles/s41586-021-03767-x#Sec24 .Extended data figures and tables are available online at: https://www.nature.com/articles/s41586-021-03767-x#Sec23 .Copyright © The Author(s) 2021. The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19(1,2), host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.Radiolog

Identification of a Functionally Relevant Adeno-Associated Virus Rep68 Oligomeric Interface

The life cycle of the human parvovirus adeno-associated virus (AAV) is orchestrated by four Rep proteins. The large Rep proteins, Rep78 and Rep68, are remarkably multifunctional and display a range of biochemical activities, including DNA binding, nicking, and unwinding. Functionally, Rep78 and Rep68 are involved in transcriptional regulation, DNA replication, and genomic integration. Structurally, the Rep proteins share an AAA(+) domain characteristic of superfamily 3 helicases, with the large Rep proteins additionally containing an N-terminal origin-binding domain (OBD) that specifically binds and nicks DNA. The combination of these domains, coupled with dynamic oligomerization properties, is the basis for the remarkable multifunctionality displayed by Rep68 and Rep78 during the AAV life cycle. In this report, we describe an oligomeric interface formed by Rep68 and demonstrate how disruption of this interface has drastic effects on both the oligomerization and functionality of the Rep proteins. Our results support a role for the four-helix bundle in the helicase domain of Rep68 as a bona fide oligomerization domain (OD). We have identified key residues in the OD that are critical for the stabilization of the Rep68-Rep68 interface; mutation of these key residues disrupts the enzymatic activities of Rep68, including DNA binding and nicking, and compromises viral DNA replication and transcriptional regulation of the viral promoters. Taken together, our data contribute to our understanding of the dynamic and substrate-responsive Rep78/68 oligomerization that is instrumental in the regulation of the DNA transitions that take place during the AAV life cycle. IMPORTANCE: The limited genome size of small viruses has driven the evolution of highly multifunctional proteins that integrate different domains and enzymatic activities within a single polypeptide. The Rep68 protein from adeno-associated virus (AAV) combines a DNA binding and endonuclease domain with a helicase-ATPase domain, which together support DNA replication, transcriptional regulation, and site-specific integration. The coordination of the enzymatic activities of Rep68 remains poorly understood; however, Rep68 oligomerization and Rep68-DNA interactions have been suggested to play a crucial role. We investigated the determinants of Rep68 oligomerization and identified a hydrophobic interface necessary for Rep68 activity during the AAV life cycle. Our results provide new insights into the molecular mechanisms underlying the regulation of the versatile Rep proteins. Efficient production of AAV-based gene therapy vectors requires optimal Rep expression levels, and studies such as the one presented here could contribute to further optimization of AAV production schemes