Deep Sequencing of B Cell Receptor Repertoires From COVID-19 Patients Reveals Strong Convergent Immune Signatures.

Deep sequencing of B cell receptor (BCR) heavy chains from a cohort of 31 COVID-19 patients from the UK reveals a stereotypical naive immune response to SARS-CoV-2 which is consistent across patients. Clonal expansion of the B cell population is also observed and may be the result of memory bystander effects. There was a strong convergent sequence signature across patients, and we identified 1,254 clonotypes convergent between at least four of the COVID-19 patients, but not present in healthy controls or individuals following seasonal influenza vaccination. A subset of the convergent clonotypes were homologous to known SARS and SARS-CoV-2 spike protein neutralizing antibodies. Convergence was also demonstrated across wide geographies by comparison of data sets between patients from UK, USA, and China, further validating the disease association and consistency of the stereotypical immune response even at the sequence level. These convergent clonotypes provide a resource to identify potential therapeutic and prophylactic antibodies and demonstrate the potential of BCR profiling as a tool to help understand patient responses

Predictability of B cell clonal persistence and immunosurveillance in breast cancer.

Acknowledgements: The authors thank the late Nir Friedman at the Weizmann Institute for the many scientific discussions that contributed to the central idea that rooted this work. S-J.S. was supported by a Whitney Wood Scholarship awarded by the Royal College of Physicians (United Kingdom). C.C. was supported by funding from CRUK (grant numbers A17197, A27657 and A29580), an NIHR Senior Investigator Award (grant number NF-SI-0515-10090), and a European Research Council Advanced Award (grant number 694620). R.J.M.B.-R. was supported by the Wellcome Trust and University of Oxford. O.M.R. was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) and the Medical Research Council (UK; MC_UU_00002/16). B.S. is supported by an NIHR Academic Clinical Lectureship (CL-2021-13-002), Academy of Medical Sciences (SGL028\1074) and The British Medical Association Vera Down Award. We thank Breast Cancer Now for funding this work as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre. We thank the Asociación Española contra el Cáncer, Cellex foundation, and the clinical team at the Breast Cancer Unit of Vall d’Hebron University Hospital/Institute of Oncology and the Cambridge Breast Cancer Research Unit for facilitating the collection and processing of biological samples. We are very grateful for the generosity of all the participants that donated samples for analysis.Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: University of Oxford (Oxford University); doi: https://doi.org/10.13039/501100000769Funder: The British Medical Association Vera Down AwardB cells and T cells are important components of the adaptive immune system and mediate anticancer immunity. The T cell landscape in cancer is well characterized, but the contribution of B cells to anticancer immunosurveillance is less well explored. Here we show an integrative analysis of the B cell and T cell receptor repertoire from individuals with metastatic breast cancer and individuals with early breast cancer during neoadjuvant therapy. Using immune receptor, RNA and whole-exome sequencing, we show that both B cell and T cell responses seem to coevolve with the metastatic cancer genomes and mirror tumor mutational and neoantigen architecture. B cell clones associated with metastatic immunosurveillance and temporal persistence were more expanded and distinct from site-specific clones. B cell clonal immunosurveillance and temporal persistence are predictable from the clonal structure, with higher-centrality B cell antigen receptors more likely to be detected across multiple metastases or across time. This predictability was generalizable across other immune-mediated disorders. This work lays a foundation for prioritizing antibody sequences for therapeutic targeting in cancer

Effects of fetal antiepileptic drug exposure Outcomes at age 4.5 years

OBJECTIVE: To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure. METHODS: The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999–2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5). RESULTS: Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102–109), lamotrigine 106 (102–109), phenytoin 105 (102–109), valproate 96 (91–100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills. CONCLUSIONS: Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed

The geomicrobiology of gold

Microorganisms capable of actively solubilizing and precipitating gold appear to play a larger role in the biogeochemical cycling of gold than previously believed. Recent research suggests that bacteria and archaea are involved in every step of the biogeochemical cycle of gold, from the formation of primary mineralization in hydrothermal and deep subsurface systems to its solubilization, dispersion and re-concentration as secondary gold under surface conditions. Enzymatically catalysed precipitation of gold has been observed in thermophilic and hyperthermophilic bacteria and archaea (for example, Thermotoga maritime, Pyrobaculum islandicum), and their activity led to the formation of gold- and silver-bearing sinters in New Zealand's hot spring systems. Sulphate-reducing bacteria (SRB), for example, Desulfovibrio sp., may be involved in the formation of gold-bearing sulphide minerals in deep subsurface environments; over geological timescales this may contribute to the formation of economic deposits. Iron- and sulphur-oxidizing bacteria (for example, Acidothiobacillus ferrooxidans, A. thiooxidans) are known to breakdown gold-hosting sulphide minerals in zones of primary mineralization, and release associated gold in the process. These and other bacteria (for example, actinobacteria) produce thiosulphate, which is known to oxidize gold and form stable, transportable complexes. Other microbial processes, for example, excretion of amino acids and cyanide, may control gold solubilization in auriferous top- and rhizosphere soils. A number of bacteria and archaea are capable of actively catalysing the precipitation of toxic gold(I/III) complexes. Reductive precipitation of these complexes may improve survival rates of bacterial populations that are capable of (1) detoxifying the immediate cell environment by detecting, excreting and reducing gold complexes, possibly using P-type ATPase efflux pumps as well as membrane vesicles (for example, Salmonella enterica, Cupriavidus (Ralstonia) metallidurans, Plectonema boryanum); (2) gaining metabolic energy by utilizing gold-complexing ligands (for example, thiosulphate by A. ferrooxidans) or (3) using gold as metal centre in enzymes (Micrococcus luteus). C. metallidurans containing biofilms were detected on gold grains from two Australian sites, indicating that gold bioaccumulation may lead to gold biomineralization by forming secondary 'bacterioform' gold. Formation of secondary octahedral gold crystals from gold(III) chloride solution, was promoted by a cyanobacterium (P. boryanum) via an amorphous gold(I) sulphide intermediate. 'Bacterioform' gold and secondary gold crystals are common in quartz pebble conglomerates (QPC), where they are often associated with bituminous organic matter possibly derived from cyanobacteria. This may suggest that cyanobacteria have played a role in the formation of the Witwatersrand QPC, the world's largest gold deposit.Frank Reith, Maggy F. Lengke, Donna Falconer, David Craw and Gordon Southa