Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation

Differentiation of naïve peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B cell fate remain unclear. Here we identified a central role for the histone H3K79 methyltransferase DOT1L in controlling B cell differentiation. Naïve and activated murine B cells lacking Dot1L prematurely acquired plasma cell features and failed to establish germinal centers (GC) and normal humoral immune responses in vivo. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative (Myc) and pro-GC program (Bach2) and supports the expression of the H3K27 methyltransferase Ezh2, the catalytic component of Polycomb Repressor Complex 2 (PRC2). Thereby, DOT1L ensures PRC2-mediated repression of anti-proliferative and plasma cell differentiation program. Our findings show that DOT1L is a critical regulator of the core transcriptional and epigenetic landscape in B cells and establishes an epigenetic barrier warranting B cell naivety

The Giant Pacific Oyster (Crassostrea gigas) as a modern analog for fossil ostreoids: Isotopic (Ca, O, C) and elemental (Mg/Ca, Sr/Ca, Mn/Ca) proxies

Modern analogs are an essential part of palaeoclimate studies, because they provide the basis for the understanding of geochemical signatures of fossils. Ostreoids are common in many sedimentary sequences and because of their fast growth, high temporal resolution sampling of past seasonal variability is possible. Here, two shell structures of modern Giant Pacific Oysters (Crassostrea gigas), the chalky substance and foliate layers, have been sampled for trace element distributions (Mg, Sr, Mn) and stable isotope variability (C, O, Ca). Oxygen isotopes exhibit a clear seasonal signature. Mean carbon isotope values of different oysters agree within 0.1‰, but ontogenic variability is complicated by shell growth patterns and potential small vital effects. The calcium isotope ratios are found to be constant throughout ontogeny within analytical precision at a value of δ44/40Ca = 0.68 ± 0.16‰ (2 sd) SRM–915a which is consistent with other bivalve species. Calcium isotope ratios in oyster shell material might thus be a possible proxy for palaeo seawater calcium isotope ratios. Element/Ca ratios are significantly higher in the chalky substance than in the foliate layers and especially high Sr/Ca and Mn/Ca ratios are observed for the first growth season of the oysters. Mg/Ca ratios in the chalky substance show a negative correlation with δ18O values, compatible with a temperature dependence, whereas this correlation is absent in the foliate layers. Seasonal changes of Sr/Ca are controlled by metabolic processes, whereas for Mn/Ca an additional environmental control is evident

Histone methyltransferase DOT1L controls state-specific identity during B cell differentiation

Differentiation of naïve peripheral B cells into terminally differentiated plasma cells is characterized by epigenetic alterations, yet the epigenetic mechanisms that control B-cell fate remain unclear. Here, we identified a role for the histone H3K79 methyltransferase DOT1L in controlling B-cell differentiation. Mouse B cells lacking Dot1L failed to establish germinal centers (GC) and normal humoral immune responses in vivo. In vitro, activated B cells in which Dot1L was deleted showed aberrant differentiation and prematurely acquired plasma cell characteristics. Similar results were obtained when DOT1L was chemically inhibited in mature B cells in vitro. Mechanistically, combined epigenomics and transcriptomics analysis revealed that DOT1L promotes expression of a pro-proliferative, pro-GC program. In addition, DOT1L indirectly supports the repression of an anti-proliferative plasma cell differentiation program by maintaining the repression of Polycomb Repressor Complex 2 (PRC2) targets. Our findings show that DOT1L is a key modulator of the core transcriptional and epigenetic landscape in B cells, establishing an epigenetic barrier that warrants B-cell naivety and GC B-cell differentiation

Resilience trinity: Safeguarding ecosystem functioning and services across three different time horizons and decision contexts

Ensuring ecosystem resilience is an intuitive approach to safeguard the functioning of ecosystems and hence the future provisioning of ecosystem services (ES). However, resilience is a multi‐faceted concept that is difficult to operationalize. Focusing on resilience mechanisms, such as diversity, network architectures or adaptive capacity, has recently been suggested as means to operationalize resilience. Still, the focus on mechanisms is not specific enough. We suggest a conceptual framework, resilience trinity, to facilitate management based on resilience mechanisms in three distinctive decision contexts and time‐horizons: 1) reactive, when there is an imminent threat to ES resilience and a high pressure to act, 2) adjustive, when the threat is known in general but there is still time to adapt management and 3) provident, when time horizons are very long and the nature of the threats is uncertain, leading to a low willingness to act. Resilience has different interpretations and implications at these different time horizons, which also prevail in different disciplines. Social ecology, ecology and engineering are often implicitly focussing on provident, adjustive or reactive resilience, respectively, but these different notions of resilience and their corresponding social, ecological and economic tradeoffs need to be reconciled. Otherwise, we keep risking unintended consequences of reactive actions, or shying away from provident action because of uncertainties that cannot be reduced. The suggested trinity of time horizons and their decision contexts could help ensuring that longer‐term management actions are not missed while urgent threats to ES are given priority

MMN and Differential Waveform

A mismatch negativity response (MMN) and a new differential waveform were derived in an effort to evaluate a neural refractory or recovery effect in adult listeners. The MMN was elicited using oddball test runs in which the standard and deviant stimuli differed in frequency. To derive the differential waveform, the same standard and deviant stimuli were presented alone. MMN responses were obtained by subtracting the averaged responses to standards from the deviants. The differential waveforms were obtained by subtracting the averaged responses to standards presented alone from deviants presented alone. Scalp topography for the MMN and differential waveforms were similar. A significant (p < .05) positive and negative correlation was found between the earlier and later components of the bimodal MMN and the N1 and P2 component of the differential waveform, respectively. Further, N1 and P2 of the differential waveform were significant (p < .05) predictor variables of early and late peak amplitudes of the MMN. These results suggest that refractory effects may overlay/modify the morphology of the MMN waveform

Pre-transplantation Risks and Transplant-Techniques in Haematopoietic Stem Cell Transplantation for Acute Leukaemia

Background: The role of conditioning intensity and stem cell source on modifying pre-transplantation risk in allogeneic haematopoietic stem cell transplantation (HSCT) is a matter of debate, but crucial when benchmarking centres. Methods: This Retrospective, multicenter exploratory-validation analysis of 9103 patients, (55.5% male, median age 50 years; 1–75 years range) with an allogeneic HSCT between 2010 and 2016 from a matched sibling (N = 8641; 95%) or matched unrelated donor (N = 462; 5%) for acute myeloid (N = 6432; 71%) or acute lymphoblastic (N = 2671; 29%) leukaemia in first complete remission, and reported by 240 centres in 30 countries to the benchmark database of the European Society for Blood and Marrow Transplantation (EBMT) searched for factors associated with use of transplant techniques (standard N = 6375;70% or reduced intensity conditioning N = 2728;30%, respectively bone marrow N = 1945;21% or peripheral blood N = 7158;79% as stem cell source), and their impact on outcome. Findings: Treatment groups differed significantly from baseline population (p < 0.001), and within groups regarding patient-, disease-, donor-, and centre-related pre-transplantation risk factors (p < 0.001); choice of technique did depend on pre-transplantation risk factors and centre (p < 0.001). Probability of overall survival at 5 years decreased systematically and significantly with increasing pre-transplantation risk score (score 2 vs 0/1 HR: 1·2, 95% c.i. [1·1–1·.3], p = 0.002; score 3 vs 0/1 HR: 1·5, 95% c.i. [1·3–1·7], p < 0.001; score 4/5/6 vs 0/1 HR: 1·9, 95% c.i. [1·6–2·2], p < 0.001) with no significant differences between treatment groups (likelihood ratio test on interaction: p = 0.40). Overall survival was significantly associated with selection steps and completeness of information (p < 0.001). Interpretation: Patients' pre-transplantation risk factors determine survival, independent of transplant techniques. Transplant techniques should be regarded as centre policy, not stratification factor in benchmarking. Selection criteria and completeness of data bias outcome. Outcomes may be improved more effectively through better identifying pre-transplantation factors as opposed to refinement of transplant techniques. Funding: The study was funded by EBMT

Surveillance for pancreatic cancer in high-risk individuals

Background: Surveillance of individuals at high risk of pancreatic ductal adenocarcinoma (PDAC) and its precursors might lead to better outcomes. The aim of this study was to determine the prevalence and outcomes of PDAC and high-risk neoplastic precursor lesions among such patients participating in surveillance programmes. Methods: A multicentre study was conducted through the International CAncer of the Pancreas Screening (CAPS) Consortium Registry to identify high-risk individuals who had undergone pancreatic resection or progressed to advanced PDAC while under surveillance. High-risk neoplastic precursor lesions were defined as: pancreatic intraepithelial neoplasia (PanIN) 3, intraductal papillary mucinous neoplasia (IPMN) with high-grade dysplasia, and pancreatic neuroendocrine tumours at least 2 cm in diameter. Results: Of 76 high-risk individuals identified in 11 surveillance programmes, 71 had undergone surgery and five had been diagnosed with inoperable PDAC. Of the 71 patients who underwent resection, 32 (45 per cent) had PDAC or a high-risk precursor (19 PDAC, 4 main-duct IPMN, 4 branch-duct IPMN, 5 PanIN-3); the other 39 patients had lesions thought to be associated with a lower risk of neoplastic progression. Age at least 65 years, female sex, carriage of a gene mutation and location of a lesion in the head/uncinate region were associated with high-risk precursor lesions or PDAC. The survival of high-risk individuals with low-risk neoplastic lesions did not differ from that in those with high-risk precursor lesions. Survival was worse among patients with PDAC. There was no surgery-related mortality. Conclusion: A high proportion of high-risk individuals who had surgical resection for screening- or surveillance-detected pancreatic lesions had a high-risk neoplastic precursor lesion or PDAC