Calcium isotopes in scleractinian fossil corals since the Mesozoic: Implications for vital effects and biomineralization through time

We present a Cenozoic record of δ^(44/40)Ca from well preserved scleractinian fossil corals, as well as fossil coral δ^(44/40)Ca data from two time periods during the Mesozoic (84 and 160 Ma). To complement the coral data, we also extend existing bulk pelagic carbonate records back to ∼80 Ma. The same fossil corals used for this study were previously shown to be excellently preserved, and to be faithful archives of past seawater Mg/Ca and Sr/Ca since ∼200 Ma (Gothmann et al., 2015). We find that the δ^(44/40)Ca compositions of bulk pelagic carbonates from ODP Site 807 (Ontong Java Plateau) and DSDP Site 516 (Rio Grande Rise) have not varied by more than ∼±0.20‰ over the last ∼80 Myr. In contrast, the δ^(44/40)Ca compositions of Mesozoic and Early Cenozoic fossil corals are ∼1‰ lighter than those of modern corals. The observed change in coral δ^(44/40)Ca does not likely reflect secular variations in seawater δ^(44/40)Ca. Instead, we propose that it reflects a vital effect of calcification – specifically, a sensitivity of coral Ca isotope discrimination to changing seawater [Ca] and/or pH. Support for this hypothesis comes from the presence of an empirical correlation between our coral δ^(44/40)Ca record and records of seawater [Ca] and pH since the Mesozoic (Lowenstein et al., 2003 and Hönisch et al., 2012). We explore various mechanisms that could give rise to such a vital effect, including: (1) changes in calcification rate, (2) changes in proton pumping in exchange for Ca^(2+), (3) variable Rayleigh distillation from an isolated calcifying fluid, and (4) changes in the calcium mass balance of the extracellular calcifying fluid (termed here the “leaky Ca model”). We test for the dependence of seawater δ^(44/40)Ca on external seawater [Ca] by measuring the δ^(44/40)Ca of cultured corals grown in seawater solutions with [Ca] ranging from 10 to 15 mmol/kg. Corals grown under elevated [Ca] conditions show a slight, ∼0.15‰ depletion of δ^(44/40)Ca at higher seawater [Ca] – a supportive but not definitive result

Reproducibility and day time bias correction of optoelectronic leg volumetry: a prospective cohort study

Background Leg edema is a common manifestation of various underlying pathologies. Reliable measurement tools are required to quantify edema and monitor therapeutic interventions. Aim of the present work was to investigate the reproducibility of optoelectronic leg volumetry over 3 weeks' time period and to eliminate daytime related within-individual variability. Methods Optoelectronic leg volumetry was performed in 63 hairdressers (mean age 45 ± 16 years, 85.7% female) in standing position twice within a minute for each leg and repeated after 3 weeks. Both lower leg (legBD) and whole limb (limbBF) volumetry were analysed. Reproducibility was expressed as analytical and within-individual coefficients of variance (CVA, CVW), and as intra-class correlation coefficients (ICC). Results A total of 492 leg volume measurements were analysed. Both legBD and limbBF volumetry were highly reproducible with CVA of 0.5% and 0.7%, respectively. Within-individual reproducibility of legBD and limbBF volumetry over a three weeks' period was high (CVW 1.3% for both; ICC 0.99 for both). At both visits, the second measurement revealed a significantly higher volume compared to the first measurement with a mean increase of 7.3 ml ± 14.1 (0.33% ± 0.58%) for legBD and 30.1 ml ± 48.5 ml (0.52% ± 0.79%) for limbBF volume. A significant linear correlation between absolute and relative leg volume differences and the difference of exact day time of measurement between the two study visits was found (P < .001). A therefore determined time-correction formula permitted further improvement of CVW. Conclusions Leg volume changes can be reliably assessed by optoelectronic leg volumetry at a single time point and over a 3 weeks' time period. However, volumetry results are biased by orthostatic and daytime-related volume changes. The bias for day-time related volume changes can be minimized by a time-correction formula

An Efficient Coding Hypothesis Links Sparsity and Selectivity of Neural Responses

To what extent are sensory responses in the brain compatible with first-order principles? The efficient coding hypothesis projects that neurons use as few spikes as possible to faithfully represent natural stimuli. However, many sparsely firing neurons in higher brain areas seem to violate this hypothesis in that they respond more to familiar stimuli than to nonfamiliar stimuli. We reconcile this discrepancy by showing that efficient sensory responses give rise to stimulus selectivity that depends on the stimulus-independent firing threshold and the balance between excitatory and inhibitory inputs. We construct a cost function that enforces minimal firing rates in model neurons by linearly punishing suprathreshold synaptic currents. By contrast, subthreshold currents are punished quadratically, which allows us to optimally reconstruct sensory inputs from elicited responses. We train synaptic currents on many renditions of a particular bird's own song (BOS) and few renditions of conspecific birds' songs (CONs). During training, model neurons develop a response selectivity with complex dependence on the firing threshold. At low thresholds, they fire densely and prefer CON and the reverse BOS (REV) over BOS. However, at high thresholds or when hyperpolarized, they fire sparsely and prefer BOS over REV and over CON. Based on this selectivity reversal, our model suggests that preference for a highly familiar stimulus corresponds to a high-threshold or strong-inhibition regime of an efficient coding strategy. Our findings apply to songbird mirror neurons, and in general, they suggest that the brain may be endowed with simple mechanisms to rapidly change selectivity of neural responses to focus sensory processing on either familiar or nonfamiliar stimuli. In summary, we find support for the efficient coding hypothesis and provide new insights into the interplay between the sparsity and selectivity of neural responses

Oncoplastic Breast Consortium consensus conference on nipple-sparing mastectomy

Purpose Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion. Methods The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology. Results Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference. Conclusions In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques

Aerosols Transmit Prions to Immunocompetent and Immunodeficient Mice

Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrPC, efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrPC selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrPSc and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories

Plasmacytoid Dendritic Cells Sequester High Prion Titres at Early Stages of Prion Infection

In most transmissible spongiform encephalopathies prions accumulate in the lymphoreticular system (LRS) long before they are detectable in the central nervous system. While a considerable body of evidence showed that B lymphocytes and follicular dendritic cells play a major role in prion colonization of lymphoid organs, the contribution of various other cell types, including antigen-presenting cells, to the accumulation and the spread of prions in the LRS are not well understood. A comprehensive study to compare prion titers of candidate cell types has not been performed to date, mainly due to limitations in the scope of animal bioassays where prohibitively large numbers of mice would be required to obtain sufficiently accurate data. By taking advantage of quantitative in vitro prion determination and magnetic-activated cell sorting, we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion infection. Robust estimates for infectious titers were obtained by statistical modelling using a generalized linear model. Whilst prions were detectable in B and T lymphocytes and in antigen-presenting cells like dendritic cells and macrophages, highest infectious titers were determined in two cell types that have previously not been associated with prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. At 30 days after infection, NK cells were more than twice, and pDCs about seven-fold, as infectious as lymphocytes respectively. This result was unexpected since, in accordance to previous reports prion protein, an obligate requirement for prion replication, was undetectable in pDCs. This underscores the importance of prion sequestration and dissemination by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. We furthermore report the first evidence for a release of prions from lymphocytes and DCs of scrapie-infected mice ex vivo, a process that is associated with a release of exosome-like membrane vesicles

Oncoplastic Breast Consortium consensus conference on nipple-sparing mastectomy.

Purpose Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion. Methods The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology. Results Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference. Conclusions In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques

Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells.

BACKGROUND: Aging is characterized by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of aging on B cell development, we profiled gene expression and chromatin features genome-wide, including histone modifications and chromosome conformation, in bone marrow pro-B and pre-B cells from young and aged mice. RESULTS: Our analysis reveals that the expression levels of most genes are generally preserved in B cell precursors isolated from aged compared with young mice. Nonetheless, age-specific expression changes are observed at numerous genes, including microRNA encoding genes. Importantly, these changes are underpinned by multi-layered alterations in chromatin structure, including chromatin accessibility, histone modifications, long-range promoter interactions, and nuclear compartmentalization. Previous work has shown that differentiation is linked to changes in promoter-regulatory element interactions. We find that aging in B cell precursors is accompanied by rewiring of such interactions. We identify transcriptional downregulation of components of the insulin-like growth factor signaling pathway, in particular downregulation of Irs1 and upregulation of Let-7 microRNA expression, as a signature of the aged phenotype. These changes in expression are associated with specific alterations in H3K27me3 occupancy, suggesting that Polycomb-mediated repression plays a role in precursor B cell aging. CONCLUSIONS: Changes in chromatin and 3D genome organization play an important role in shaping the altered gene expression profile of aged precursor B cells. Components of the insulin-like growth factor signaling pathways are key targets of epigenetic regulation in aging in bone marrow B cell precursors