Global declines in coral reef calcium carbonate production under ocean acidification and warming

Ocean warming and acidification threaten the future growth of coral reefs. This is because the calcifying coral reef taxa that construct the calcium carbonate frameworks and cement the reef together are highly sensitive to ocean warming and acidification. However, the global-scale effects of ocean warming and acidification on rates of coral reef net carbonate production remain poorly constrained despite a wealth of studies assessing their effects on the calcification of individual organisms. Here, we present global estimates of projected future changes in coral reef net carbonate production under ocean warming and acidification. We apply a meta-analysis of responses of coral reef taxa calcification and bioerosion rates to predicted changes in coral cover driven by climate change to estimate the net carbonate production rates of 183 reefs worldwide by 2050 and 2100. We forecast mean global reef net carbonate production under representative concentration pathways (RCP) 2.6, 4.5, and 8.5 will decline by 76, 149, and 156%, respectively, by 2100. While 63% of reefs are projected to continue to accrete by 2100 under RCP2.6, 94% will be eroding by 2050 under RCP8.5, and no reefs will continue to accrete at rates matching projected sea level rise under RCP4.5 or 8.5 by 2100. Projected reduced coral cover due to bleaching events predominately drives these declines rather than the direct physiological impacts of ocean warming and acidification on calcification or bioerosion. Presently degraded reefs were also more sensitive in our analysis. These findings highlight the low likelihood that the world’s coral reefs will maintain their functional roles without near-term stabilization of atmospheric CO2 emissions

The role of Foxa2 in the pancreatic β cell

Glucose homeostasis is a tightly-regulated process involving multiple tissues in the body. The pancreas is an endoderm-derived organ responsible for glucose-sensing as well as the subsequent secretion of insulin, the hormone responsible for the promotion of glucose uptake and restoring glucose levels to physiological baseline. Foxa2 (Forkhead box a2 ) encodes a winged-helix transcription factor expressed in the pancreas during embryogenesis and throughout adulthood. Foxa2 is a known transcriptional regulator and is necessary for murine survival beyond embryonic day 11 (E11). Because of the early lethality of Foxa2 −/− mice, the precise role of this gene in pancreatic function has not yet been fully elucidated. To investigate the role of Foxa2 in the pancreas, a mouse model harboring a β cell-specific deletion was generated which utilizes Cre recombinase under control of the rat Insulin 2 promoter to delete Foxa2 as early as E14.5. Foxa2 loxP/loxP;Ins.Cre mice are growth-delayed and succumb to hyperinsulinemic hypoglycemia 7–12 days after birth. Along with improper calcium influx and insulin secretion from mutant islets in response to glucose and amino acids, my findings reveal several targets of Foxa2, including Sur1 and Kir6.2, the components of the KATP channel. One additional target, Hadhsc, encodes an enzyme involved in fatty acid oxidation. Interestingly, the human orthologues of these three genes, SUR1, KIR6.2, and SCHAD, are mutated in some patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI). A second model, under current investigation, has three genetics requirements and will utilize the drug doxycycline as part of the Tet-On™ Gene Expression System to inducibly delete Foxa2 in adult mice. Utilizing the Z/AP reporter line with alkaline phosphatase as a readout of Cre activity, I chose an effective transgenic promoter line to facilitate the β cell-specific deletion of Foxa2 at the timepoint(s) of our choice. Through comparison of a series of physiological tests conducted before and after doxycycline treatment (Foxa2 deletion), I will soon be able to assess the role of Foxa2 in adult mice. Although further investigation is necessary, these studies will further elucidate the role of Foxa2 in the pancreas and strengthen our understanding of the regulation of glucose homeostasis

The role of Foxa2 in the pancreatic β cell

Glucose homeostasis is a tightly-regulated process involving multiple tissues in the body. The pancreas is an endoderm-derived organ responsible for glucose-sensing as well as the subsequent secretion of insulin, the hormone responsible for the promotion of glucose uptake and restoring glucose levels to physiological baseline. Foxa2 (Forkhead box a2 ) encodes a winged-helix transcription factor expressed in the pancreas during embryogenesis and throughout adulthood. Foxa2 is a known transcriptional regulator and is necessary for murine survival beyond embryonic day 11 (E11). Because of the early lethality of Foxa2 −/− mice, the precise role of this gene in pancreatic function has not yet been fully elucidated. To investigate the role of Foxa2 in the pancreas, a mouse model harboring a β cell-specific deletion was generated which utilizes Cre recombinase under control of the rat Insulin 2 promoter to delete Foxa2 as early as E14.5. Foxa2 loxP/loxP;Ins.Cre mice are growth-delayed and succumb to hyperinsulinemic hypoglycemia 7–12 days after birth. Along with improper calcium influx and insulin secretion from mutant islets in response to glucose and amino acids, my findings reveal several targets of Foxa2, including Sur1 and Kir6.2, the components of the KATP channel. One additional target, Hadhsc, encodes an enzyme involved in fatty acid oxidation. Interestingly, the human orthologues of these three genes, SUR1, KIR6.2, and SCHAD, are mutated in some patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI). A second model, under current investigation, has three genetics requirements and will utilize the drug doxycycline as part of the Tet-On™ Gene Expression System to inducibly delete Foxa2 in adult mice. Utilizing the Z/AP reporter line with alkaline phosphatase as a readout of Cre activity, I chose an effective transgenic promoter line to facilitate the β cell-specific deletion of Foxa2 at the timepoint(s) of our choice. Through comparison of a series of physiological tests conducted before and after doxycycline treatment (Foxa2 deletion), I will soon be able to assess the role of Foxa2 in adult mice. Although further investigation is necessary, these studies will further elucidate the role of Foxa2 in the pancreas and strengthen our understanding of the regulation of glucose homeostasis

Foxa2 regulates multiple pathways of insulin secretion

The regulation of insulin secretion by pancreatic β cells is perturbed in several diseases, including adult-onset (type 2) diabetes and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). The first mouse model for PHHI has a conditional deletion of the gene encoding the winged-helix transcription factor Foxa2 (Forkhead box a2, formerly Hepatocyte nuclear factor 3β) in pancreatic β cells. Using isolated islets, we found that Foxa2 deficiency resulted in excessive insulin release in response to amino acids and complete loss of glucose-stimulated insulin secretion. Most PHHI cases are associated with mutations in SUR1 (Sulfonylurea receptor 1) or KIR6.2 (Inward rectifier K(+) channel member 6.2), which encode the subunits of the ATP-sensitive K(+) channel, and RNA in situ hybridization of mutant mouse islets revealed that expression of both genes is Foxa2 dependent. We utilized expression profiling to identify additional targets of Foxa2. Strikingly, one of these genes, Hadhsc, encodes short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase, deficiency of which has been shown to cause PHHI in humans. Hadhsc is a direct target of Foxa2, as demonstrated by cotransfection as well as in vivo chromatin immunoprecipitation experiments using isolated islets. Thus, we have established Foxa2 as an essential activator of genes that function in multiple pathways governing insulin secretion

Transcriptional program of the endocrine pancreas in mice and humans

International audienceThe Endocrine Pancreas Consortium was formed in late 1999 to derive and sequence cDNA libraries enriched for rare transcripts expressed in the mammalian endocrine pancreas. Over the past 3 years, the Consortium has generated 20 cDNA libraries from mouse and human pancreatic tissues and deposited >150,000 sequences into the public expressed sequence tag databases. A special effort was made to enrich for cDNAs from the endocrine pancreas by constructing libraries from isolated islets. In addition, we constructed a library in which fetal pancreas from Neurogenin 3 null mice, which consists of only exocrine and duct cells, was subtracted from fetal wild-type pancreas to enrich for the transcripts from the endocrine compartment. Sequence analysis showed that these clones cluster into 9,464 assembly groups (approximating unique transcripts) for the mouse and 13,910 for the human sequences. Of these, >4,300 were unique to Consortium libraries. We have assembled a core clone set containing one cDNA for each assembly group for the mouse and have constructed the corresponding microarray, termed "PancChip 4.0," which contains >9,000 nonredundant elements. We show that this PancChip is highly enriched for genes expressed in the endocrine pancreas. The mouse and human clone sets and corresponding arrays will be important resources for diabetes research

Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial

[EN] Background: Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab. Methods: In this ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomised, phase 3 trial, we recruited adult patients (age ≥18 years) if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66–85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1–2), every 2 weeks (cycles 3–6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration (Ctrough; cycle 3, day 1 pre-dose). The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose. This trial is registered with ClinicalTrials.gov, NCT03277105. Findings: Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5–9·3), overall response and Ctrough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89–1·37). The geometric means ratio for Ctrough was 107·93% (90% CI 95·74–121·67), and the maximum Ctrough was 593 μg/mL (SD 306) in the subcutaneous group and 522 μg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 [13%] of 260 patients evaluable for safety in the subcutaneous group and 36 [14%] of 258 patients in the intravenous group), neutropenia (34 [13%] and 20 [8%]), and thrombocytopenia (36 [14%] and 35 [14%]). Pneumonia was the only serious adverse event in more than 2% of patients (seven [3%] in the subcutaneous group and 11 [4%] in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1]). Interpretation: Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. These data could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies