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

Managing the whole landscape: historical, hybrid, and novel ecosystems

The reality confronting ecosystem managers today is one of heterogeneous, rapidly transforming landscapes, particularly in the areas more affected by urban and agricultural development. A landscape management framework that incorporates all systems, across the spectrum of degrees of alteration, provides a fuller set of options for how and when to intervene, uses limited resources more effectively, and increases the chances of achieving management goals. That many ecosystems have departed so substantially from their historical trajectory that they defy conventional restoration is not in dispute. Acknowledging novel ecosystems need not constitute a threat to existing policy and management approaches. Rather, the development of an integrated approach to management interventions can provide options that are in tune with the current reality of rapid ecosystem change

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

Numerical Analysis and Experimental Study of Fiber Bundles and Multi-core Photonic Crystal Fibers for use in Endoscopes

Flexible endoscopes for confocal and multiphoton imaging have the potential to revolutionize the medical field by obviating the need for invasive biopsies; however, these high expectations can be achieved only by reducing endoscope size and by improving image resolution. In this dissertation, methods for enhancing the performance of current endoscopes are explored by studying the properties of multi-core fibers using numerical modeling and experimental analysis. Numerical simulation tools are based on the normal mode expansion of the fields, coupled mode theory, and the multipole method. Image fibers (multi-core step-index fibers commonly used in fiber endoscopes) have small, closely spaced cores that are predicted through basic theoretical analysis to be strongly coupled. These image fibers are explained to successfully transmit images because of nonuniformities in their cross-section that reduce inter-core coupling. The wavelength, average core size, and degree of variation in core size determine the strength of coupling between adjacent cores, such that fibers with smaller cores at longer wavelengths require more nonuniformity in order for reliable image transmission. Guidelines are given for assessing the performance of image fibers in a particular system. In addition, due to the random nature of this effect, strong core coupling can be observed experimentally, demonstrating that the quality of images from current endoscopes is still compromised by crosstalk. Multi-core photonic crystal fibers (PCFs) are a potential alternative for use in flexible endoscopes. PCFs achieve tighter mode confinement than image fibers and are therefore predicted to allow higher core densities with less crosstalk and, ultimately, improved image contrast and resolution. The fabrication of these fibers, however, typically introduces nonuniformities into the photonic crystal cladding. Random nonuniformities in the air hole size and location are shown to reduce the coupling length and the coupling efficiency. When the air holes are large, variations in the lattice of less than 1% are sufficient to cause essentially independent core propagation. Nonuniformities are also shown to increase the core birefringence although the dispersion and loss of PCFs are rather robust to variations. Understanding the characteristics of core coupling is a first step towards improving the design of current endoscopes

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

Influence of Disease and Patient Characteristics on Daratumumab Exposure and Clinical Outcomes in Relapsed or Refractory Multiple Myeloma

Objective: The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM). Patients and Methods Baseline myeloma type, albumin levels, renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies were evaluated using data from two clinical studies—GEN501 (N = 104) and SIRIUS (N = 124). Results: Daratumumab clearance was approximately 110% higher in IgG myeloma patients than non-IgG myeloma patients, leading to significantly lower exposure in IgG myeloma patients based on maximum trough serum concentrations (p < 0.0001). However, the overall response rate was similar for IgG and non-IgG myeloma patients (odds ratio 1.08, 95% confidence interval 0.54–2.17, p = 0.82). For a given exposure, the drug effect was significantly higher (approximately two times) in IgG versus non-IgG patients (p = 0.03). The influence of other patient and disease characteristics on daratumumab exposure was minimal and no significant effect on efficacy was observed (p ≥ 0.1). The incidences of infections and overall grade 3 or higher adverse events in subpopulations were generally consistent with that of the overall population. Conclusion: Due to competition with the MM-produced IgG M-protein for neonatal Fc receptor protection from clearance, IgG-based monoclonal antibodies in general may have significantly higher clearance and lower concentrations in IgG MM patients compared with non-IgG MM patients. Careful evaluation of the impact of exposure and patient and disease characteristics on safety and efficacy is warranted for all IgG-based monoclonal antibodies used in MM. Electronic supplementary material The online version of this article (doi:10.1007/s40262-017-0598-1) contains supplementary material, which is available to authorized users

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