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[This corrects the article DOI: 10.1371/journal.pone.0203126.].[This corrects the article DOI: 10.1371/journal.pone.0203126.].

Induced pluripotent stem cell (iPSC) technology enables the creation and selection of pluripotent cells with specific genetic traits. This report describes a pluripotent cell line created specifically to form replacement pancreatic cells as a therapy for insulin-dependent diabetes. Beginning with primary pancreatic tissue acquired through organ donation, cells were isolated, re-programmed using non-integrating vectors and exposed to a four day differentiation protocol to generate definitive endoderm, a developmental precursor to pancreas. The best performing iPSC lines were then subjected to a 12-day basic differentiation protocol to generate endocrine pancreas precursors. The line that most consistently generated highly pure populations was selected for further development. This approach created an iPSC-variant cell line, SR1423, with a genetic profile correlated with preferential differentiation toward endodermal lineage at the loss of mesodermal potential. This report further describes an improved differentiation protocol that, coupled with SR1423, generated populations of greater than 60% insulin-expressing cells that secrete insulin in response to glucose and are capable of reversing diabetes in rodents. Created and banked following cGMP guidelines, SR1423 is a candidate cell line for the production of insulin-producing cells useful for the treatment of diabetes.

We examined data and patterns in clinical islet transplant studies registered on ClinicalTrials.gov (CTgov) for treatment of type 1 diabetes (T1D), with a goal of extracting insights to apply in the design of a pluripotent stem cell‐derived islet therapy. Clinical islet transplantation, as a cell therapy (rather than solid organ transplant) is a unique precedent for stem cell‐based islet therapies. Registration activity shows that the field is not growing significantly, and newer registrations suggest that the reasons for stagnation include need for a more optimal site of infusion/transplantation, and especially a need for better immune protective strategies to advance a more effective and durable therapy for T1D. Stem Cells Translational Medicine 2019;8:209&214 Current versus future islet transplantation. Currently islets from cadaveric donors are infused into the portal vein of recipients, often two donors are required for adequate islet mass. These non‐encapsulated, allogeneic cells are highly immunogenic and systemic pharmacologic immune suppression is required. Future islet transplantation will likely be accomplished using encapsulated pluripotent stem cell‐derived islets transplanted onto the (highly vascular) omentum of recipients, with the goal of encapsulation to completely or significantly reduce the allogeneic immune rejection response.

Bayesian additive regression trees (BART) is a Bayesian approach to flexible nonlinear regression which has been shown to be competitive with the best modern predictive methods such as those based on bagging and boosting. BART offers some advantages. For example, the stochastic search Markov chain Monte Carlo (MCMC) algorithm can provide a more complete search of the model space and variation across MCMC draws can capture the level of uncertainty in the usual Bayesian way. The BART prior is robust in that reasonable results are typically obtained with a default prior specification. However, the publicly available implementation of the BART algorithm in the R package BayesTree is not fast enough to be considered interactive with over a thousand observations, and is unlikely to even run with 50,000 to 100,000 observations. In this article we show how the BART algorithm may be modified and then computed using single program, multiple data (SPMD) parallel computation implemented using the Message Passing Interface (MPI) library. The approach scales nearly linearly in the number of processor cores, enabling the practitioner to perform statistical inference on massive datasets. Our approach can also handle datasets too massive to fit on any single data repository.

The production of a homogenous population of human cardiomyocytes that can be expanded may facilitate development of replacement tissue lost as a result of cardiac disease and injury. We evaluated the utility of activated leukocyte cell-adhesion molecule, CD166 (ALCAM) expression as a marker for isolating cardiomyocytes from differentiating cultures of human embryonic stem cells (hESCs). Using RT-qPCR, immunohistochemistry and DNA methylation studies, we evaluated the developmental age of hESC-derived cardiomyocytes. We demonstrate that cardiomyocytes derived from hESC cultures express ALCAM and that this surface antigen can be used to select a population of differentiated cells that are enriched for cardiomyocytes. Expression of contractile proteins and ion channels, and DNA methylation patterns, suggest that ALCAM-enriched cardiomyocytes have an embryonic phenotype. Selected cardiomyocyte populations survive sorting, adhere to collagen-coated tissue culture plastic and proliferate in short-term culture. Long-term survival of cardiomyocytes was achieved by culturing cells in 3D aggregates.

Los Alamos National Laboratory is home to many large supercomputing clusters. These clusters require an enormous amount of power (∼500-2000 kW each), and most of this energy is converted into heat. Thus, cooling the components of the supercomputer becomes a critical and expensive endeavor. Recently, a project was initiated to investigate the effect that changes to the cooling system in a machine room had on three large machines that were housed there. Coupled with this goal was the aim to develop a general good-practice for characterizing the effect of cooling changes and monitoring machine node temperatures in this and other machine rooms. This article focuses on the statistical approach used to quantify the effect that several cooling changes to the room had on the temperatures of the individual nodes of the computers. The largest cluster in the room has 1600 nodes that run a variety of jobs during general use. Since extremes temperatures are important, a Normal distribution plus generalized Pareto distribution for the upper tail is used to model the marginal distribution, along with a Gaussian process copula to account for spatio-temporal dependence. A Gaussian Markov random field (GMRF) model is used to model the spatial effects on the node temperatures as the cooling changes take place. This model is then used to assess the condition of the node temperatures after each change to the room. The analysis approach was used to uncover the cause of a problematic episode of overheating nodes on one of the supercomputing clusters. This same approach can easily be applied to monitor and investigate cooling systems at other data centers, as well. Supplementary materials for this article are available online.

Although most Americans paid little attention to Cambodia during Dwight D.Eisenhower's presidency, the nation's proximity to China and the global ideological struggle with the Soviet Union guaranteed US vigilance throughout Southeast Asia.

Predicting the next major drought is of paramount interest to water managers globally. Estimating the onset of groundwater drought is of particular importance, as groundwater resources are often assumed to be more resilient when surface water resources begin to fail. A potential source of long-term forecasting is offered by possible periodic controls on groundwater level via teleconnections with oscillatory ocean–atmosphere systems. However, relationships between large-scale climate systems and regional to local-scale rainfall, evapotranspiration (ET) and groundwater are often complex and non-linear so that the influence of long-term climate cycles on groundwater drought remains poorly understood. Furthermore, it is currently unknown whether the absolute contribution of multi-annual climate variability to total groundwater storage is significant. This study assesses the extent to which multi-annual variability in groundwater can be used to indicate the timing of groundwater droughts in the UK. Continuous wavelet transforms show how repeating teleconnection-driven 7-year and 16–32-year cycles in the majority of groundwater sites from all the UK's major aquifers can systematically control the recurrence of groundwater drought; and we provide evidence that these periodic modes are driven by teleconnections. Wavelet reconstructions demonstrate that multi-annual periodicities of the North Atlantic Oscillation, known to drive North Atlantic meteorology, comprise up to 40 % of the total groundwater storage variability. Furthermore, the majority of UK recorded droughts in recent history coincide with a minimum phase in the 7-year NAO-driven cycles in groundwater level, providing insight into drought occurrences on a multi-annual timescale. Long-range groundwater drought forecasts via climate teleconnections present transformational opportunities to drought prediction and its management across the North Atlantic region.

Excess aldosterone accelerates chronic kidney disease progression. This phase 2 clinical trial assessed BI 690517, an aldosterone synthase inhibitor, for efficacy, safety, and dose selection. This was a multinational, randomised, controlled, phase 2 trial. People aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 30 to less than 90 mL/min/1·73 m2, a urine albumin to creatinine ratio (UACR) of 200 to less than 5000 mg/g, and serum potassium of 4·8 mmol/L or less, taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, were enrolled. Participants were randomly assigned (1:1) to 8 weeks of empagliflozin or placebo run-in, followed by a second randomisation (1:1:1:1) to 14 weeks of treatment with once per day BI 690517 at doses of 3 mg, 10 mg, or 20 mg, or placebo. Study participants, research coordinators, investigators, and the data coordinating centre were masked to treatment assignment. The primary endpoint was the change in UACR measured in first morning void urine from baseline (second randomisation) to the end of treatment. This study is registered with ClinicalTrials.gov (NCT05182840) and is completed. Between Feb 18 and Dec 30, 2022, of the 714 run-in participants, 586 were randomly assigned to receive BI 690517 or placebo. At baseline, 33% (n=196) were women, 67% (n=390) were men, 42% (n=244) had a racial identity other than White, and mean participant age was 63·8 years (SD 11·3). Mean baseline eGFR was 51·9 mL/min/1·73 m2 (17·7) and median UACR was 426 mg/g (IQR 205 to 889). Percentage change in first morning void UACR from baseline to the end of treatment at week 14 was –3% (95% CI –19 to 17) with placebo, –22% (–36 to –7) with BI 690517 3 mg, –39% (–50 to –26) with BI 690517 10 mg, and –37% (–49 to –22) with BI 690517 20 mg monotherapy. BI 690517 produced similar UACR reductions when added to empagliflozin. Investigator-reported hyperkalaemia occurred in 10% (14/146) of those in the BI 690517 3 mg group, 15% (22/144) in the BI 690517 10 mg group, and 18% (26/146) in the BI 690517 20 mg group, and in 6% (nine of 147) of those receiving placebo, with or without empagliflozin. Most participants with hyperkalaemia did not require intervention (86% [72/84]). Adrenal insufficiency was an adverse event of special interest reported in seven of 436 study participants (2%) receiving BI 690517 and one of 147 participants (1%) receiving matched placebo. No treatment-related deaths occurred during the study. BI 690517 dose-dependently reduced albuminuria with concurrent renin–angiotensin system inhibition and empagliflozin, suggesting an additive efficacy for chronic kidney disease treatment without unexpected safety signals. Boehringer Ingelheim.

Drought forecasting and early warning systems for water resource extremes are increasingly important tools in water resource management in Europe where increased population density and climate change are expected to place greater pressures on water supply. In this context, the North Atlantic Oscillation (NAO) is often used to indicate future water resource behaviours (including droughts) over Europe, given its dominant control on winter rainfall totals in the North Atlantic region. Recent hydroclimate research has focused on the role of multiannual periodicities in the NAO in driving low frequency behaviours in some water resources, suggesting that notable improvements to lead-times in forecasting may be possible by incorporating these multiannual relationships. However, the importance of multiannual NAO periodicities for driving water resource behaviour, and the feasibility of this relationship for indicating future droughts, has yet to be assessed in the context of known non-stationarities that are internal to the NAO and its influence on European meteorological processes. Here we quantify the time–frequency relationship between the NAO and a large dataset of water resources records to identify key non-stationarities that have dominated multiannual behaviour of water resource extremes over recent decades. The most dominant of these is a 7.5-year periodicity in water resource extremes since approximately 1970 but which has been diminishing since 2005. Furthermore, we show that the non-stationary relationship between the NAO and European rainfall is clearly expressed at multiannual periodicities in the water resource records assessed. These multiannual behaviours are found to have modulated historical water resource anomalies to an extent that is comparable to the projected effects of a worst-case climate change scenario. Furthermore, there is limited systematic understanding in existing atmospheric research for non-stationarities in these periodic behaviours which poses considerable implications to existing water resource forecasting and projection systems, as well as the use of these periodic behaviours as an indicator of future water resource drought.