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The purpose of this study was to predict a safe starting dose of AMG 181, a human anti‐α4β7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two‐compartment model with parallel linear and target‐mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK. An Emax PD model was used to relate AMG 181 concentration and free α4β7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg−1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α4β7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day−1 and 2900 mL, respectively. The estimated EC50 for free α4β7 receptor was 14 ng·mL−1. At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α4β7 receptor EC10. Predictions for both Cmax and AUC matched with those observed in the first‐in‐human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone. e00098

The purpose of this study was to predict a safe starting dose of AMG 181, a human anti‐ α 4 β 7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic ( PK ) and pharmacodynamic ( PD ) data. A two‐compartment model with parallel linear and target‐mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK . An E max PD model was used to relate AMG 181 concentration and free α 4 β 7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg −1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α 4 β 7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day −1 and 2900 mL, respectively. The estimated EC 50 for free α 4 β 7 receptor was 14 ng·mL −1 . At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α 4 β 7 receptor EC 10 . Predictions for both C max and AUC matched with those observed in the first‐in‐human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone. e00098

Assembling an informed group of scholars, this volume focuses on the study and practice of central agencies, regulation, budgeting, energy and science policy, and governing instruments. A overview that looks beyond Doern’s tremendous body of work, Policy: From Ideas to Implementation is also a survey of the methods and central issues of the Canadian and international public policy disciplines.

By the end of April 1994, much of the bullishness for the US dollar had been crushed. Implied volatility was pushed down to particularly low levels in US dollar/Deutschmark and sterling/US dollar. Only in US dollar/yen, where the currency has flirted nervously with Y100/US$ on several occasions, has volatility sustainably remained bid. With 1/3 of the year now over, the market must ask itself whether it should back its long-term view (based on the still-strong economic fundamentals in the US economy) and take advantage of the current dip in volatility, or whether it should sell volatility on the assumption that the long-term view cannot be sustained in the face of the strong supply of dollars that constantly caps any rally. Royal Bank of Scotland economists' forecasts for the 3rd and 4th quarters of 1994 are presented. Using their predictions for sterling/US dollar, potential methods of hedging the view that sterling will depreciate to $1.42 in the 4th quarter are also presented.

We present a novel algorithm for scheduling the observations of time-domain imaging surveys. Our integer linear programming approach optimizes an observing plan for an entire night by assigning targets to temporal blocks, enabling strict control of the number of exposures obtained per field and minimizing filter changes. A subsequent optimization step minimizes slew times between each observation. Our optimization metric self-consistently weights contributions from time-varying airmass, seeing, and sky brightness to maximize the transient discovery rate. We describe the implementation of this algorithm on the surveys of the Zwicky Transient Facility and present its on-sky performance.

The occurrence of extreme precipitation events in New Zealand regularly results in devastating impacts to the local society and environment. An automated atmospheric river (AR) detection technique (ARDT) is applied to construct a climatology (1979–2019) of extreme midlatitude moisture fluxes conducive to extreme precipitation. A distinct seasonality exists in AR occurrence aligning with seasonal variations in the midlatitude jet streams. The formation of the Southern Hemisphere winter split jet enables AR occurrence to persist through all seasons in northern regions of New Zealand, while southern regions of the country exhibit a substantial (50%) reduction in AR occurrence as the polar jet shifts southward during the cold season. ARs making landfall on the western coast of New Zealand (90% of all events) are characterized by a dominant northwesterly moisture flux associated with a distinct dipole pressure anomaly, with low pressure to the southwest and high pressure to the northeast of New Zealand. Precipitation totals during AR events increase with AR rank (five-point scale) throughout the country, with the most substantial increase on the windward side of the Southern Alps (South Island). The largest events (rank 5ARs) produce 3-day precipitation totals exceeding 1000 mm. ARs account for up to 78% of total precipitation and up to 94% of extreme precipitation on the west coast of the South Island. Assessment of the multiscale atmospheric processes associated with AR events governing extreme precipitation in the Southern Alps of New Zealand should remain a priority given their hydrological significance and impact on people and infrastructure.

Background A fundamental ethical issue in African genomics research is how socio-cultural factors impact perspectives, acceptance, and utility of genomic information, especially in stigmatizing conditions like orofacial clefts (OFCs). Previous research has shown that gatekeepers (e.g., religious, political, family or community leaders) wield considerable influence on the decision-making capabilities of their members, including health issues. Thus, their perspectives can inform the design of engagement strategies and increase exposure to the benefits of genomics testing/research. This is especially important for Africans underrepresented in genomic research. Our study aims to investigate the perspectives of gatekeepers concerning genomic risk information (GRI) in the presence of OFCs in a sub-Saharan African cohort. Methods Twenty-five focus group discussions (FGDs) consisting of 214 gatekeepers (religious, community, ethnic leaders, and traditional birth attendants) in Lagos, Nigeria, explored the opinions of participants on genomic risk information (GRI), OFC experience, and the possibility of involvement in collaborative decision-making in Lagos, Nigeria. Transcripts generated from audio recordings were coded and analyzed in NVivo using thematic analysis. Results Three main themes—knowledge, beliefs, and willingness to act—emerged from exploring the perspective of gatekeepers about GRI in this group. We observed mixed opinions regarding the acceptance of GRI. Many participants believed their role is to guide and support members when they receive results; this is based on the level of trust their members have in them. However, participants felt they would need to be trained by medical experts to do this. Also, religious and cultural beliefs were crucial to determining participants’ understanding of OFCs and the acceptance and utilization of GRI. Conclusions Incorporating cultural sensitivity into public engagement could help develop appropriate strategies to manage conflicting ideologies surrounding genomic information in African communities. This will allow for more widespread access to the advances in genomics research in underrepresented populations. We also recommend a synergistic relationship between community health specialists/scientists, and community leaders, including spiritual providers to better understand and utilize GRI.

Kidney stones (also known as urinary stones or nephrolithiasis) are highly prevalent, affecting approximately 10% of adults worldwide, and the incidence of stone disease is increasing. Kidney stone formation results from an imbalance of inhibitors and promoters of crystallization, and calcium-containing calculi account for over 80% of stones. In most patients, the underlying aetiology is thought to be multifactorial, with environmental, dietary, hormonal and genetic components. The advent of high-throughput sequencing techniques has enabled a monogenic cause of kidney stones to be identified in up to 30% of children and 10% of adults who form stones, with ~35 different genes implicated. In addition, genome-wide association studies have implicated a series of genes involved in renal tubular handling of lithogenic substrates and of inhibitors of crystallization in stone disease in the general population. Such findings will likely lead to the identification of additional treatment targets involving underlying enzymatic or protein defects, including but not limited to those that alter urinary biochemistry.Mutations in ~35 genes have been identified as monogenic causes of kidney stone disease, and gene variants have been associated with stone disease in the general population. Here, the authors discuss the genetic and molecular basis of kidney stone disease and nephrocalcinosis.

Inorganic polyphosphate is a ubiquitous, linear biopolymer built of up to thousands of phosphate residues that are linked by energy-rich phosphoanhydride bonds. Polyphosphate kinases of the family 2 (PPK2) use polyphosphate to catalyze the reversible phosphorylation of nucleotide phosphates and are highly relevant as targets for new pharmaceutical compounds and as biocatalysts for cofactor regeneration. PPK2s can be classified based on their preference for nucleoside mono- or diphosphates or both. The detailedmechanism of PPK2s and the molecular basis for their substrate preference is unclear, which is mainly due to the lack of high-resolution structures with substrates or substrate analogs. Here, we report the structural analysis and comparison of a class I PPK2 (ADP-phosphorylating) and a class III PPK2 (AMP- and ADP-phosphorylating), both complexed with polyphosphate and/or nucleotide substrates. Together with complementary biochemical analyses, these define the molecular basis of nucleotide specificity and are consistent with a Mg2+ catalyzed in-line phosphoryl transfer mechanism. This mechanistic insight will guide the development of PPK2 inhibitors as potential antibacterials or genetically modified PPK2s that phosphorylate alternative substrates.

Modern MRI image processing methods have yielded quantitative, morphometric, functional, and structural assessments of the human brain. These analyses typically exploit carefully optimized protocols for specific imaging targets. Algorithm investigators have several excellent public data resources to use to test, develop, and optimize their methods. Recently, there has been an increasing focus on combining MRI protocols in multi-parametric studies. Notably, these have included innovative approaches for fusing connectivity inferences with functional and/or anatomical characterizations. Yet, validation of the reproducibility of these interesting and novel methods has been severely hampered by the limited availability of appropriate multi-parametric data. We present an imaging protocol optimized to include state-of-the-art assessment of brain function, structure, micro-architecture, and quantitative parameters within a clinically feasible 60-min protocol on a 3-T MRI scanner. We present scan–rescan reproducibility of these imaging contrasts based on 21 healthy volunteers (11 M/10 F, 22–61 years old). The cortical gray matter, cortical white matter, ventricular cerebrospinal fluid, thalamus, putamen, caudate, cerebellar gray matter, cerebellar white matter, and brainstem were identified with mean volume-wise reproducibility of 3.5%. We tabulate the mean intensity, variability, and reproducibility of each contrast in a region of interest approach, which is essential for prospective study planning and retrospective power analysis considerations. Anatomy was highly consistent on structural acquisition (~1–5% variability), while variation on diffusion and several other quantitative scans was higher (~<10%). Some sequences are particularly variable in specific structures (ASL exhibited variation of 28% in the cerebral white matter) or in thin structures (quantitative T2 varied by up to 73% in the caudate) due, in large part, to variability in automated ROI placement. The richness of the joint distribution of intensities across imaging methods can be best assessed within the context of a particular analysis approach as opposed to a summary table. As such, all imaging data and analysis routines have been made publicly and freely available. This effort provides the neuroimaging community with a resource for optimization of algorithms that exploit the diversity of modern MRI modalities. Additionally, it establishes a baseline for continuing development and optimization of multi-parametric imaging protocols. ► Presents and evaluates a 60-min multi-parametric imaging protocol at 3T. ► Assesses brain function, structural, micro-architecture, and quantitative parameters. ► Tabulates intensity, variability, and reproducibility of MR contrasts. ► Provides a resource for study planning and algorithm optimization. ► Establishes a baseline for development multi-parametric imaging protocols.