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At least 631 records · Page 35

A Systematic Assessment of US Food and Drug Administration Dosing Recommendations For Drug Development Programs Amenable to Response‐Guided Titration

A key goal in drug development is optimized dosing for patients. Interactions between drug developers and regulatory scientists throughout development are important for the optimization of dosing and serve as a forum to discuss approaches for optimal dosing, such as precision or individualized dosing. To date, there has not been a systematic assessment of the advice provided by the US Food and Drug Administration (FDA) to drug developers from an individualized dosing perspective. Here, we reviewed FDA recommendations on dose selection for efficacy trials at end‐of‐phase meetings between the FDA and drug developers for 76 new molecular entities approved between 2013 and 2017 that are considered amenable for an individualized dosing method, response‐guided titration. Forty FDA dosing recommendations were identified as specific to dose selection and design of the respective efficacy trials and subsequently: (i) characterized based on if they were supportive of individualized dosing and (ii) compared with dosing regimens used in efficacy trials and labeling at approval to evaluate if FDA recommendations were implemented. Of these 40 recommendations for efficacy trials, 35 (88%) were considered supportive of individualized dosing. Eighteen of these 40 recommendations (45%) were incorporated into efficacy trials and 11 (28%) were incorporated into labeling. This research suggests that early FDA‐sponsor interactions can support the study of doses in efficacy trials that may lead to individualized dosing strategies in labeling.

Wang, Lingshan↗

Accelerated development of CuSbS 2 thin film photovoltaic device prototypes

Development of alternative thin film photovoltaic technologies is an important research topic because of the potential of low-cost, high-efficiency solar cells to produce terawatt levels of clean power. However, this development of unexplored yet promising absorbers can be hindered by complications that arise during solar cell fabrication. Here, a high-throughput combinatorial method is applied to accelerate development of photovoltaic devices, in this case, using the novel CuSbS2 absorber via a newly developed three-stage self-regulated growth process to control absorber purity and orientation. Photovoltaic performance of the absorber, using the typical substrate CuInxGa1 - xSe2 (CIGS) device architecture, is explored as a function of absorber quality and thickness using a variety of back contacts. This study yields CuSbS2 device prototypes with ~1% conversion efficiency, suggesting that the optimal CuSbS2 device fabrication parameters and contact selection criteria are quite different than for CIGS, despite the similarity of these two absorbers. The CuSbS2 device efficiency is at present limited by low short-circuit current because of bulk recombination related to defects, and a small open-circuit voltage because of a theoretically predicted cliff-type conduction band offset between CuSbS2 and CdS. Overall, these results illustrate both the potential and limits of combinatorial methods to accelerate the development of thin film photovoltaic devices using novel absorbers.

14 SOLAR ENERGY↗

Wood and water: How trees modify wood development to cope with drought

Societal Impact Statement Drought plays a conspicuous role in forest mortality, and is expected to become more severe in future climate scenarios. Recent surges in drought‐associated forest tree mortality have been documented worldwide. For example, recent droughts in California and Texas killed approximately 129 million and 300 million trees, respectively. Drought has also induced acute pine tree mortality across east‐central China, and across extensive areas in southwest China. Understanding the biological processes that enable trees to modify wood development to mitigate the adverse effects of drought will be crucial for the development of successful strategies for future forest management and conservation. Summary Drought is a recurrent stress to forests, causing periodic forest mortality with enormous economic and environmental costs. Wood is the water‐conducting tissue of tree stems, and trees modify wood development to create anatomical features and hydraulic properties that can mitigate drought stress. This modification of wood development can be seen in tree rings where not only the amount of wood but also the morphology of the water‐conducting cells are modified in response to environmental conditions. In this review, we provide an overview of how trees conduct water, and how trees modify wood development to affect water conduction properties in response to drought. We discuss key needs for new research, and how new knowledge of wood formation can play a role in the conservation of forests under threat by climate change.

Rodriguez‐Zaccaro, F. Daniela↗

Predicting Fracture Network Development in Crystalline Rocks

The geometric properties of fractures influence whether they propagate, arrest, or coalesce with other fractures. Thus, quantifying the relationship between fracture network characteristics may help predict fracture network development, and perhaps precursors to catastrophic failure. To constrain the relationship and predictability of fracture characteristics, we deform eight one centimeter tall rock cores under triaxial compression while acquiring in situ X-ray tomograms. The tomograms reveal precise measurements of the fracture network characteristics above the spatial resolution of 6.5 µm. We develop machine learning models to predict the value of each characteristic using the other characteristics, and excluding the macroscopic stress or strain imposed on the rock. The models predict fracture development more accurately in the experiments performed on granite and monzonite, than the experiments on marble. Fracture network development may be more predictable in these igneous rocks because their microstructure is more mechanically homogeneous than the marble, producing more systematic fracture development that is not strongly impeded by grain contacts and cleavage planes. The varying performance of the models suggest that fracture volume, length, and aperture are the most predictable of the characteristics, while fracture orientation is the least predictable. Orientation does not correlate with length, as suggested by the idea that the orientation evolves with increasing differential stress and thus fracture length. This difference between the observed and expected relationship between orientation and length highlights the influence of mechanical heterogeneities and local stress perturbations on fracture growth as fractures propagate, link, and coalesce.

58 GEOSCIENCES↗

Machine learning methods for particle stress development in suspension Poiseuille flows

Numerical simulations are used to study the dynamics of a developing suspension Poiseuille flow with monodispersed and bidispersed neutrally buoyant particles in a planar channel, and machine learning is applied to learn the evolving stresses of the developing suspension. The particle stresses and pressure develop on a slower time scale than the volume fraction, indicating that once the particles reach a steady volume fraction profile, they rearrange to minimize the contact pressure on each particle. Here we consider how the stress development leads to particle migration, time scales for stress development, and present a new physics-informed Galerkin neural network that allows for learning the particle stresses when direct measurements are not possible. The particle fluxes are compared with the Suspension Balance Model with good agreement. We show that when stress measurements are possible, the MOR-physics operator learning method can also capture the particle stresses.

97 MATHEMATICS AND COMPUTING↗

Microstructural development in DED stainless steels: applying welding models to elucidate the impact of processing and alloy composition

Austenitic stainless steel microstructures produced by directed energy deposition (DED)are analogous to those developed during welding, particularly high energy density welding. To better understand microstructural development during DED, theories of microstructural evolution,which have been established to contextualize weld microstructures, are applied in this study to microstructural development in DED austenitic stainless steels. Phenomenological welding models that describe the development of oxide inclusions, compositional microsegregation, ferrite,matrix austenite grains, and dislocation substructures are utilized to clarify microstructural evolution during deposition of austenitic stainless steels. Two different alloys, 304L and 316L, arecompared to demonstrate the broad applicability of this framework for understanding microstmctural development during the DED process. Despite differences in grain morphology and solidification mode for these two alloys (which can be attributed to compositional differences),similar tensile properties are achieved. It is the fine-scale compositional segregation and dislocation structures that ultimately determine the strength of these materials. The evolution of microsegregation and dislocation structures is shown to be dependent on the rapid solidification and thermomechanical history of the DED processing method and not the composition of the starting material.

36 MATERIALS SCIENCE↗

DownScaleBench for developing and applying a deep learning based urban climate downscaling- first results for high-resolution urban precipitation climatology over Austin, Texas

Abstract Cities need climate information to develop resilient infrastructure and for adaptation decisions. The information desired is at the order of magnitudes finer scales relative to what is typically available from climate analysis and future projections. Urban downscaling refers to developing such climate information at the city (order of 1 – 10 km) and neighborhood (order of 0.1 – 1 km) resolutions from coarser climate products. Developing these higher resolution (finer grid spacing) data needed for assessments typically covering multiyear climatology of past data and future projections is complex and computationally expensive for traditional physics-based dynamical models. In this study, we develop and adopt a novel approach for urban downscaling by generating a general-purpose operator using deep learning. This ‘DownScaleBench’ tool can aid the process of downscaling to any location. The DownScaleBench has been generalized for both in situ (ground- based) and satellite or reanalysis gridded data. The algorithm employs an iterative super-resolution convolutional neural network (Iterative SRCNN) over the city. We apply this for the development of a high-resolution gridded precipitation product (300 m) from a relatively coarse (10 km) satellite-based product (JAXA GsMAP). The high-resolution gridded precipitation datasets is compared against insitu observations for past heavy rain events over Austin, Texas, and shows marked improvement relative to the coarser datasets relative to cubic interpolation as a baseline. The creation of this Downscaling Bench has implications for generating high-resolution gridded urban meteorological datasets and aiding the planning process for climate-ready cities.

Singh, Manmeet (ORCID:0000000233747149)↗

Development of the multigroup cross section library for the CASL neutronics simulator MPACT: Method and procedure

The MPACT neutronics module of the Consortium for Advanced Simulation of Light Water Reactors (CASL) core simulator is a 3D whole core transport code being developed for the CASL toolset known as the Virtual Environment for Reactor Analysis (VERA). Key characteristics of the MPACT code include a subgroup method for resonance self-shielding and a whole-core transport solver with a 2D/1D synthesis method. The AMPX and SCALE code packages have been significantly improved to include intermediate resonance parameters, as well as new modules to enhance the accuracy of resonance data and scattering matrices for the Bondarenko approach and transport cross sections of hydrogen. In addition, CASL XSTools have been developed to generate the MPACT multigroup cross section library. A simple super-homogenization method for 238U has been developed to resolve reaction rate discrepancy issues caused by angle-dependent total cross sections, poor scattering matrices, and a poor resonance interference model at coarse group structure. Here, due to the limitation of computing capacity that can occur even in high performance computing, a new 51-group structure has been developed for efficient simulation that is applicable for both pressurized water reactor (PWR) and boiling water reactor (BWR) simulations. A new ENDF/B-VII.1 MPACT 51-group library has been developed using the AMPX/SCALE and XSTools code packages, and it has been verified and validated by performing various benchmark calculations.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗

Indispensable role for mouse ELP3 in embryonic stem cell maintenance and early development

ELP3, a core component of Elongator, has been implicated in translational regulation via modification of tRNA at the wobble position. However, the precise biological function of ELP3 in early mouse development has not yet been defined. We here provide evidence that ELP3 plays crucial roles in mouse embryonic stem cell (ESC) maintenance and early development. ELP3 was detected ubiquitously in blastocysts and E10.5 embryos and shown to be increased during ESC differentiation. Depletion of ELP3 in ESC led to aberrant cell cycle progression, along with reduced expression of genes for pluripotency. Interestingly, our analyses revealed that, although the mRNA levels of the genes related to cell cycle were increased, protein levels were diminished in knockdown (KD) ESCs. The data, therefore, suggest that ELP3 function is critical for translational efficiency of the genes. Consistent with a proliferation defect in KD cells, Elp3 knockout (KO) embryos suffered from severe growth retardation and failed to develop beyond E12.5. In conclusion, we have demonstrated that ELP3 plays an indispensable role in ESC survival, differentiation and embryonic development in mouse. - Highlights: • Mouse ELP3 expression was examined during ESC differentiation and development. • ELP3 depletion caused catastrophic cell cycle progression due to an aberrant translation. • Elp3 KO animals exhibited embryonic lethality with severe growth retardation.

60 APPLIED LIFE SCIENCES↗

Dynamic autophagic activity affected the development of thoracic aortic dissection by regulating functional properties of smooth muscle cells

The aortic medial degeneration is the key histopathologic feature of Thoracic aortic dissection (TAD). The aim of this study was to identify the change of autophagic activity in the aortic wall during TAD development, and to explore the roles of autophagy on regulating functional properties of smooth muscle cells (SMCs). Firstly, compared with control group (n = 11), the increased expression of autophagic markers Beclin1 and LC3 was detected in the aortic wall from TAD group (n = 23) by immunochemistry and western blot. We found that more autophagic vacuoles were present in the aortic wall of TAD patients using Transmission electron microscopy. Next, autophagic activity was examined in AD mice model established by β-aminopropionitrile fumarate (BAPN) and angiotensin II. Immunochemistry proved that autophagic activity was dynamically changed during AD development. Beclin1 and LC3 were detected up-regulated in the aortic wall in the second week after BAPN feeding, earlier than the fragmentation or loss of elastic fibers. When AD occurred in the 4th week, the expression of Beclin1 and LC3 began to decrease, but still higher than the control. Furthermore, autophagy was found to inhibit starvation-induced apoptosis of SMCs. Meanwhile, blockage of autophagy could suppress PDGF-induced phenotypic switch of SMCs. Taken together, autophagic activity was dynamically changed in the aortic wall during TAD development. The abnormal autophagy could regulate the functional properties of aortic SMCs, which might be the potential pathogenesis of TAD. - Highlights: • Autophagy is up-regulated in aorta wall from thoracic aorta dissection (TAD) patient. • Autophagic activity is dynamically changed during TAD development. • Dynamically change of autophagy is associated with pathological process of TAD. • Autophagy participate in the development of TAD by regulating function of SMCs.

60 APPLIED LIFE SCIENCES↗

MafB is required for development of the hindbrain choroid plexus

The choroid plexus (ChP) is a non-neural epithelial tissue that produces cerebrospinal fluid (CSF). The ChP differentiates from the roof plate, a dorsal midline structure of the neural tube. However, molecular mechanisms underlying ChP development are poorly understood compared to neural development. MafB is a bZip transcription factor that is known to be expressed in the roof plate. Here we investigated the role of MafB in embryonic development of the hindbrain ChP (hChP) using Mafb-deficient mice. Immunohistochemical analyses revealed that MafB is expressed in the roof plate and early hChP epithelial cells but its expression disappears at a later embryonic stage. We also found that the Mafb-deficient hChP exhibits delayed differentiation and results in hypoplasia compared to the wild-type hChP. Furthermore, the Mafb-deficient hChP exhibits increased apoptotic cell death and decreased proliferating cells at E12.5, an early stage of hChP development. Collectively, our findings reveal that MafB play an important role in promoting hChP development during embryogenesis. - Highlights: • MafB is expressed in the roof plate and the early hindbrain choroid plexus (hChP). • Loss of MafB causes delayed differentiation and hypoplasia of the embryonic hChP. • The Mafb-deficient hChP exhibits increased apoptosis and decreased proliferation.

42 ENGINEERING↗

Stearic acid suppresses mammary gland development by inhibiting PI3K/Akt signaling pathway through GPR120 in pubertal mice

It has been demonstrated that dietary high fat diet negatively affects the pubertal mammary gland development. The aim of the present study was to investigate the effects of stearic acid (SA), an 18-carbon chain saturated fatty acid, on mammary gland development in pubertal mice and to explore the underlying mechanism. Our results demonstrated that dietary supplementation of 2% SA suppressed mammary duct development, with significant reduction of terminal end bud (TEB) number and ductal branch. In accord, the expression of proliferative marker Cyclin D1 was markedly decreased by dietary SA. Furthermore, dietary SA led to increase of G protein-coupled receptor 120 (GPR120) expression and inhibition of PI3K/Akt signaling pathway in mammary gland of pubertal mice. In good agreement with the in vivo findings, the in vitro results showed that 40 μM SA significantly suppressed proliferation of mouse mammary epithelial cell HC11 by regulating mRNA and/or protein expression of proliferative markers such as Cyclin D1/3, p21, and PCNA. Meanwhile, SA activated GPR120 and inhibited PI3K/Akt signaling pathway in a GPR120-dependent manner. In addition, SA-induced inhibition of PI3K/Akt signaling pathway, suppression of HC11 proliferation, and alteration of proliferative markers expression were abolished by knockdown of GPR120 with siRNA. Collectively, these findings showed that SA suppressed mammary gland development of pubertal mice, which was coincident with the SA-inhibited HC11 proliferation, and was associated with inhibition of PI3K/Akt signaling pathway through activation of GPR120. These data provided new insights into the regulation of mammary gland development by dietary fatty acids. - Highlights: • Dietary supplementation of 2% SA suppressed mammary duct growth in pubertal mice. • SA inhibited HC11 proliferation by regulating expression of proliferative markers. • SA enhanced GPR120 and inhibited PI3K/Akt in mice mammary gland and HC11 cells. • Knockdown of GPR120 eliminated SA-suppressed PI3K/Akt and HC11 proliferation.

60 APPLIED LIFE SCIENCES↗

Copine1 regulates neural stem cell functions during brain development

Highlights: • Copine1 is highly expressed in neural lineage cells at early developmental stages. • Copine1 regulates the proliferation of embryonic neural stem cells (NSCs). • Copine1 regulates the differentiation of NSCs into neuronal and glial lineages. • mTOR signaling pathway is involved in Copine1-meidated neural development. Copine 1 (CPNE1) is a well-known phospholipid binding protein in plasma membrane of various cell types. In brain cells, CPNE1 is closely associated with AKT signaling pathway, which is important for neural stem cell (NSC) functions during brain development. Here, we investigated the role of CPNE1 in the regulation of brain NSC functions during brain development and determined its underlying mechanism. In this study, abundant expression of CPNE1 was observed in neural lineage cells including NSCs and immature neurons in human. With mouse brain tissues in various developmental stages, we found that CPNE1 expression was higher at early embryonic stages compared to postnatal and adult stages. To model developing brain in vitro, we used primary NSCs derived from mouse embryonic hippocampus. Our in vitro study shows decreased proliferation and multi-lineage differentiation potential in CPNE1 deficient NSCs. Finally, we found that the deficiency of CPNE1 downregulated mTOR signaling in embryonic NSCs. These data demonstrate that CPNE1 plays a key role in the regulation of NSC functions through the activation of AKT-mTOR signaling pathway during brain development.

60 APPLIED LIFE SCIENCES↗

SIRT7 is an important regulator of cartilage homeostasis and osteoarthritis development

Highlights: • Sirt7 knockout mice are resistant to the development of aging-associated osteoarthritis. • Sirt7 knockout mice are resistant to the development of forced exercise-induced osteoarthritis. • Attenuation of SIRT7 in chondrocytes increases the expression of extracellular matrixes. • SIRT7 suppresses transcriptional activity of SOX9 via deacylation activity. • SIRT7 is important for cartilage homeostasis and osteoarthritis development. Sirtuins (SIRT1–7) are NAD{sup +}-dependent deacetylase/deacylases that regulate a wide variety of biological functions. Although the roles of sirtuins in cartilage homeostasis and cartilage diseases have been well studied, there is no information on the contribution of SIRT7 to cartilage homeostasis and osteoarthritis (OA) pathologies. Here, we demonstrate that Sirt7 knockout mice are resistant to the development of aging-associated OA and forced exercise-induced OA. Attenuation of Sirt7 in the murine chondrogenic cell line ATDC5 increased the deposition of a glycosaminoglycan-rich extracellular matrix and the mRNA expression of extracellular matrix components such as Col2a1 and Acan. Mechanistically, we found that SIRT7 suppressed the transcriptional activity of SOX9, which is an important transcription factor in chondrocytes, and that the enzymatic activity of SIRT7 was required for its function. Our results indicate that SIRT7 is a novel important regulator of cartilage homeostasis and OA development.

60 APPLIED LIFE SCIENCES↗

Notch signaling regulates the expression of glycolysis-related genes in a context-dependent manner during embryonic development

Highlights: • Notch does not regulate glycolysis genes during early embryonic development. • Notch regulates glycolysis genes differently in the brain at the larval stage. • Notch-mediated glycolysis gene regulation is context-dependent during development. Glycolysis, the classic pathway for producing energy, has been known to be involved in neural development. Notch signaling also contributes to neural development and regulation of glycolysis in various tissues. However, the role of Notch signaling in glycolysis-related gene regulation during neural development is poorly understood. Here, we analyzed mRNA expression patterns and levels of glucose transporters (GLUT) as well as rate-limiting enzymes in glycolysis using zebrafish mib1{sup ta52b} mutants, in which Notch signaling was deficient at the early embryonic and larval stages. Our results indicated that in neural tissues, Notch signaling positively regulates glut1a and glut3a expression and negatively regulates hk2 expression at the larval stage but may not regulate them during early embryonic stages. Therefore, these results suggest that Notch signaling regulates glycolysis-related gene expression in a context-dependent manner in neural tissues at different developmental stages.

60 APPLIED LIFE SCIENCES↗

The role of Zhx2 transcription factor in bipolar cell differentiation during mouse retinal development

Highlights: • Zhx2 is expressed in developing retina. • Zhx2 is essential for subsets of bipolar cell proper differentiation. • Overexpression of Zhx2 showed perturbation of bipolar differentiation. We found that the Zhx2 gene (whose product is known to act as a tumor suppressor in hepatocellular carcinoma) is expressed in embryonic retinal progenitors and in developing cone bipolar cells in the postnatal retina, as well as in Müller glia in the mature retina. To examine the functions of Zhx2 protein during retinal development, we performed loss- and gain-of-function analyses using a retinal explant culture system. We introduced a plasmid encoding Zhx2 shRNA into isolated mouse retinas at E17.5, and the retinas were cultured as explants. After 3 days of culture, proliferation was slightly enhanced, leading to retinas thicker than in the control, but this phenomenon was observed only transiently. After 14 days of the culture, the thickness and gross morphology of retinas expressing sh-Zhx2 were indistinguishable from those of the control. The numbers of rod cells, amacrine cells, and Müller glia were the same in both groups. However, although the total number of bipolar cells was the same, the experimental group saw an increased population of ON bipolar cells, and decreased numbers of a subset of OFF bipolar cells. We also examined the effects of overexpression of Zhx2. Although Zhx2 acts as a tumor suppressor, its overexpression in developing retinas did not lead to any discernible difference in retinal thickness, suggesting that proliferation activity was not affected. After 14 days of explant culture, the total number of bipolar cells decreased, and subset composition was altered. Taken together, these results suggest that Zhx2 plays roles in the regulation of bipolar cell subset fate determination during retinal development.

60 APPLIED LIFE SCIENCES↗

Stromal interaction molecule 1 is required for neonatal testicular development in mice

Highlights: • STIM1 is found in Sertoli cells and associated with neonatal testicular development. • STIM1 is required for Sertoli cell orientation and germ cell survival. • Stim1 knockdown in neonatal testis altered the testicular phenotype and induced ROS. • ROS inhibition partially rescued the Stim1 knockdown phenotype in neonatal testes. • STIM1 can maintain neonatal testicular development by inhibiting ROS activation. Stromal interaction molecule 1 (STIM1) is a transmembrane endoplasmic reticulum protein, and it serves as a Ca{sup 2+} sensor and activator of store-operated Ca{sup 2+} entry (SOCE). We have previously identified STIM1 in the proteome profile of mice neonatal testes, revealing STIM1 to be associated with neonatal testicular development. Here, to further explore the location and function of STIM1 in mice testes, we studied the effect of Stim1 gene knockdown on neonatal testicular development by testicular culture. Our results revealed that STIM1 was primarily located in Sertoli cells. Knockdown of Stim1 gene using morpholino in neonatal testis caused the mislocation of Sertoli cells and loss of germ cells, which were associated with the aberrant reactive oxygen species (ROS) activation, while inhibition of ROS could partly rescue the phenotypes caused by Stim1 gene knockdown. In conclusion, our study suggests that STIM1 can maintain neonatal testicular development by inhibiting ROS activation.

60 APPLIED LIFE SCIENCES↗

Strategic health assessment for large scale industry development activities: An introduction

Attention to the determinants of health and health equity in impact assessment remains under-utilised at the project, Environmental Impact Assessment, level. Determinants focussed health impact assessment has developed at an upstream, policy level, but tends to assess draft proposals rather than form the basis of policies and plans. Project level health (risk) impact assessment tends to focus on a project by project basis, and generally eschews a broad model of health. One answer to this ‘health and impact assessment’ problem is to shift attention to the strategic level, in a similar manner to, and learning from, the development of Strategic Environmental Assessment and its theoretical and practical derivatives. In this article we explain the need for this shift both conceptually and practically by navigating the literature. Our analysis derives specifically from developing the Strategic Health Impact Assessment section of new international industry HIA guidance, coupled with work in and around health impact assessment and policy analysis for the past decade. We develop characteristics of conducting strategic health assessments for multiple industry development activities at the supra national, national or regional level. Our intended audience are public administrators, industry planners and financial sector investors. A particular focus is low and middle income countries, now seen by industry as emerging markets.

54 ENVIRONMENTAL SCIENCES↗