Internal Domain Research Articles

Impact dynamics of ferrofluid droplet on a PDMS substrate under the influence of magnetic field

We report the impact dynamics of a ferrofluid droplet on a PDMS substrate in the presence of a non-uniform magnetic field. Based on high-speed imaging, we unravel the various characteristic behaviors of the impinging ferrofluid droplet under the influence of a vertically applied magnetic field. We show that the magnetic, viscous, inertial, and interfacial energies non-trivially affect the equilibrium shape of the impacting ferrofluid droplet. Consequently, we reveal that the collective role of these forces ensures the ferrofluid droplet exhibits essentially three typical equilibrium shapes, i.e., no spike, single spike, and multiple spikes assemblies. Based on a phase diagram, we demonstrate the role of various dynamic forces in dictating the droplet’s equilibrium shape. We report the universality constant exhibited by the non-dimensionalized droplet diameter (ratio of the droplet’s equilibrium diameter to the semi-minor axis width of the ellipsoidal droplet just before impact), irrespective of the magnetic Bond number, on a PDMS substrate to be around 1.3. Consequently, we investigated the internal flow domain of the ferrofluid flow field in the presence of a magnetic field, essentially to understand its characteristic spreading behavior. Following bright-field visualization, we observed chain-like clustering of the magnetic nanoparticles inside the ferrofluid flow domain in a direction perpendicular to the magnet. Insights from bright field visualization enable us to qualitatively argue that the chaining phenomena of the nano-sized particles (present inside ferrofluid) in a direction perpendicular to the substrate ensure the formation of single/multiple assemblies of spikes. In addition, we also argue that the chain-formation of the magnetic nanoparticles increases the viscous force of the ferrofluid droplet in the presence of a magnetic field. This augmented viscous energy of the fluid in the presence of a magnetic field ensures the inverse relationship of the spreading diameter with magnetic field strength. The inference of the present study could be beneficial in the rational design of wide-ranging applications, such as ink-jet printing or 3D printing, requiring controlled droplet spreading phenomena.

Observation of Buried Magnetic Domains in Grain-Oriented Electrical Steel

Bulk-sensitive microscopic measurements of buried magnetic domains are reported. Utilizing a new magneto-optical effect in the hard X-ray regime, referred to as X-ray magnetic circularly polarized emission (XMCPE), the internal transverse domains in a grain-oriented (GO) electrical steel sheet are unambiguously observed. This allows the lateral shapes of the transverse domains to be successfully visualized. In addition, we discuss the magnetic domain structure of the supplementary domains below the surface from measurements performed at several pairs of incident and exit angles.

Detrital modes of buried Permian sandstones of the Puglia 1 well (Puglia Region, Southern Italy)

Permian siliciclastic input, around Mediterranean region, recorded a frame of Pangaea supercontinent breakup. Apulia region had registered it in a sedimentary cycle during final Paleotethys closure and subsequent Neotethys opening, after Variscan orogenesis. Here is provided a compositional insight of Permian siliciclastic succession intercepted in an explorative well log, Puglia 1 well, up to 6110 m till 7070 m in depth, of ENI’s property. The succession, about 760 m in thickness, consists of sandstone, mudstone and breccia. Sandstones are quartzolithic with quartz and metasedimentary lithic fragments abundance, while diagenetic minerals consist of ankerite, dolomite and calcite cements (related to dedolomitization-calcitization processes of the first carbonates), with iron oxides. The resultant provenance is related to eroded Devonian-Carboniferous Variscan orogen, where metasedimentary rocks occur both in Calabria-Peloritani, southern Alps and internal domains of the Circum-Mediterranean orogenic belts.

Research on the submarine floating movement in waves involving the water holes

When a submarine with a large volume superstructure floats up, the water on the back of the superstructure is large. In order to ensure the safety of submarine floating, it is necessary to study the stability and attitude change of submarine floating. In the present study, STAR-CCM + software is used to construct a numerical wave pool based on the numerical wave making theory. Based on the overset grid, the calculation method for internal and external domains interaction is adopted, and the uncertainty of the numerical calculations is analyzed using the model floating test results. What's more, the numerical results of the hull longitudinal and vertical velocities, and heel and pitch angles are close to the test results, except for the peak values. Compared to the test results, the average error of the amplitude of the numerical results was within 10%.It can thus be concluded that the numerical simulations were credible, which confirmed that the proposed numerical method can be applied to simulating the emergency ascent of a submarine with flow holes. Finally, a numerical prediction method for submarine floating movement in waves considering the superstructure water hole is proposed. The characteristics of the submarine buoyancy and emergence in waves are explored for various wave directions, wave heights and wavelengths. The results indicate that beam waves have a greater impact on the lateral orientation of the submarine, while the head waves are more effective on the longitudinal direction. Furthermore, the heel angle of the submarine is higher in beam and oblique waves compared to that in head waves. The longitudinal displacement shows a descending trend as the wave height increases. As the submarine exits the water, the hull posture is affected by waves, and the heel and pitch angles tend to increase by the rise of wave height. Based on a given wavelength range of 1∼3L, the higher wavelengths increases the longitudinal and lateral displacements of the hull, and reduces its heel and yaw angles. For shorter wavelengths, the hull responds faster to variations induced by the wave disturbances. It can be concluded that submarines should avoid surfacing in shorter wavelengths as well as in beam waves. The proposed numerical methods and conclusions of the present study can be considered as a reference in the scope of submarine floating movement.

Tracking the structural dynamics of SERCA regulation in real time.

Calcium (Ca2+) signaling in eukaryotic cells is integral to biological processes such as neuronal activity, transcription, and muscle contraction-relaxation. Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) proteins play a vital role in this intricate signaling network by returning Ca2+ to the sarco/endoplasmic reticulum (SR/ER), thereby resetting the signal and restoring SR/ER Ca2+ levels. SERCA activity is optimised for different tissues and developmental stages by expression of different isoforms and by regulatory factors such as regulatory peptides, Ca2+ concentration and internal regulatory domains. Mutations are known to cause Brody's (SERCA1) and Darier's (SERCA2) diseases, and dysregulation of SERCA2a is associated with heart failure. To investigate the kinetic and structural effects of SERCA regulation, we performed time-resolved x-ray solution scattering (TR-XSS) experiments on two SERCA isoforms. In our TR-XSS setup the reaction is initiated by laser-induced ATP release, and the resulting structural dynamics are then monitored in real time using synchrotron x-ray pulses. We investigated the effect of Ca2+ concentration on SERCA1a in native membranes and identified three distinct structural states that developed slower under high-Ca2+ conditions and showed structural differences compared to the low-Ca2+ condition. The SERCA2b isoform has a unique regulatory domain consisting of an 11th transmembrane helix and a luminal extension loop that increases its Ca2+ affinity and lowers the maximal turnover rate. We collected TR-XSS datasets for SERCA2b with and without this regulatory region and observed differences in the reaction-cycle kinetics that indicate a loss of control of transitions between states. In summary, we have developed a synchrotron-based x-ray technique and determined the kinetic and structural basis of regulation of P-type ATPase transport across biological membranes.

Architecture and function of the meiotic metazoan HORMAD chromatin binding region (CBR).

During early meiotic prophase, the chromosome axis is formed by DNA-binding cohesin proteins, filamentous axis core proteins, and meiotic HORMA domain (HORMAD) proteins. HORMADs are master regulators of meiotic recombination, recruiting Spo11 and associated proteins to create DNA double-strand breaks (DSBs) and promoting their repair as interhomolog crossovers (COs). In earlier work, we discovered a central chromatin binding region (CBR) domain in the S. cerevisiae HORMAD protein Hop1 (SNU, unpublished), and further found that diverse eukaryotes including many plants and metazoans within the opisthokonta family also possess a central CBR with variable architecture. In fungi such as Vanderwaltozyma polyspora and Saccharomyces cerevisiae, Hop1 has an internal CBR domain containing a variant plant homeodomain (PHD) zinc finger domain and a DNA-binding winged helix-turn-helix domain (wHTH), plus a conserved C-terminal extension (HTH-C). Similarly, metazoan HORMAD CBR domains are predicted to contain a canonical PHD domain and a wHTH domain. Here we show two x-ray crystal structures of metazoan HORMAD CBRs from Schistosoma mansoni (blood fluke) and Patiria miniata (starfish). Both structures contain PHD and wHTH domains like the fungal Hop1 CBR, but do not contain a C-terminal extension (HTH-C). The PHD domain contains two beta strands with a conserved pocket that we propose binds a histone tail. We are currently pursuing both biochemical and cell-based approaches to determine the molecular basis for the HORMAD CBR-chromatin interaction and identify any specificity for histone tail modifications. This work will define how the HORMAD CBR modulates chromosome axis architecture and localization in diverse eukaryotes.

Elucidation of a dynamic interplay between guanine nucleotide and the ternary complex of a beta-adrenergic receptor, its agonist and stimulatory G protein.

Heterotrimeric G proteins, composed of α, β, and γ subunits, are molecular switches which can be regulated to either turn on or turn off based on their binding to transmembrane G-protein-coupled receptors (GPCRs) and guanine nucleotides, GTP or GDP. Coupled with their receptors, G proteins play a critical role in determining the specificity and temporal characteristics of the cellular responses of a diverse array of extracellular stimuli. G proteins decouple from GPCRs upon GTP binding to their Gα subunits, allowing both Gα and Gβγ to interact with downstream effector proteins. What is the role of GDP and GTP binding in the activation and dissociation of G proteins and what Gα conformational changes does GTP/GDP binding trigger? Answering these questions requires detailed time-resolved structural information. In this study we focused on interactions of GTP and GDP with stimulatory G protein (Gs), which is coupled with a prototypical GPCR, the beta-adrenergic receptor (βAR) using Rosetta modeling and all-atom molecular dynamics simulations. We found that GTP/GDP binding indirectly alters Gsα conformation by causing inter-domain rearrangement while directly causing α5 helix tilting, thus favoring Gsα dissociation. GTP/GDP binding also enhances correlations between Gsα inter-domain arrangement and Gsα conformational changes. Specifically, we found negative correlation between α5 titling angle and α1–α5 stacking which was different from the apo Gs protein case we observed previously. In summary, we analyzed conformational specificities of Gs protein–guanine nucleotide interactions and found correlations between Gs dissociation and its internal domain rearrangement. This provides intrinsic molecular insights into the understanding of G protein activation and may be beneficial for the design of safe and efficacious pharmaceuticals in precisely controlling the signaling properties of βARs.

Rift thermal inheritance in the SW Alps (France): insights from RSCM thermometry and 1D thermal numerical modelling

Abstract. Conceptual models of orogenic accretionary prisms assume that peak temperatures (Tmax⁡) increase towards the internal domains as crustal rocks are accreted from the lower to the upper plate. However, the recognition of pre-orogenic heating events in mountain belts questions the magnitude of thermal overprint during nappe stacking. Using Raman spectroscopy on carbonaceous material (RSCM) to calculate Tmax⁡, we have investigated the thermal record of Lower Jurassic to Eocene strata exposed along six stratigraphic sections at the front of the Digne Nappe (SW Alps), from the Devoluy Massif to the Castellane Arc. Our results highlight two groups of depth-dependent temperatures: (1) a regionally extensive and constant Tmax⁡ up to 300–330 ∘C measured in the Jurassic succession and (2) regionally variable lower temperatures (<150 ∘C) recorded either in the Upper Mesozoic or the syn-orogenic sequence. Modelling shows that the highest palaeotemperatures were achieved during the Early Cretaceous (∼ 130 Ma), associated with the Valaisan–Vocontian rifting, while the lowest Tmax⁡ reflect post-rift thermal relaxation in the Alpine foreland basin. This study provides a striking new example where mid-crustal palaeotemperatures measured in sediments accreted from the downgoing plate are inherited. An estimated peak thermal gradient of 80–90 ∘C km−1 requires a crustal thickness of 8–10 km during the Early Cretaceous, hence placing constraints for tectonic reconstruction of rift domains and geophysical interpretation of current crustal thickness in the SW Alps. These results call for the careful interpretation of palaeothermal data when they are used to identify past collisional thermal events. Where details of basin evolution are lacking, high-temperature records may be misinterpreted as syn-orogenic, which can in turn lead to an overestimation of both orogenic thickening and horizontal displacement in mountain belts.

Classification of Liver Fibrosis From Heterogeneous Ultrasound Image

With the advances in deep learning, including Convolutional Neural Networks (CNN), automated diagnosis technology using medical images has received considerable attention in medical science. In particular, in the field of ultrasound imaging, CNN trains the features of organs through an amount of image data, so that an expert-level automatic diagnosis is possible only with images of actual patients. However, CNN models are also trained on the features that reflect the inherent bias of the imaging machine used for image acquisition. In other words, when the domain of data used for training is different from that of data applied for an actual diagnosis, it is unclear whether consistent performance can be provided by the domain bias. Therefore, we investigate the effect of domain bias on the model with liver ultrasound imaging data obtained from multiple domains. We have constructed a dataset considering the manufacturer and the year of manufacturing of 8 ultrasound imaging machines. First, training and testing were performed by dividing the entire data, in a commonly used method. Second, we have utilized the training data constructed according to the number of domains for the machine learning process. Then we have measured and compared the performance on internal and external domain data. Through the above experiment, we have analyzed the effect of domains of data on model performance. We show that the performance scores evaluated with the internal domain data and the external domain data do not match. We especially show that the performance measured in the evaluation data including the internal domain was much higher than the performance measured in the evaluation data consisting of the external domain. We also show that 3-level classification performance is slightly improved over 5-level classification by mitigating class imbalance by integrating similar classes. The results highlight the need to develop a new methodology for mitigating the machine bias problem so that the model can work correctly even on external domain data, as opposed to the usual approach of constructing evaluation data in the same domain as the training data.

Is self-perception of oral health associated with expectations of employability?

The aim of this study was to develop and validate a questionnaire that allows a systematic evaluation of the impact of self-perceived oral health on expectations of getting a job on adult population seeking dental care, and to describe its associations with demographic characteristics, job related, and health coverage variables. We designed a descriptive cross-sectional study including men and women aged 18 to 65 years from a population seeking dental services in a walk-in clinic. In a first stage we design and validated an instrument on a sample of 100 subjects. The questionnaire was registered in a Likert scale, with higher scores represented higher impact of the oral status self-perception on employability. We calculated internal consistency, construct validity, and domains validation. The final instrument consisted in an 18-item questionnaire (Cronbach α = 0.814), grouped into two domains based on exploratory and confirmatory factor analysis. The total variance explained with values >1 was 66 percent, grouping questions into six components. One domain refers to oral health status and importance of dental aesthetics, while the other refers to specific job-seeking elements. In a second stage we applied the questionnaire on 800 participants from the same population of reference. Women, people who intended to change jobs, those younger than 40 years old, having health insurance, and higher educational level showed statistically significant higher scores than their counterparts (p<0.001). We developed a tool that enables evaluating the impact of self-perceived oral health on expectations of getting a job for adults seeking emergency care in a dental clinic.

Sharp Observability Inequalities for Hyperbolic Systems with Potentials

This paper is devoted to a sharp internal/boundary observability inequality for a hyperbolic system with a zero order potential. For this purpose, we first establish a new Carleman estimate for hyperbolic operator in H1-norm. Based on this Carleman estimate and a modified auxiliary optimal control problem, we obtain Carleman estimate for hyperbolic operator in L2-norm. Then, by virtue of a modified energy estimate and a delicate treatment of the observation region, we obtain an internal observability estimate with the observability constant of the order exp (C‖q‖2/3L∞(Q;ℝN×N)), with q the potential involved in the system. We also address the same problem for boundary observation. Compared with the related results in the literature, the main contributions of this paper are the observability constant is sharper, the waiting time T is shorter and the internal (or boundary) observation domain is smaller.

OMNIDIRECTIONAL MILLIMETER-WAVELENGTH ANTENNAS BASED ON SEGMENTAL DIELECTRIC RESONATORS WHICH SUPPORT WHISPERING GALLERY MODES

Subject and Purpose. The subject of investigation is a new class of resonant-type transmit antennas intended for operation at millimeter wavelengths. The model under consideration is based on the idea of diffractional re-emission of waves into the azimuthal direction by local inhomo-geneities of the basically cylindrical structure. The purpose of the work is to justify the possibility of using such an effect for creating antennas with a circular radiation pattern, and to suggest an appropriate design. Methods and Methodology. The research program included both experimental work and application of advanced computer simulation techniques. The modern methods employed have allowed studying electromagnetic field distributions both in internal domains of the dielectric resonators and in the far-field zones of the resonator-based antennas. Results. Design solutions have been proposed for resonant-type, omnidirectional transmit antennas to operate in the millimeter waveband. The characteristic parameters are sizes of their radiating elements, specifically the segmental members equidistantly disposed along the azimuthal direction on the cylindrical surfaces of dielectric disks. The radiational characteristics of such antennas, with segments of either localized or extended dimension (compared with the operating wavelength) have been investigated. Electric field intensity distributions in the far-field region and the respective gain factors of the antennas have been studied. Conclusions. The antennas based on segmental dielectric resonators have been shown to form multi-lobe radiation patterns covering the angular sector of 0–360 along the azimuth. By placing the local segments at the resonant field’s antinodes (of the operating mode) it is possible to achieve relatively high values of the gain, reaching 15.5 dB at the lobe maxima

CicerSpTEdb2.0: An Upgrade of Cicer Species Transposable Elements Database.

To meet the critical demand of LTR-RTs data-driven research, we updated the CicerSpTEdb database to version 2.0, which includes more accurate intact LTR-RT elements with annotation of internal domains. We also added the ability to BLAST against TEs of Cicer species. As a result, 3701 intact LTR-RTs were detected in the studied genomes, including 2840 Copia and 861 Gypsy elements. Of the 3701 intact LTR-RTs, 588 were in C. arietinum, including 475 Copia and 113 Gypsy. While 1373 were detected in C. reticulatum, including 1041 Copia and 332 Gypsy. Furthermore, 1740 were found in C. echinospermum, including 1324 Copia and 416 Gypsy. Based on LTR-RT clades, the analysis classified the 3701 identified intact LTR-RTs in the studied genomes as Ale (850), SIRE (740), unknown (455), Ikeros (323), Reina (290), Tork (290), Ivana (282), Tekay (197), Athila (128), TAR (99), CRM (31), and Ogre (16) elements. The newly updated CicerSpTEdb2.0 will be a valuable resource for TEs of Cicer species and their comparative genomics.Database URL: http://cicersptedb.easyomics.org/index.php.

Philosophical-Anthropological Concepts of Subject and Subjectivity as a Genesis of Women’s Emancipation

The study examine the problems existing in the Ottoman Empire of the second half of the 19th century and the beginning of the 20th century, which are related to the philosophical-antropological categories of subject and subjectivity in male-female relationships, the identification of female-male identities, to the internal domains of their coverage, as well as the possibilities of women’s emancipation and realization of their rights in a patriarchal society. The philosophical concepts of woman-subject and subjectivity were studied based on the philosophical-anthropological-feminist contexts of the works of Western Armenian female authors who were engaged in literary activities in the second half of the 19th century and the beginning of the 20th century, as well as the contexts of socio-cultural and conceptual transformations of women’s emancipation. Their manifestations and changes in society are viewed as the genesis of women’s emancipation. This is an interdisciplinary study, so the material has been analyzed in the context of mutual connections and relationships between Philosophy, Literary Studies and Anthropology. The research is unprecedented since analysis of this kind has been attempted for the first time. It is also important and up-to-date in terms of analyses of women’s issues in the scope of Armenological Studies.

Remnants of SIRE1 retrotransposons in human genome?

Evolution is unaimed changes in time that a genome is shaped by a collection of random mutations, recombination, integrations, and reorganizations. Transposable elements (TEs) are mobile fragments representing a major portion of most eukaryotic genomes, and are therefore considered as a key player in evolution. They are one of the main sources of genetic variability and have a large impact on genome structure and stability in eukaryotes. In this study, the plant SIRE1 retrotransposon insertions were demonstrated in the human genome by using barley SIRE1 interretrotransposon amplified polymorphism PCR (IRAP-PCR) primers. According to the IRAP-PCR analysis, different distribution patterns were observed for 24 participants used in this study. The polymorphism ratios of SIRE1 were calculated, and among all samples they were detected between 0 to 38%. Similarly, internal domains and LTR sequences of SIRE1 were investigated by sequencing. Partial GAG, RT and ENV gene sequences were detected in the human genome by performing sequence and bioinformatic analyses. According to the bioinformatic analysis, partial SIRE1 ENV sequences were interestingly detected in both human and chimpanzee chromosome 1. Partial SIRE1 ENV sequences in chromosome 1 were also found to be associated with neuroblastoma breakpoint family members' (NBPFs) in humans. Polymorphic TE insertions in the human genome may be an essential source of natural genetic variation with subtle effects on genome regulation, providing considerable source material for ongoing human evolution.

A new nonlinear spring‐dashpot model of CPRF of NPP structure based on coupled BEM‐FEM approach

AbstractIn this paper, a BEM‐FEM coupled model of combined piled raft foundation (CPRF) is proposed for both the frequency domain and the time domain dynamic analyses of a NPP structure in the linear, equivalent linear and nonlinear soil domain. The piles are modeled using the finite element method as a beam element, while the raft and internal domain of soil are modeled using the eight nodded brick element. It is assumed that the piles are rigidly connected with the raft. The nonlinearity of soil is modeled using the hyperbolic stress–strain relation and Modified Drucker–Prager Model. The boundary of the layered soil domain is modeled using the boundary element method. For simplification, it is assumed that the raft and piles are rigidly connected with the soil that means there are no slip and separation conditions at the interface of pile‐soil and raft‐soil. In order to validate the proposed approach, numerical results, that is, impedances in the horizontal, vertical and rocking directions, are compared with the published literature. Further, dynamic analyses of a lumped structure founded on CPRF is carried out in the time domain and frequency domain using these impedances and results are compared with the FEM. It is found that the spring‐dashpot models give the reasonably good agreement with finite element method for linear, equivalent linear and nonlinear models for both frequency domain and time domain analyses. Moreover, practical application of proposed model is shown for a very large problem of raft‐pile‐soil‐structure interaction such as a NPP structure on the layered soil. It was found that the nonlinearity significantly increases the response of the NPP structure. The proposed model has many advantage over the finite element model, for example, first it is very simple and second it reduced the computation time significantly with the good accuracy.

Reading Self-Concept and Motivation: A Perspective from Students with Reading Difficulties

This study investigates the relationship between reading self-concept and motivation among a group of male and female students with reading difficulties, also exploring this according to gender variables. The paper also seeks to determine to what extent reading self-concept can predict reading motivation among these target students. The study sample comprised a group of 100 mixed male and female students studying at upper-primary schools in Al-Kharj, Saudi Arabia, all of whom faced reading difficulties (RD). The researcher prepared and applied two tools in questionnaire form, the Reading Self-Concept Scale questionnaire (RSCSQ) and the Reading Motivation Scale questionnaire (RMSQ), both of which had acceptable validity and reliability. The study found a significant positive correlation between the total RSCSQ score and its reading ability domain and the total RMSQ score with each of its two domains. There is a significant positive correlation between the reading difficulties domain and the external reading motivation domain but no correlation between the reading difficulty domain and the total RMSQ score and its internal reading motivation domain. Second, the study found that for students with RD, while reading self-concept and its reading ability domain can predict reading motivation; the reading difficulty domain cannot predict reading motivation. These results were consistent both among the group and between gender variables.

Development and Evaluation of the Algorithm CErtaInty Tool (ACE-IT) to Assess Electronic Medical Record and Claims-based Algorithms' Fit for Purpose for Safety Outcomes.

Electronic health record (EHR) or medical claims-based algorithms (i.e., operational definitions) can be used to define safety outcomes using real-world data. However, existing tools do not allow researchers and decision-makers to adequately appraise whether a particular algorithm is fit for purpose (FFP) to support regulatory decisions on drug safety surveillance. Our objective was to develop a tool to enable regulatory decision-makers and other stakeholders to appraise whether a given algorithm is FFP for a specific decision context. We drafted a set of 77 generic items informed by regulatory guidance documents, existing instruments, and publications. The outcome of ischemic stroke served as an exemplar to inform the development of draft items. The items were designed to be outcome independent. We conducted a three-round online Delphi panel to develop and refine the tool and achieve consensus on items (>70% agreement) among panel participants composed of regulators, researchers from pharmaceutical organizations, academic clinicians, methodologists, pharmacoepidemiologists, and cardiologists. We conducted a qualitative analysis of panel responses. Five pairs of reviewers independently evaluated two ischemic stroke algorithm validation studies to test its application. We developed a user guide, with explanation and elaboration for each item, guidance on essential and additional elements for user responses, and an illustrative example of a complete assessment. Furthermore, we conducted a 2-h online stakeholder panel of 16 participants from regulatory agencies, academic institutions, and industry. We solicited input on key factors for an FFP assessment, their general reaction to the Algorithm CErtaInty Tool (ACE-IT), limitations of the tool, and its potential use. The expert panel reviewed and made changes to the initial list of 77 items. The panel achieved consensus on 38 items, and the final version of the ACE-IT includes 34 items after removal of duplicate items. Applying the tool to two ischemic stroke algorithms demonstrated challenges in its application and identified shared concepts addressed by more than one item. The ACE-IT was viewed positively by the majority of stakeholders. They identified that the tool could serve as an educational resource as well as an information-sharing platform. The time required to complete the assessment was identified as an important limitation. We consolidated items with shared concepts and added a preliminary screen section and a summary assessment box based on their input. The final version of the ACE-IT is a 34-item tool for assessing whether algorithm validation studies on safety outcomes are FFP. It comprises the domains of internal validity (24 items), external validity (seven items), and ethical conduct and reporting of the validation study (three items). The internal validity domain includes sections on objectives, data sources, population, outcomes, design and setting, statistical methods, reference standard, accuracy, and strengths and limitations. The external validity domain includes items that assess the generalizability to a proposed target study. The domain on ethics and transparency includes items on ethical conduct and reporting of the validation study. The ACE-IT supports a structured, transparent, and flexible approach for decision-makers to appraise whether electronic health record or medical claims-based algorithms for safety outcomes are FFP for a specific decision context. Reliability and validity testing using a larger sample of participants in other therapeutic areas and further modifications to reduce the time needed to complete the assessment are needed to fully evaluate its utility for regulatory decision-making.

Non-Canonical FLT3 Mutations (FLT3m) in Patients (Pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) - Outcomes and Prognosis after FLT3 Inhibitor (FLT3i) and Venetoclax Based Regimens

Non-Canonical FLT3 Mutations (FLT3m) in Patients (Pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) - Outcomes and Prognosis after FLT3 Inhibitor (FLT3i) and Venetoclax Based Regimens

Bmf-500: An Orally Bioavailable Covalent Inhibitor of FLT3 with High Selectivity and Potent Antileukemic Activity in FLT3-Mutated AML

Activating mutations of the FMS-like tyrosine kinase 3 (FLT3) are the most frequent genetic alteration in AML and are associated with poor prognosis. Though several FLT3 inhibitors have entered clinical trials and reached commercialization, adverse events and dose-limiting toxicities often restrict the therapeutic window and limit their long-term use. Such limitations impact the ability to achieve long-lasting response in patients and ultimately result in therapy-induced resistance. Exquisite potency combined with high selectivity and improved safety profile is expected to help improve tolerance and overall treatment outcomes of FLT3-targeted therapy. BMF-500 was designed as a highly potent and selective, covalent, small molecule inhibitor of FLT3, that binds irreversibly to a reactive cysteine in the kinase active site. BMF-500 is a picomolar inhibitor with markedly improved potency over gilteritinib, a reversible inhibitor of FLT3. BMF-500 selectively killed AML cells harboring FLT3 activating mutations, including MV4-11 and MOLM-13, and engineered cells expressing FLT3 internal tandem duplications (FLT3-ITD) and/or FLT3 tyrosine kinase domain (TKD) mutations. In ex vivo cultures, BMF-500 as a single agent induced potent growth inhibition of patient-derived AML cells harboring either FLT3-ITD or FLT3 non-ITD mutations. The potent covalent inhibition of FLT3 by BMF-500 manifested in effective and durable cellular response that was improved over gilteritinib. For example, a 3-hour exposure followed by wash-out of BMF-500 outperformed 4 days of continuous exposure to gilteritinib, at all concentrations tested. In cells harboring FLT3 activating mutations, BMF-500 induced dose-dependent inhibition of FLT3 phosphorylation and downstream signaling, including phospho-STAT5 and phospho-ERK. A 1-hour pulse treatment with BMF-500 was sufficient to achieve deep and durable target inhibition for greater than 24 hours, an effect not observed with gilteritinib under similar conditions. Profiling BMF-500 across a broad panel of kinases and key cell-surface receptors revealed high selectivity for FLT3 mutants and selectivity against cKit. Potent FLT3 inhibition and high selectivity of BMF-500 translated to sustained tumor regression and improved survival in both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML. Orally administered BMF-500 was well tolerated over 4 weeks of dosing. Study results including efficacy and PD response will be presented. Collectively these data demonstrate BMF-500 to be a novel FLT3 inhibitor with best-in-class potential, given its efficacy, durability, and selectivity in comparison to existing FLT3 inhibitors.