Miracle-dz/UniFAR-FTUs huggingface dataset:
In vitro to Clinical Translation of Combinatorial Effects of Doxorubicin and Abemaciclib in Rb-Positive Triple Negative Breast Cancer: A Systems-Based Pharmacokinetic/Pharmacodynamic Modeling Approach

Background Doxorubicin (DOX) and its pegylated liposomal formulation (L_DOX) are the standard of care for triple-negative breast cancer (TNBC). However, resistance to DOX often occurs, motivating the search for alternative treatment approaches. The retinoblastoma protein (Rb) is a potential pharmacological target for TNBC treatment since its expression has been associated with resistance to DOX-based therapy. Methods DOX (0.01–20 μM) combination with abemaciclib (ABE, 1–6 μM) was evaluated over 72 hours on Rb-positive (MDA-MB-231) and Rb-negative (MDA-MB-468) TNBC cells. Combination indices (CI) for DOX+ABE were calculated using Compusyn software. The TNBC cell viability time-course and fold-change from the control of phosphorylated-Rb (pRb) protein expression were measured with CCK8-kit and enzyme-linked immunosorbent assay. A cell-based pharmacodynamic (PD) model was developed, where pRb protein dynamics drove cell viability response. Clinical pharmacokinetic (PK) models for DOX, L_DOX, and ABE were developed using data extracted from the literature. After scaling cancer cell growth to clinical TNBC tumor growth, the time-to-tumor progression (TTP) was predicted for human dosing regimens of DOX, ABE, and DOX+ABE. Results DOX and ABE combinations were synergistic (CI<1) in MDA-MB-231 and antagonistic (CI>1) in MDA-MB-468. The maximum inhibitory effects (Imax) for both drugs were set to one. The drug concentrations producing 50% of Imax for DOX and ABE were 0.565 and 2.31 μM (MDA-MB-231) and 0.121 and 1.61 μM (MDA-MB-468). The first-orders rate constants of abemaciclib absorption (ka) and doxorubicin release from L_DOX (kRel) were estimated at 0.31 and 0.013 h−1. Their linear clearances were 21.7 (ABE) and 32.1 L/h (DOX). The estimated TTP for intravenous DOX (75 mg/m2 every 21 days), intravenous L_DOX (50 mg/m2 every 28 days), and oral ABE (200 mg twice a day) were 125, 31.2, and 8.6 days shorter than drug-free control. The TTP for DOX+ABE and L_DOX+ABE were 312 days and 47.5 days shorter than control, both larger than single-agent DOX, suggesting improved activity with the DOX+ABE combination. Conclusion The developed translational systems-based PK/PD model provides an in vitro-to-clinic modeling platform for DOX+ABE in TNBC. Although model-based simulations suggest improved outcomes with combination over monotherapy, tumor relapse was not prevented with the combination. Hence, DOX+ABE may not be an effective treatment combination for TNBC.
Dual-Fortified Lentil Products—A Sustainable New Approach to Provide Additional Bioavailable Iron and Zinc in Humans

ABSTRACT Background Iron (Fe) and zinc (Zn) deficiencies are global health problems affecting 20% and 33% of the world's population, respectively. Lentil (Lens culinaris Medik.), part of the staple food supply in many countries, can be a potential vehicle for Fe and Zn fortification. Objective We developed a dual-fortification protocol to fortify 3 milled lentil product types (LPTs) [red-football (RF), red-split (RS), and yellow-split (YS)], with NaFeEDTA and ZnSO4.H2O to increase the bioavailable content of Fe and Zn. Methods Appropriate Fe and Zn doses were determined to fortify lentils based on RDAs. Relative Fe bioavailability (RFeB%) and phytic acid (PA) content were assessed using an in vitro Caco-2 cell bioassay and PA analysis, respectively. One-factor ANOVA determined the differences in colorimetric score; concentrations of Fe, Zn, and PA; and RFeB% among samples. The least significant difference was calculated with significance level set at P < 0.05. Results Fe and Zn concentration and RFeB% increased and PA concentration decreased significantly in dual-fortified lentils. Dual-fortified lentil samples had higher RFeB% compared with Fe-fortified (single) samples in all 3 LPTs, whereas RFeB% decreased in Zn-fortified (single) RF and YS samples by 43.4% and 36%, respectively. The RF, RS, and YS samples, fortified with 16 mg Fe and 8 mg Zn/100 g of lentils, provided 27 mg Fe and 14 mg Zn, 28 mg Fe and 13.4 mg Zn, and 29.9 mg Fe and 12.1 mg Zn, respectively. RFeB% of RF, RS, and YS lentil samples increased by 91–307%, 114–522%, and 122–520%, respectively. Again, PA concentrations of RF, RS, and YS lentils were reduced by 0.63–0.53, 0.83–0.71, and 0.96–0.79 mg/g, respectively. Conclusions Dual-fortified lentil consumption can cost-effectively provide a significant part of the daily bioavailable Fe and Zn requirements of people with these 2 globally important micronutrient deficiencies.
Pharmacokinetic and Pharmacodynamic Comparison of Two Formulations of a Fixed-Dose Combination of Gemigliptin/Rosuvastatin 50/20 mg: A Randomized, Open-Label, Single-Dose, Two-Way Crossover Study

Purpose A fixed-dose combination (FDC) of gemigliptin/rosuvastatin 50/20 mg as a monolayer tablet has been used to treat patients with both type 2 diabetes mellitus and dyslipidemia. To improve the stability of the FDC, a new FDC formulation as a bilayer tablet was developed. This study aimed to compare the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the FDC of gemigliptin/rosuvastatin 50/20 mg between the newly developed bilayer tablet and the approved monolayer tablet in healthy subjects. Materials and Methods A randomized, open-label, single-dose, two-treatment, two-way crossover study was conducted. Subjects received a single dose of the FDC of gemigliptin/rosuvastatin 50/20 mg as the bilayer tablet or the monolayer tablet in each period with a 7-day washout. For PK and PD analyses, serial blood samples were collected up to 72 hours after dosing to determine plasma concentrations of gemigliptin, its active metabolite LC15-0636 and rosuvastatin, and plasma dipeptidyl peptidase-4 (DPP-4) activity. PK and PD parameters were calculated using non-compartmental methods and compared between the two formulations. Results A total of 48 healthy subjects were randomized, and 45 subjects completed the study. The concentration–time profiles of gemigliptin, LC15-0636 and rosuvastatin were comparable between the two formulations. All geometric mean ratios (90% confidence intervals) of the bilayer tablet to the monolayer tablet for maximum plasma concentration and area under concentration–time curve from 0 to last measurable time point of the three compounds fulfilled the bioequivalence criteria of 0.80–1.25. Likewise, area under plasma DPP-4 activity inhibition from baseline-time curve from 0 to last measurable time point and maximum inhibition of plasma DPP-4 activity were similar between the two formulations. Conclusion The FDC of gemigliptin/rosuvastatin 50/20 mg as the bilayer tablet showed equivalent PK and PD properties with the FDC of gemigliptin/rosuvastatin 50/20 mg as the monolayer tablet in healthy subjects. These results suggest that the newly developed bilayer tablet can become an alternative formulation to the commercially available monolayer tablet.
NIR Spectroscopy and Imaging Techniques for Evaluation of Fish Quality—A Review

Abstract Fish is a highly perishable product and it is particularly important to pay attention to its quality changes. Maintenance of the high quality of fish and fishery products necessitates development of means for precise and rapid quality evaluation. Near-infrared (NIR) spectroscopy and imaging techniques are proven technologies that can provide useful information for the estimation of quality attributes in fish and fishery products due to fast speed, noninvasiveness, ease of use, and minimal sample preparation. The aim of this review is to communicate perspectives and aspects relating to NIR spectroscopy and imaging techniques with regard to evaluation of chemical composition (fat, protein, and moisture), microbiological (freshness, spoilage, and nematodes), and sensory (flavor, texture, and color) attributes of fish and fishery products. Moreover, the usefulness of NIR spectroscopy and imaging techniques for fish authentication and classification are presented. Finally, some viewpoints on the current situation and suggestions for future research directions are proposed.
Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs

Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation is increasingly used as a tool in drug product development, not only in support of clinical pharmacology applications (e.g., drug-drug interaction, dose selection) but also from quality perspective, enhancing drug product understanding. This report provides a summary of the status and the application of PBPK absorption modeling and simulation in new drug application (NDA) submissions to the U.S. Food and Drug Administration to support drug product quality (e.g., clinically relevant dissolution specifications, active pharmaceutical ingredient (API) particle size distribution specifications). During the 10 years from 2008 to 2018, a total of 24 NDA submissions included the use of PBPK absorption modeling and simulations for biopharmaceutics-related assessment. In these submissions, PBPK absorption modeling and simulation served as an impactful tool in establishing the relationship of critical quality attributes (CQAs) including formulation variables, specifically in vitro dissolution, to the in vivo performance. This article also summarizes common practices in PBPK approaches and proposes future directions for the use of PBPK absorption modeling and simulation in drug product quality assessment. Graphical abstract
Hip Range of Motion and Strength and Energy Flow During Windmill Softball Pitching.

CONTEXT Inadequate hip range of motion (ROM) and isometric strength (ISO) may interfere with energy flow through the kinetic chain and result in increased injury susceptibility. OBJECTIVE To examine the relationship of hip ROM and ISO with energy flow through the trunk and pitching-arm segments during the windmill softball pitch in youth athletes. A subsequent purpose was to examine the relationship between energy flow and pitch speed. DESIGN Descriptive laboratory study. SETTING University research laboratory. PATIENTS OR OTHER PARTICIPANTS A sample of 29 youth softball pitchers (age = 11.2 ± 1.3 years, height = 155.0 ± 10.4 cm, mass = 53.2 ± 12.6 kg). MAIN OUTCOME MEASURE(S) Bilateral hip internal-rotation and external-rotation (ER) ROM and ISO were measured. Net energy outflow and peak rates of energy outflow from the distal ends of the trunk, humerus, and forearm were calculated for the acceleration phase of the windmill softball pitch, and pitch speed was measured. RESULTS Regression analysis revealed an effect of drive-hip ER ISO on the net energy flow out of the distal ends of the trunk (P = .045) and humerus (P = .002). Specifically, increased drive-hip ER ISO was associated with increased net energy outflow from the trunk to the humerus and from the humerus to the forearm. No significant effects of hip ROM or other hip ISO measures were observed. Additionally, pitchers who achieved higher peak rates of distal outflow tended to achieve higher pitch speeds. CONCLUSIONS An association was present between drive-hip ER ISO and the net energy flow out of the distal ends of the trunk and humerus during the acceleration phase of the windmill softball pitch, emphasizing the importance of hip and lower body strength in executing the whole-body windmill pitch. Overall, energy-flow analysis is an interesting new way to analyze pitching mechanics and will aid in furthering our understanding of performance and injury risk in windmill softball pitching.
Epoxidation and Baeyer–Villiger oxidation using hydrogen peroxide and a lipase dissolved in ionic liquids

Epoxidation and Baeyer–Villiger oxidation of olefins and (cyclic) ketones were successfully carried out in hydrogen-bond-donating (HBD) ionic liquids, using a lipase-catalysed cascade and hydrogen peroxide as the terminal oxidant. The effect of the ionic liquids turned out to be twofold. The HBD ionic liquids exhibited a substantial positive solvent effect on the second step of the cascade, namely the oxygen transfer by peracid. In addition, we found that the Candida antarctica B lipase (CaLB) dissolved in 1-(3-hydroxypropyl)-3-methyl imidazolium nitrate 1a and 1-butyl-3-methylimidazolium nitrate 2a. This stable enzyme-ionic liquid solution opens the possibility for continuous chemical processing.
Dry Media Synthesis of Novel Pyrrolo-pyrimidines

A series of new 2-thioxo-3,7-disubstituted-5,6-diphenylpyrrolo[2,3-d]pyrimidin-4(1H) -ones have been synthesized by the condensation of 2-amino3-ethylcarboxylate-4,5-diphenyl pyrroles with mono-substituted arylthioureas in dry media under microwave irradiations. All the synthesized compounds were screened for their antifungal and antibacterial activities and found to possess mild to moderate antimicrobial activities. Keywords: Thioureas, Pyrrolo-pyrimidines, Microwave irradiation, Antimicrobial activities. DOI: 10.3126/jncs.v25i0. 3306 Journal of Nepal Chemical Society Volume 25, 2010 pp 83-88
Delivery of recombinant SARS-CoV-2 envelope protein into human cells

SARS-CoV-2 envelope protein (S2-E) is a conserved membrane protein that is essential to coronavirus assembly and budding. Here, we describe the recombinant expression and purification of S2-E into amphipol-class amphipathic polymer solutions. The physical properties of amphipols underpin their ability to solubilize and stabilize membrane proteins without disrupting membranes. Amphipol delivery of S2-E to pre-formed planar bilayers results in spontaneous membrane integration and formation of viroporin ion channels. Amphipol delivery of the S2-E protein to human cells results in membrane integration followed by retrograde trafficking to a location adjacent to the endoplasmic reticulum-to-Golgi intermediate compartment (ERGIC) and the Golgi, which are the sites of coronavirus replication. Delivery of S2-E to cells enables both chemical biological approaches for future studies of SARS-CoV-2 pathogenesis and development of “Trojan Horse” anti-viral therapies. This work also establishes a paradigm for amphipol-mediated delivery of membrane proteins to cells.
Tomato roots secrete tomatine to modulate the bacterial assemblage of the rhizosphere.

Saponins are a group of plant specialized metabolites which are widely distributed in angiosperm plants and have various biological activities. The present study focused on α-tomatine, a major saponin present in tissues of tomato (Solanum lycopersicum) plants. α-Tomatine is responsible for defense against plant pathogens and herbivores, but its biological function in the rhizosphere remains unknown. Secretion of tomatine was higher at the early growth than the green-fruit stage in hydroponically grown plants, and the concentration of tomatine in the rhizosphere of field-grown plants was higher than that of the bulk soil at all growth stages. The effects of tomatine and its aglycone tomatidine on the bacterial communities in the soil were evaluated in vitro, revealing that both compounds influenced the microbiome in a concentration-dependent manner. Numerous bacterial families were influenced in tomatine/tomatidine-treated soil as well as in the tomato rhizosphere. Sphingomonadaceae species, which are commonly observed and enriched in tomato rhizospheres in the fields, were also enriched in tomatine- and tomatidine-treated soils. Moreover, a jasmonate-responsive ETHYLENE RESPONSE FACTOR 4 mutant associated with low tomatine production caused the root-associated bacterial communities to change with a reduced abundance of Sphingomonadaceae. Taken together, our results highlight the role of tomatine in shaping the bacterial communities of the rhizosphere and suggest additional functions of tomatine in belowground biological communication.
Functional outcomes with Carillon device over 1 year in patients with functional mitral regurgitation of Grades 2+ to 4+: results from the REDUCE‐FMR trial

The objective of this study was to compare functional outcomes through 1 year in patients with core‐lab verified moderate to severe (Grades 2+ to 4+) functional mitral regurgitation (FMR) treated with the Carillon device or control in the blinded sham‐controlled REDUCE‐FMR (Carillon Mitral Contour System for Reducing Functional Mitral Regurgitation) study.
Use of angiotensin receptor blocker is associated with improved 1 year mortality in heart failure with mid‐range ejection fraction

Current evidence about the effect of angiotensin receptor blocker (ARB) on the outcome of heart failure with mid‐range ejection fraction (HFmrEF) is lacking. We aim to assess the association between use of ARB and 1 year all‐cause mortality after hospitalization for HFmrEF.
Public Opinions and Concerns Regarding the Canadian Prime Minister’s Daily COVID-19 Briefing: Longitudinal Study of YouTube Comments Using Machine Learning Techniques

Background During the COVID-19 pandemic in Canada, Prime Minister Justin Trudeau provided updates on the novel coronavirus and the government’s responses to the pandemic in his daily briefings from March 13 to May 22, 2020, delivered on the official Canadian Broadcasting Corporation (CBC) YouTube channel. Objective The aim of this study was to examine comments on Canadian Prime Minister Trudeau’s COVID-19 daily briefings by YouTube users and track these comments to extract the changing dynamics of the opinions and concerns of the public over time. Methods We used machine learning techniques to longitudinally analyze a total of 46,732 English YouTube comments that were retrieved from 57 videos of Prime Minister Trudeau’s COVID-19 daily briefings from March 13 to May 22, 2020. A natural language processing model, latent Dirichlet allocation, was used to choose salient topics among the sampled comments for each of the 57 videos. Thematic analysis was used to classify and summarize these salient topics into different prominent themes. Results We found 11 prominent themes, including strict border measures, public responses to Prime Minister Trudeau’s policies, essential work and frontline workers, individuals’ financial challenges, rental and mortgage subsidies, quarantine, government financial aid for enterprises and individuals, personal protective equipment, Canada and China’s relationship, vaccines, and reopening. Conclusions This study is the first to longitudinally investigate public discourse and concerns related to Prime Minister Trudeau’s daily COVID-19 briefings in Canada. This study contributes to establishing a real-time feedback loop between the public and public health officials on social media. Hearing and reacting to real concerns from the public can enhance trust between the government and the public to prepare for future health emergencies.
The inverse variance–flatness relation in stochastic gradient descent is critical for finding flat minima

Significance One key ingredient in deep learning is the stochastic gradient descent (SGD) algorithm, which allows neural nets to find generalizable solutions at flat minima of the high-dimensional loss function. However, it is unclear how SGD finds flat minima. Here, by analyzing SGD-based learning dynamics together with the loss function landscape, we discovered a robust inverse relation between weight fluctuation and loss landscape flatness opposite to the fluctuation–dissipation relation in physics. The reason for this inverse relationship is that the SGD noise strength and its correlation time depend inversely on the landscape flatness. Essentially, SGD serves as a landscape-dependent annealing algorithm to search for flat minima. These theoretical insights can lead to more efficient algorithms, e.g., for preventing catastrophic forgetting. Despite tremendous success of the stochastic gradient descent (SGD) algorithm in deep learning, little is known about how SGD finds generalizable solutions at flat minima of the loss function in high-dimensional weight space. Here, we investigate the connection between SGD learning dynamics and the loss function landscape. A principal component analysis (PCA) shows that SGD dynamics follow a low-dimensional drift–diffusion motion in the weight space. Around a solution found by SGD, the loss function landscape can be characterized by its flatness in each PCA direction. Remarkably, our study reveals a robust inverse relation between the weight variance and the landscape flatness in all PCA directions, which is the opposite to the fluctuation–response relation (aka Einstein relation) in equilibrium statistical physics. To understand the inverse variance–flatness relation, we develop a phenomenological theory of SGD based on statistical properties of the ensemble of minibatch loss functions. We find that both the anisotropic SGD noise strength (temperature) and its correlation time depend inversely on the landscape flatness in each PCA direction. Our results suggest that SGD serves as a landscape-dependent annealing algorithm. The effective temperature decreases with the landscape flatness so the system seeks out (prefers) flat minima over sharp ones. Based on these insights, an algorithm with landscape-dependent constraints is developed to mitigate catastrophic forgetting efficiently when learning multiple tasks sequentially. In general, our work provides a theoretical framework to understand learning dynamics, which may eventually lead to better algorithms for different learning tasks.
Metastable–solid phase diagrams derived from polymorphic solidification kinetics

Significance Kinetic stabilization of metastable phases in rapidly cooled metals and alloys has been established in experiments for decades. However, atomistic theories that can quantitatively predict the solidification conditions that produce nonequilibrium phases are still in their infancy. Recent advances in pulsed power/laser technologies, as well as in situ characterization, have brought to bear unprecedented understanding of matter at extreme temperatures and pressures. However, accurate predictions of kinetic stabilization of metastable phases that are necessary for physical interpretation of these experiments are lacking. This work provides a blueprint for development of kinetic phase maps of materials undergoing rapid solidification from first principles. Through atomistic simulations, the phases dominating nucleation are identified, and their kinetic stabilities during the growth stage are characterized. Nonequilibrium processes during solidification can lead to kinetic stabilization of metastable crystal phases. A general framework for predicting the solidification conditions that lead to metastable-phase growth is developed and applied to a model face-centered cubic (fcc) metal that undergoes phase transitions to the body-centered cubic (bcc) as well as the hexagonal close-packed phases at high temperatures and pressures. Large-scale molecular dynamics simulations of ultrarapid freezing show that bcc nucleates and grows well outside of the region of its thermodynamic stability. An extensive study of crystal–liquid equilibria confirms that at any given pressure, there is a multitude of metastable solid phases that can coexist with the liquid phase. We define for every crystal phase, a solid cluster in liquid (SCL) basin, which contains all solid clusters of that phase coexisting with the liquid. A rigorous methodology is developed that allows for practical calculations of nucleation rates into arbitrary SCL basins from the undercooled melt. It is demonstrated that at large undercoolings, phase selections made during the nucleation stage can be undone by kinetic instabilities amid the growth stage. On these bases, a solidification–kinetic phase diagram is drawn for the model fcc system that delimits the conditions for macroscopic grains of metastable bcc phase to grow from the melt. We conclude with a study of unconventional interfacial kinetics at special interfaces, which can bring about heterogeneous multiphase crystal growth. A first-order interfacial phase transformation accompanied by a growth-mode transition is examined.