Miracle-dz/UniFAR-FTUs huggingface dataset:
NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity

Simple Summary Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow, where cancer cells are unable to complete the maturation process towards white blood cells, but instead continue to proliferate. We are developing a novel chemotherapeutic drug, NEO212, that has shown anticancer activity in different preclinical cancer models, including AML. In the current study, we demonstrate that NEO212 forces AML cells to resume the differentiation process and progress towards the macrophage phenotype, which is accompanied by a loss of proliferation. NEO212 is able to achieve this growth-inhibitory effect even in AML cells that are resistant to other chemotherapeutic drugs in clinical use, such as cytarabine and temozolomide. In mouse models with AML, we found that treatment with NEO212 was well tolerated and resulted in an apparent cure of these animals. We propose that NEO212 should be developed further and evaluated in clinical trials with AML patients. Abstract Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and found to be partially effective; however, the presence of O6-methylguanine DNA methyltransferase (MGMT; a DNA repair enzyme) in tumor cells confers profound treatment resistance against TMZ. We are developing a novel anticancer compound, called NEO212, where TMZ was covalently conjugated to perillyl alcohol (a naturally occurring monoterpene). NEO212 has revealed robust therapeutic activity in a variety of preclinical cancer models, including AML. In the current study, we investigated its impact on a panel of human AML cell lines and found that it exerted cytotoxic potency even against MGMT-positive cells that were highly resistant to TMZ. Furthermore, NEO212 strongly stimulated the expression of a large number of macrophage-associated marker genes, including CD11b/ITGAM. This latter effect could not be mimicked when cells were treated with TMZ or an equimolar mix of individual agents, TMZ plus perillyl alcohol. The superior cytotoxic impact of NEO212 appeared to involve down-regulation of MGMT protein levels. In a mouse model implanted with TMZ-resistant, MGMT-positive AML cells, two 5-day cycles of 25 mg/kg NEO212 achieved an apparent cure, as mice survived >300 days without any signs of disease. In parallel toxicity studies with rats, a 5-day cycle of 200 mg/kg NEO212 was well tolerated by these animals, whereas animals that were given 200 mg/kg TMZ all died due to severe leukopenia. Together, our results show that NEO212 exerts pleiotropic effects on AML cells that include differentiation, proliferation arrest, and eventual cell death. In vivo, NEO212 was well tolerated even at dosages that far exceed the therapeutic need, indicating a large therapeutic window. These results present NEO212 as an agent that should be considered for development as a therapeutic agent for AML.
The Study of Nanosized Silicate-Substituted Hydroxyapatites Co-Doped with Sr2+ and Zn2+ Ions Related to Their Influence on Biological Activities

Nanosized silicate-substituted hydroxyapatites, characterized by the general formula Ca9.8−x−nSrnZnx(PO4)6−y(SiO4)y(OH)2 (where: n = 0.2 [mol%]; x = 0.5–3.5 [mol%]; y = 4–5 [mol%]), co-doped with Zn2+ and Sr2+ ions, were synthesized with the help of a microwave-assisted hydrothermal technique. The structural properties were determined using XRD (X-ray powder diffraction) and Fourier-transformed infrared spectroscopy (FT-IR). The morphology, size and shape of biomaterials were detected using scanning electron microscopy techniques (SEM). The reference strains of Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa were used to assess bacterial survivability and the impact on biofilm formation in the presence of nanosilicate-substituted strontium-hydroxyapatites. Safety evaluation was also performed using the standard cytotoxicity test (MTT) and hemolysis assay. Moreover, the mutagenic potential of the materials was assessed (Ames test). The obtained results suggest the dose-dependent antibacterial activity of nanomaterials, especially observed for samples doped with 3.5 mol% Zn2+ ions. Moreover, the modification with five SiO4 groups enhanced the antibacterial effect; however, a rise in the toxicity was observed as well. No harmful activity was detected in the hemolysis assay as well as in the mutagenic assay (Ames test).
Deviations from Mendelian Inheritance on Bovine X-Chromosome Revealing Recombination, Sex-of-Offspring Effects and Fertility-Related Candidate Genes

Transmission ratio distortion (TRD), or significant deviations from Mendelian inheritance, is a well-studied phenomenon on autosomal chromosomes, but has not yet received attention on sex chromosomes. TRD was analyzed on 3832 heterosomal single nucleotide polymorphisms (SNPs) and 400 pseudoautosomal SNPs spanning the length of the X-chromosome using 436,651 genotyped Holstein cattle. On the pseudoautosomal region, an opposite sire-TRD pattern between male and female offspring was identified for 149 SNPs. This finding revealed unique SNPs linked to a specific-sex (Y- or X-) chromosome and describes the accumulation of recombination events across the pseudoautosomal region. On the heterosomal region, 13 SNPs and 69 haplotype windows were identified with dam-TRD. Functional analyses for TRD regions highlighted relevant biological functions responsible to regulate spermatogenesis, development of Sertoli cells, homeostasis of endometrium tissue and embryonic development. This study uncovered the prevalence of different TRD patterns across both heterosomal and pseudoautosomal regions of the X-chromosome and revealed functional candidate genes for bovine reproduction.
Some estimators and tests for accelerated hazards model using weighted cumulative hazard difference

For a censored two-sample problem, Chen and Wang [Y.Q. Chen and M. -C. Wang, Analysis of accelerated hazards models, J. Am. Statist. Assoc. 95 (2000), pp. 608–618] introduced the accelerated hazards model. The scale-change parameter in this model characterizes the association of two groups. However, its estimator involves the unknown density in the asymptotic variance. Thus, to make an inference on the parameter, numerically intensive methods are needed. The goal of this article is to propose a simple estimation method in which estimators are asymptotically normal with a density-free asymptotic variance. Some lack-of-fit tests are also obtained from this. These tests are related to Gill–Schumacher type tests [R.D. Gill and M. Schumacher, A simple test of the proportional hazards assumption, Biometrika 74 (1987), pp. 289–300] in which the estimating functions are evaluated at two different weight functions yielding two estimators that are close to each other. Numerical studies show that for some weight functions, the estimators and tests perform well. The proposed procedures are illustrated in two applications.
Thermal-Optical Mechanical Waves of the Excited Microelongated Semiconductor Layer in a Rotational Field

This work focuses on presenting a novel model describing a layer of an excited microelongated semiconductor material. During the photo-excitation processes, the model is investigated in a rotational field. The model introduced the microelongation scalar function, which describes the microelement processes according to the micropolar-thermoelasticity theory. The model studies the interaction case between optical-thermo-mechanical waves under the effect of rotation parameters when the microelongation parameters are taken into consideration according to the photo-thermoelasticity theory. The main governing equations have been taken in a dimensionless form during the electronic and thermoelastic deformation and they have been studied under the harmonic wave technique. The general solutions of the basic fields of isotropic, homogeneous, and linear microelongated semiconductor medium are obtained in two dimensions (2D). Many conditions are taken at the free surface of the medium to obtain the complete solutions. The physical parameters of silicon (Si) are used to illustrate the numerical simulation of the main fields. Several comparisons were performed and illustrated graphically under the influence of different parameters of relaxation time and rotation.
Inference and Parameter Estimation for Diffusion Processes

Diffusion processes provide a natural way of modelling a variety of physical and economic phenomena. It is often the case that one is unable to observe a diffusion process directly, and must instead rely on noisy observations that are discretely spaced in time. Given these discrete, noisy observations, one is faced with the task of inferring properties of the underlying diffusion process. For example, one might be interested in inferring the current state of the process given observations up to the present time (this is known as the filtering problem). Alternatively, one might wish to infer parameters governing the time evolution the diffusion process. In general, one cannot apply Bayes’ theorem directly, since the transition density of a general nonlinear diffusion is not computationally tractable. In this thesis, we investigate a novel method of simplifying the problem. The stochastic differential equation that describes the diffusion process is replaced with a simpler ordinary differential equation, which has a random driving noise that approximates Brownian motion. We show how one can exploit this approximation to improve on standard methods for inferring properties of nonlinear diffusion processes.
A general methodology for bootstrapping in non-parametric frontier models

The Data Envelopment Analysis method has been extensively used in the literature to provide measures of firms' technical efficiency. These measures allow rankings of firms by their apparent performance. The underlying frontier model is non-parametric since no particular functional form is assumed for the frontier model. Since the observations result from some data-generating process, the statistical properties of the estimated efficiency measures are essential for their interpretations. In the general multi-output multi-input framework, the bootstrap seems to offer the only means of inferring these properties (i.e. to estimate the bias and variance, and to construct confidence intervals). This paper proposes a general methodology for bootstrapping in frontier models, extending the more restrictive method proposed in Simar & Wilson (1998) by allowing for heterogeneity in the structure of efficiency. A numerical illustration with real data is provided to illustrate the methodology.
Expression of a Form of Cerebellar Motor Memory Requires Learned Alterations to the Activity of Inhibitory Molecular Layer Interneurons

Procedural memories formed in the cerebellum in response to motor errors depend on changes to Purkinje cell (PC) spiking patterns that correct movement when the erroneous context is repeated. Because molecular layer interneurons (MLIs) inhibit PCs, learning-induced changes to MLI output may participate in reshaping PC spiking patterns. However, it remains unclear whether error-driven learning alters MLI activity and whether such changes are necessary for the memory engram. We addressed this knowledge gap by measuring and manipulating MLI activity in the flocculus of both sexes of mice before and after vestibulo-ocular reflex (VOR) adaptation. We found that MLIs are activated during vestibular stimuli and that their population response exhibits a phase shift after the instantiation of gain-increase VOR adaptation, a type of error-driven learning thought to require climbing-fiber-mediated instructive signaling. Although acute optogenetic suppression of MLI activity did not affect baseline VOR performance, it negated the expression of gain-increase learning, demonstrating a specific role of MLI activity changes in motor memory expression. This effect was transitory; after a multiday consolidation period, the expression of VOR gain-increase learning was no longer sensitive to MLI activity suppression. Together, our results indicate that error-driven alteration of MLI activity is necessary for labile, climbing-fiber-induced motor memory expression. SIGNIFICANCE STATEMENT In the cerebellum, motor learning induces an associative memory of the sensorimotor context of an erroneous movement that, when recalled, results in a new pattern of output that improves subsequent trials of performance. Our study shows that error-driven motor learning induces changes to the activity pattern of cerebellar molecular layer interneurons (MLIs) and that this new pattern of activity is required to express the corrective motor memory.
A Bibliometric Analysis of Publications on Drinking Water Research in India

Every creature on this planet needs water to survive and water is one of the most significant natural resources. A moderate attempt has been made in this study to understand the research trends in drinking water in India during the period of 1990 – 2019, based on Science Citation Index Expanded the Web of Science Core Collection by Clarivate Analysis. A total 74,277 documents were found, of which ‎68,029 research articles, in that 2903 articles were drinking water publications relating to India. The results indicated that the annual number of research articles have increased from about eight articles in early years 1990 to 269 articles in the latest year 2019. Also out of 2903 drinking water articles 2306 (79%) were country independent articles and 597 (21%) articles were internationally collaborative articles with 104 countries. The researchers used top three Web of Science categories ‘environmental sciences’, ‘water resources’ and ‘toxicology’. The study found that the Environmental Monitoring and Assessment was the most productive journal and Indian Institutes of Technology was the most productive institution among top ten most productive institutions in India.
Accurate Characterization for Continuous-Time Linear Equalization in CMOS Optical Receivers

Recently published CMOS optical receivers consist of a limited-bandwidth first-stage transimpedance amplifier (TIA) followed by an equalizer. Limiting the TIA’s bandwidth improves the gain and reduces the noise but introduces a significant inter-symbol interference (ISI) that is dealt with by the subsequent equalizer. Continuous-time linear equalizer (CTLE) is a commonly used equalizer in both electrical and optical links. However, recent research reported different findings about CTLE-based optical receivers. Some research papers concluded that CTLEs boost high-frequency noise compared to a full-bandwidth design. Other publications reported that high-frequency noise remains unaffected while white noise is significantly reduced. This work aims to solve this discrepancy by presenting an accurate analysis for CTLE-based optical receivers considering noise, gain, and jitter. We show that the noise performance depends on the pole/zero locations of the limited-bandwidth (LBW)-TIA and the follow-on equalizer. A properly designed CTLE-based receiver achieves a $2.5 \times $ higher gain and a $1.74\times $ better noise than the full-bandwidth design. The CTLE is also compared to the well-known decision feedback equalizer (DFE). The noise performance of the CTLE-based receiver lies between that of finite and infinite impulse response DFE-based receivers but achieves better gain than both architectures.
Comparison of daughter's performance of progeny tested sires with pedigree selected sires in Holstein Friesian crossbred cattle

The present study was conducted to compare the estimated breeding values of progeny tested sires and pedigree selected sires for test day milk yield of crossbred Holstein Friesian cattle. First lactation milk yield records (1,20,198) of 12,971 daughters sired by 267 sires were collected from INAPH database maintained by NDDB. Variance and covariance components for test-day milk yield (TDMY) were estimated by different random regression test day models (RRTDM), viz. Cubic B- Spline function, Quadratic B-Spline function, Legendre polynomial (LP) function and Wilmink function using Average Information Restricted Maximum Likelihood (AIREML). Considering various criteria for comparison of different orders of TDMs, LP of 6th order for TDMY was the best fitted model for further estimation of breeding values. The heritability estimates ranged from 0.15 to 0.39 for TDMY using Leg_2 model. The additive genetic correlations were higher than the phenotypic correlations among different TDs. The additive genetic correlations between test day yields varied from 0.73 to 0.99. The expected progeny difference (EPD) for TDMYcalculated based on dam’s yield for the top ten and bottom ten PS bulls was 2,662.5 kg; whereas, the actual progeny difference (APD) for these bulls was -28.47 kg. While, EPD for top 10 and bottom 10 PT bulls selected based on EBVs was 2,820.52 kg whereas the APD for PT bulls was 890.48 kg. The difference in expected and actual MY of progeny was higher in PS bulls as compared to PT bulls indicating that the pedigree information for EPDs had a poor association with APDs and sire superiority is not reflected in progeny’s actual performance. The rank correlation between ranks of all PS and PT bulls were very poor and non-significant. The bulls selected based on estimated breeding values will give faster genetic progress and decision to select replacement bulls based on breeding values instead of dam’s yield will have positive effect on genetic progress.
TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

Dysfunctions of the thyroid hormone (TH) transporting monocarboxylate transporter MCT8 lead to a complex X-linked syndrome with abnormal serum TH concentrations and prominent neuropsychiatric symptoms (Allan-Herndon-Dudley syndrome, AHDS). The key features of AHDS are replicated in double knockout mice lacking MCT8 and organic anion transporting protein OATP1C1 (Mct8/Oatp1c1 DKO). In this study, we characterize impairments of brain structure and function in Mct8/Oatp1c1 DKO mice using multimodal magnetic resonance imaging (MRI) and assess the potential of the TH analogue 3,3′,5-triiodothyroacetic acid (TRIAC) to rescue this phenotype. Structural and functional MRI were performed in 11-weeks-old male Mct8/Oatp1c1 DKO mice (N = 10), wild type controls (N = 7) and Mct8/Oatp1c1 DKO mice (N = 13) that were injected with TRIAC (400 ng/g bw s.c.) daily during the first three postnatal weeks. Grey and white matter volume were broadly reduced in Mct8/Oatp1c1 DKO mice. TRIAC treatment could significantly improve white matter thinning but did not affect grey matter loss. Network-based statistic showed a wide-spread increase of functional connectivity, while graph analysis revealed an impairment of small-worldness and whole-brain segregation in Mct8/Oatp1c1 DKO mice. Both functional deficits could be substantially ameliorated by TRIAC treatment. Our study demonstrates prominent structural and functional brain alterations in Mct8/Oatp1c1 DKO mice that may underlie the psychomotor deficiencies in AHDS. Additionally, we provide preclinical evidence that early-life TRIAC treatment improves white matter loss and brain network dysfunctions associated with TH transporter deficiency.
Residuals and Their Variance Patterns

One of the most important aspects of the analysis of data by regression methods is the examination of residuals. This implies the careful inspection of the differences, ei = yi – ŷ i , i = 1,2, …, n, between the observed values yi , and the corresponding values yi which are predicted by the fitted model at the n observation sites. There are many ways of looking at residuals; for basic references see Anscombe and Tukey (1963) and Anscombe (1961, 1967), or see the expository accounts by Draper and Smith (1966, Chapter 3) and Wooding (1969). Important basic techniques are the inspection of the magnitude of individual residuals to detect the presence of outliers and the plotting of the residuals against their corresponding fitted values, or against the corresponding values of the independent variables, or against the corresponding values of “new” variables, and (in all cases) observing the pattern thus formed. An “ideal” pattern for most plots, that implies no denial of the regression assumptions, occurs when.
Determination of Leuprolide–Fatty Acid Conjugate in Rat Plasma Using LC-MS/MS and Its Pharmacokinetics after Subcutaneous Administration in Rats

Leuprolide is a synthetic nonapeptide drug (pyroGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt) that acts as a gonadotropin-releasing hormone agonist. The continuous administration of therapeutic doses of leuprolide inhibits gonadotropin secretion, which is used in androgen-deprivation therapy for the treatment of advanced prostate cancer, central precocious puberty, endometriosis, uterine fibroids, and other sex-hormone-related conditions. To improve the pharmacokinetic properties of peptide drugs, a fatty acid was conjugated with leuprolide for long-term action. In this study, we developed a simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of leuprolide and leuprolide–oleic acid conjugate (LOC) levels. The developed method was validated in terms of linearity, precision, accuracy, recovery, matrix effect, and stability according to the US Food and Drug Administration guidelines, and the parameters were within acceptable limits. Subsequently, the pharmacokinetics of leuprolide and LOCs were evaluated. In vivo rat subcutaneous studies revealed that conjugation with fatty acids significantly altered the pharmacokinetics of leuprolide. After the subcutaneous administration of fatty-acid-conjugated leuprolide, the mean absorption time and half-life were prolonged. To the best of our knowledge, this is the first study showing the effects of fatty acid conjugates on the pharmacokinetics of leuprolide using a newly developed UPLC-MS/MS method for the simultaneous quantification of leuprolide and LOCs.
Fourier-Based Near-Field Three-Dimensional Image Reconstruction in a Multistatic Imaging Structure Using Dynamic Metasurface Antennas

Due to physical layer compression, and consequently, the failure to produce uniform radiation patterns, it is not possible to apply fast Fourier-based image reconstruction algorithms to raw measurements collected from coded metasurface antennas in computational imaging. An effective solution in the literature is a sub-wavelength sampling of the aperture. However, this solution is currently limited to a panel-to-probe model which requires a mechanical raster scan. On the other hand, existing works are based on time-division multiplexing. This means that only a single transmit/receive channel is active in each time slot. In this paper, we introduce a panel-to-panel model in a multistatic structure. Based on this model, two pre-processing (for two different individually measured signal and combined measured signal (CMS) scenarios) are derived to convert the raw measurements into the space-frequency domain. Then, by using the output data from the pre-processing stage and according to the configuration of the introduced imaging system, the range migration algorithm is adapted. The importance of the proposed solution for the CMS scenario is that, for the first time, it demonstrates the capability of using dynamic metasurface antenna diversity to achieve simultaneous data acquisition. The performance of the proposed approach is compared with state-of-art works in terms of reconstructed image quality and computational complexity using numerical simulations and analytical discussions.