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The crystalline state of ibuprofen (IBU) confined in mesoporous silica was characterized using low-field time-domain nuclear magnetic resonance (TD-NMR). IBU was loaded into ordered (Santa Barbara Amorphous-15 [SBA-15]; SBA) or nonordered mesoporous silica (Sylysia 320; SYL) using a well-known incipient wetness impregnation method. The dissolution profile of IBU from the silica was measured. The IBU-loaded SBA showed a relatively higher drug concentration at 10 and 20 min, which was typical of a supersaturated solution. However, it did not maintain that concentration. By contrast, the IBU-loaded SYL did not show such a dissolution profile in the early stage. To characterize the crystalline state of IBU confined in silica, the T

In centrifugal compressors, it is common to observe a rapid reduction in surge margin toward high rotational speed, which shows a non-linear surge characteristic against the change of rotational speed. This paper presents a comprehensive experimental and numerical study to understand the flow mechanisms leading to the non-linear surge behavior in a high-speed centrifugal compressor. It shows that for the studied compressor, there are two critical flow coefficients (ϕ = 0.255 and 0.136) where the stability of the compressor stage is significantly weakened. At a higher speed, the impeller rotating stall happens at the first critical point where the diffuser instability is also enhanced. This is caused by the increase of the flow non-uniformity at the impeller exit as well as increased diffuser inflow angle due to the impeller compressibility effect. Therefore, both the impeller and diffuser’s instability are matched and trigger the surge at a high flow coefficient. In contrast, at a lower speed, the diffuser instability is not enhanced by the impeller rotating stall, this mismatch of the two component’s instability allows the compressor to pass through the first critical point and extend the surge limit to the second critical point where the diffuser reaches the stability limit and causes the rotating stall spontaneously. By these different behaviors at each speed, the non-linearity of the surge characteristic is established.

The centrifugal compressor of a turbocharger is affected by the opening and closing of the engine intake manifold and consequently experiences a pulsating backpressure. The imposed pulsating conditions generate internal losses and reduce the overall compressor performance and efficiency. However, previous studies have shown that these dynamic conditions can also lead to a surge margin improvement, benefiting the lower limit of stability, in certain conditions. The stability of the compressor arises from the flow behaviour in the inlet region and the interaction between the rotating and stationary components at the inlet. In this paper, the computational flow field of the inlet region of a centrifugal compressor under pulsating flow has been studied. A full stage, 3D URANS model of a compressor exposed to pulsating backpressure has been solved using ANSYS-CFX for the near surge operating point. The transient behaviour of this operating point has been studied at six instances in time within one cycle of the pulse. The flow field is assessed using Mach number, static entropy, static pressure and local flow direction in the inlet region. Flow separation regions have been identified. The authors propose that the variation in flow field at the inlet due to the dynamic response to the imposed boundary condition could explain the improvement in surge margin under pulsating flow conditions for this compressor system.

Room-temperature operations of rechargeable Mg coin-cell batteries have been achieved using a Mg alloy negative electrode and a spinel MgMn2O4 (MMO)-positive electrode. The present work focuses on clarifying the effects of the physiochemical properties of the MMO powder including the specific surface area (SBET) and porosity of the positive electrode on Mg battery performances in practical applications. Finally, optimal specific surface area and porosity parameters were obtained that ensured excellent battery performances as a standard coin-cell at room temperature. A typical MMO powder synthesized using a modified sol–gel method with propylene oxide-driven complex polymerization had a large SBET > 200 m2 g−1, and more than 90% porosity with a triple-tiered 3D open-channel network. Here we evaluated the discharge capacity and the cyclability for room-temperature operation as a function of SBET in a full cell with a Mg negative electrode as well as half cells with a carbon graphite electrode. Irrespective of whether half cells or a full cell was used, the initial discharge capacity was found to depend linearly on the SBET of the porous MMO powder in a Mg tetrakis(hexafluoroisopropyl)borate/triglyme electrolyte with a wide potential window, ΔE > 3.6 V. Eventually, the maximum discharge capacity of 220 mA h g−1 was realized at 25 °C in the full cell using the 3D open-channel nanostructure with SBET = 236 m2 g−1. The cyclability in the full cell with the Mg alloy negative electrode, however, degraded with the increasing SBET, while no cyclability degradation was observed in the half cell with the carbon electrode. A possible mechanism is discussed regarding passivation of the Mg alloy electrode in discharge/charge cycles.

The purpose of this study was to accumulate enhanced technical knowledge about the powder properties of direct compaction grades of mannitol that could lead to new tablet formulations. Fifteen different commercial direct compaction grades of mannitol were tested. Ten different powder properties representing flowability, particle size, specific surface area and manufacturing properties were measured. In addition, model tablets of each mannitol grade were prepared, and their disintegration time, friability, and tensile strength were measured. The data were analyzed by principle component analysis and a Kohonen self-organizing map to find correlations between powder properties. Self-organizing map clustering successfully classified the test grades into 5 distinct clusters having different powder properties. Each cluster was well characterized by statistical profiling. Subsequently, the contribution of the powder properties to the tablet properties was investigated by a least absolute shrinkage- and selection operator (Lasso) regression model. Mannitol grades with a larger particle size (D90) were prone to produce tablets with longer disintegration time, while a larger specific surface area of the particles was positively associated with tablets with higher mechanical strength. Our findings provide valuable information for the design of tablet formulations.

We sought to demonstrate the usefulness of the T2 relaxation behaviors measured by time domain NMR (TD-NMR) for the quantitative evaluation of the crystallinity of an active pharmaceutical ingredient (API). This study used indomethacin as a model API. After blending amorphous and crystalline indomethacin powders at a designated ratio, T2 relaxation curves were measured by TD-NMR. Subsequently, we acquired a calibration curve to quantify crystallinity by curve fitting analysis. Validation demonstrated a good correlation between the theoretical and experimental percentage of crystallinity. Thus, this study succeeded in a precise estimation of crystallinity of indomethacin using TD-NMR. We also investigated whether the technique is practical by testing indomethacin powders with unknown proportion of crystallinity, and then compared their estimated crystallinity with that found using conventional evaluation techniques. The quantitative performance of the TD-NMR technique was comparable to that of Raman spectroscopy. Furthermore, indomethacin powder blended with excipients, which can be used to produce tablets, was tested. The TD-NMR technique was still able to quantify the crystallinity of indomethacin, even when excipients were incorporated into the sample. Therefore, the present study expands the horizon for evaluating the crystallinity of APIs in pharmaceutical sciences.

The development of a robust amide-bond formation remains a critical aspect of N-methylated peptide synthesis. In this study, we synthesized a variety of dipeptides in high yields, without severe racemization, from equivalent amounts of amino acids. Highly reactive N-methylimidazolium cation species were generated in situ to accelerate the amidation. The key to success was the addition of a strong Brønsted acid. The developed amidation enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation. In addition, the amidation can be performed by using either a microflow reactor or a conventional flask. The first total synthesis of naturally occurring bulky N-methylated peptides, pterulamides I-IV, was achieved. Based on experimental results and theoretical calculations, we speculated that a Brønsted acid would accelerate the rate-limiting generation of acyl imidazolium cations from mixed carbonic anhydrides.

Gene rearrangements of MLL/KMT2A or RUNX1 are the major cause of therapy-related leukemia. Moreover, MLL rearrangements are the major cause of infant leukemia, and RUNX1 rearrangements are frequently detected in cord blood. These genes are sensitive to topoisomerase II inhibitors, and various genes have been identified as potential fusion partners. However, fetal exposure to these inhibitors is rare. Therefore, we postulated that even a proliferation signal itself might induce gene rearrangements in hematopoietic stem cells. To test this hypothesis, we detected gene rearrangements in etoposide-treated or non-treated CD34+ cells cultured with cytokines using inverse PCR. In the etoposide-treated cells, variable-sized rearrangement bands were detected in the RUNX1 and MLL genes at 3 hours of culture, which decreased after 7 days. However, more rearrangement bands were detected in the non-treated cells at 7 days of culture. Such gene rearrangements were also detected in peripheral blood stem cells mobilized by cytokines for transplantation. However, none of these rearranged genes encoded the leukemogenic oncogene, and the cells with rearrangements did not expand. These findings suggest that MLL and RUNX1 rearrangements, which occur with very low frequency in normal hematopoietic progenitor cells, may be induced under cytokine stimulation. Most of the cells with gene rearrangements are likely eliminated, except for leukemia-associated gene rearrangements, resulting in the low prevalence of leukemia development.

Clustering is employed in various fields. However, the conventional method does not consider changing data. Therefore, if the data is changed, the entire dataset must be re-clustered. This article proposes a clustering method to update the clustering result obtained by a hierarchical clustering method without re-clustering when a point is inserted. This article defines the center and the radius of a cluster and determine the cluster to be inserted. The insertion location is determined by similarity based on the conventional clustering method. this research introduces the concept of outliers and consider creating a cluster caused by the insertion. By examining the multimodality of a cluster, the cluster is divided. In addition, when the number of clusters increases, data points previously inserted are updated by re-insertion. Compared with the conventional method, the experimental results demonstrate that the execution time of the proposed method is significantly smaller and clustering accuracy is comparable for some data.

We synthesised palladium and platinum complexes possessing cyclic and acyclic pincer-type polyaromatic ligands and investigated their structural effect on the catalysis. The pincer-type bis(6-arylpyridin-2-yl)benzene skeleton was constructed via Kröhnke pyridine synthesis under transition metal-free conditions on gram-scale quantity. Ligand structure significantly influenced catalytic activity toward the platinum-catalysed hydrosilylation of diphenyl acetylenes, despite the ligand-independence of the conformations and electronic properties of these complexes.

A Rh(III)-catalyzed annulative coupling of 3,5-diarylisothiazoles and alkynes is reported. The N-S bond in the isothiazole ring acts as an internal oxidant to regenerate the Rh(III) species in combination with an external Cu(II) oxidant, and the corresponding 1:2 coupling products are obtained. The remarkable difference in the reaction outcome between isothiazoles and the relevant isoxazoles has been investigated by DFT calculations, revealing that the relative stability of the enolate intermediates dictates the product selectivity.

A Lewis base catalyst Trip-SMe (Trip = triptycenyl) for electrophilic aromatic halogenation using N-halosuccinimides (NXS) is introduced. In the presence of an appropriate activator (as a noncoordinating-anion source), a series of unactivated aromatic compounds were halogenated at ambient temperature using NXS. This catalytic system was applicable to transformations that are currently unachievable except for the use of Br2 or Cl2: e.g., multihalogenation of naphthalene, regioselective bromination of BINOL, etc. Controlled experiments revealed that the triptycenyl substituent exerts a crucial role for the catalytic activity, and kinetic experiments implied the occurrence of a sulfonium salt [Trip-S(Me)Br][SbF6] as an active species. Compared to simple dialkyl sulfides, Trip-SMe exhibited a significant charge-separated ion pair character within the halonium complex whose structural information was obtained by the single-crystal X-ray analysis. A preliminary computational study disclosed that the π system of the triptycenyl functionality is a key motif to consolidate the enhancement of electrophilicity.

RUNX1 is a critical transcription factor for the emergence of definitive hematopoiesis and the precise regulation of adult hematopoiesis. Dysregulation of its regulatory network causes aberrant hematopoiesis. Recurrent genetic alterations in RUNX1, including chromosomal translocations and mutations, have been identified in both inherited and sporadic diseases. Recent genomic studies have revealed a vast mutational landscape surrounding genetic alterations in RUNX1. Accumulating pieces of evidence also indicate the leukemogenic role of wild-type RUNX1 in certain situations. Based on these efforts, part of the molecular mechanisms of disease development as a consequence of dysregulated RUNX1-regulatory networks have become increasingly evident. This review highlights the recent advances in the field of RUNX1 research and discusses the critical roles of RUNX1 in hematopoiesis and the pathobiological function of its alterations in the context of disease, particularly myeloid neoplasms, and clonal hematopoiesis.

Blastocyst formation gives rise to the inner cell mass (ICM) and trophectoderm (TE) and is followed by the differentiation of the epiblast (Epi) and primitive endoderm (PrE) within the ICM. Although these two-round cell lineage differentiations underpin proper embryogenesis in every mammal, their spatiotemporal dynamics are quite diverse among species. Here, molecular details of the blastocyst stage in cattle were dissected using an optimized in vitro culture method. Blastocyst embryos were placed on agarose gel filled with nutrient-rich media to expose embryos to both gaseous and liquid phases. Embryos derived from this "on-gel" culture were transferred to surrogate mothers on day (D) 10 after fertilization and successfully implanted. Immunofluorescent studies using on-gel-cultured embryos revealed that the proportion of TE cells expressing the pluripotent ICM marker, OCT4, which was beyond 80% on D8, was rapidly reduced after D9 and reached 0% on D9.5. This first lineage segregation process was temporally parallel with the second one, identified by the spatial separation of Epi cells expressing SOX2 and PrE cells expressing SOX17. RNA-seq comparison of TE cells from D8 in vitro fertilized embryos and D14 in vivo embryos revealed that besides drastic reduction of pluripotency-related genes, TE cells highly expressed Wnt, FGF, and VEGF signaling pathways-related genes to facilitate the functional maturation required for feto-maternal interaction. Quantitative PCR analysis of TE cells derived from on-gel culture further confirmed time-dependent increments in the expression of key TE markers. Altogether, the present study provides platforms to understand species-specific strategies for mammalian preimplantation development.

This study investigates the usefulness of machine learning for modeling complex relationships in a material library. We tested 81 types of active pharmaceutical ingredients (APIs) and their tablets to construct the library, which included the following variables: 20 types of API material properties, one type of process parameter (three levels of compression pressure), and two types of tablet properties (tensile strength (TS) and disintegration time (DT)). The machine learning algorithms boosted tree (BT) and random forest (RF) were applied to analysis of our material library to model the relationships between input variables (material properties and compression pressure) and output variables (TS and DT). The calculated BT and RF models achieved higher performance statistics compared with a conventional modeling method (i.e., partial least squares regression), and revealed the material properties that strongly influence TS and DT. For TS, true density, the tenth percentile of the cumulative percentage size distribution, loss on drying, and compression pressure were of high relative importance. For DT, total surface energy, water absorption rate, polar surface energy, and hygroscopicity had significant effects. Thus, we demonstrate that BT and RF can be used to model complex relationships and clarify important material properties in a material library.

This paper presents a single-chip 3072-element-channel (ECh) transceiver/128-subarray-channel (SCh) 2-D array IC with analog receiver (RX) and all-digital transmitter (TX) beamformer for echocardiography. The proposed IC integrates 3072-ECh transceivers that are composed of a low-power tunable amplitude three-level pulser (TA3LP), zero-power-TX-and-RX- isolation switch (ZTRSW), programmable gain-and-input-impedance low-noise amplifier (PGZLNA), bidirectional dynamically reconfigurable switched-capacitor delayer (BDR- SCD), and 24-ECh-to-1-SCh charge-domain adder (CDADD). It also has 128-SCh low-noise cable buffers (LNCBUFs) and all the related peripheral circuits, including control and interface circuits. It has an all-digital TX architecture with a digital beamformer (TX-DBF) that is free from the waveform distortion and timing error caused by long cable propagation between the main instrument unit and the IC. The TA3LP launches the three-level bipolar signals that are necessary for tissue harmonic imaging (THI). The BDR-SCD can delay 2-bit TX digital signals or an RX analog signal; 24 RX signals in an SCh are coherently delayed using BDR-SCDs, summed in the charge domain with a CDADD without signal headroom concerns, and converted into an SCh signal. The proposed IC is fabricated with a $0.18-\mu \text{m}$ high-voltage silicon-on-insulator (HV SOI) CMOS process. Each ECh transceiver occupies only a $300 ~\mu \text{m}\,\,\times 300 ~\mu \text{m}$ silicon area while having a greater than 85-dB dynamic range, 25-ns resolution, 750-ns maximum time delay, and $138-{V}_{\textrm {pp}}$ output capabilities. The total die size is 417 mm2. An ultrasound system was also made to visualize 2-D/3-D phantom images with 0.74-mW/ECh power consumption in the B-mode.

In this study, adding carbon nanotubes (CNTs) to poly (ether ether ketone) (PEEK) not only improved the mechanical properties, but also improved the thermal resistivity of PEEK owing to the CNTs’ function as an antioxidant. The PEEK–CNT composite did not show large weight loss at 450 °C. The stabilization energies (ΔG) of CNTs for 1,4-diphenoxybenzene radical and 4-phenoxyphenol radical, which are decomposition products of PEEK at 450 °C, were calculated by density functional theory, and they were estimated to be −80.3 and 150.2 kJ mol−1, respectively. It was confirmed that 1,4-diphenoxybenzene radical could be trapped in a high-temperature environment of 450 °C by the CNTs. The addition of CNTs yielded almost no change in formability, but the mechanical properties such as tensile strength and bending strength were greatly improved. The PEEK–CNT composite is expected to have improved heat resistivity and mechanical properties, as well as higher reliability, so that it can be used in the future in various fields such as aerospace and automotive.

The aim of this study was to demonstrate the usefulness of T2 measurements conducted with a time-domain NMR (TD-NMR) for the characterization of active pharmaceutical ingredients (APIs) containing solid dosage forms. A solid dispersion (SD) and a physical mixture (PM) consisting of indomethacin (IMC) and polyvinylpyrrolidone (PVP) were prepared at different weight ratios as test samples, and then their T2 relaxation curves were measured by TD-NMR. The T2 relaxation curve of IMC was quite different from that of PVP by nature. T2 values of the SD and PM samples became gradually shortened with increasing IMC content. No difference in T2 relaxation curves was observed between SD and PM. By analyzing the T2 relaxation curves in detail, we succeeded in precisely quantifying the IMC contents incorporated in the samples. Next, this study evaluated the T2 relaxation curves of amorphous and crystalline states of powdered IMC. T2 relaxation rate of crystalline IMC was slightly but significantly higher than that of amorphous IMC, proving that the T2 measurement was sensitive enough to detect these differences. Finally, a thermal stress was imposed on SD and PM samples at 60°C for 7 d, and then an amorphous-to-crystalline transformation occurred in IMC in the PM sample and was successfully monitored by T2 measurement. We believe that T2 measurement by TD-NMR is a promising analysis for the characterization of APIs in solid dosage forms, including SD-based pharmaceuticals.

SETD2, an epigenetic tumor suppressor, is frequently mutated in MLL-rearranged (MLLr) leukemia and relapsed acute leukemia (AL). To clarify the impact of SETD2 mutations on chemotherapy sensitivity in MLLr leukemia, two loss-of-function (LOF) Setd2-mutant alleles (Setd2(F2478L/WT) or Setd2(Ex6-KO/WT)) were generated and introduced, respectively, to the Mll-Af9 knock-in leukemia mouse model. Both alleles cooperated with Mll-Af9 to accelerate leukemia development that resulted in resistance to standard Cytarabine-based chemotherapy. Mechanistically, Setd2-mutant leukemic cells showed downregulated signaling related to cell cycle progression, S, and G2/M checkpoint regulation. Thus, after Cytarabine treatment, Setd2-mutant leukemic cells exit from the S phase and progress to the G2/M phase. Importantly, S and G2/M cell cycle checkpoint inhibition could resensitize the Mll-Af9/Setd2 double-mutant cells to standard chemotherapy by causing DNA replication collapse, mitotic catastrophe, and increased cell death. These findings demonstrate that LOF SETD2 mutations confer chemoresistance on AL to DNA-damaging treatment by S and G2/M checkpoint defects. The combination of S and G2/M checkpoint inhibition with chemotherapy can be explored as a promising therapeutic strategy by exploiting their unique vulnerability and resensitizing chemoresistant AL with SETD2 or SETD2-like epigenetic mutations.

The aim of this study was to demonstrate the usefulness of the time-domain NMR (TD-NMR) method to characterize the crystalline state of active pharmaceutical ingredients (APIs) containing a solid dispersion. In this study, indomethacin (IMC) was used as a model for poorly water-soluble API. Solid dispersions of IMC were prepared with polyvinylpyrrolidone (PVP) at different weight ratios. First, we measured the T1 relaxation behavior of solid dispersions. From the result, the T1 relaxation time (T1) changed according to the API content; the T1 tended to increase with increasing API content because the T1 value of amorphous IMC was longer than that of PVP. Next, we tried to monitor the amorphous-to-crystalline transformation of IMC in the solid dispersion during the thermal stress test. In the case of solid dispersion containing 90% IMC, a clear prolongation of the T1 could be observed during the thermal stress test. From the powder X-ray diffraction patterns, the change in T1 relaxation behavior must be caused by the IMC transformation from amorphous to crystalline. From these findings, we were successful in monitoring the IMC amorphous-to-crystalline transformation by the changes in T1 relaxation behavior. Our findings led us to conclude that TD-NMR is a novel approach for the evaluation of crystalline state of APIs in solid dispersions.

Organic materials absorbing near-infrared (NIR) light are very attractive for the fabrication of optoelectronic devices. In this study, we developed an ultralow energy gap copolymer TzQI-TDPP compo...

The different states of water incorporated in wet granules were studied by a low-field benchtop 1H-NMR time-domain NMR (TD-NMR) instrument. Wet granules consisting different fillers [cornstarch (CS), microcrystalline cellulose (MCC), and D-mannitol (MAN)] with different water contents were prepared using a high-speed granulator, and then their spin-spin relaxation time (T2) was measured using the NMR relaxation technique. The experimental T2 relaxation curves were analyzed by the two-component curve fitting, and then the individual T2 relaxation behaviors of solid and water in wet granules were identified. According to the observed T2 values, it was confirmed that the molecular mobility of water in CS and MCC granules was more restricted than that in the MAN granule. The state of water appeared to be associated with the drying efficiency and moisture absorption capacity of wet granules. Thus, it was confirmed that the state of water significantly affected the wet granulation process and the characteristics of the resultant granules. In the final phase of this study, the effects of binders on the molecular mobility of water in granulation fluids and wet granules were examined. The state of water in granulation fluids was substantially changed by changing the binders. The difference was still detected in wet granules prepared by addition of these fluids to the fillers. In conclusion, TD-NMR can offer valuable knowledge on wet granulation from the viewpoint of molecular mobility of water.

The aim of this study was to demonstrate the usefulness of the time domain nuclear magnetic resonance (TD-NMR) method to characterize the crystalline state of active pharmaceutical ingredients (APIs) containing solid dosage forms. In this study, carbamazepine and indomethacin are used as models for poorly water-soluble APIs. First, we measured the T1 and T2 relaxation behavior of crystalline and amorphous APIs. From the results, we were able to confirm that the T1 relaxation time measured by TD-NMR is an effective parameter for distinguishing between crystalline and amorphous states in powdered APIs. We then examined physical mixtures of APIs with polyvinylpyrrolidone and their solid dispersion. The results indicated that TD-NMR allows the evaluation of not only the crystalline form of APIs but also the miscibility of APIs and polymers. In the final phase of the study, we conducted continuous monitoring of the crystalline state of APIs incorporated into physical mixtures during the thermal stress test. Conversion to crystalline forms of the APIs was successfully monitored based on the T1 relaxation behavior. Our findings led us to conclude that TD-NMR is useful as a new approach to evaluate the crystalline state of APIs.

Fascin-1, an actin-bundling protein, is associated with poor prognosis in patients with various types of human carcinoma. However, research is limited on the role of fascin-1 in sarcoma. Solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) are rare sarcomas derived from the mesenchyme. Although the prognosis of SFT/HPC is generally favorable, fatalities are possible with repeated recurrence and distant metastasis. The current study included a total of 20 Japanese patients, who were diagnosed with SFT/HPC and underwent surgery at Kochi University Hospital from January 2000 to December 2019. The statistical relationship between recurrence and the following variables were examined: Sex, age of onset, tumor origin, tumor size, necrosis, mitosis ≥1/10 high power field (HPF; magnification, x400), Ki-67 >5% and Fascin-1. A significant association was determined between recurrence and necrosis, mitosis ≥1/10 HPF (magnification, x400), Ki-67 >5%, and Fascin-1 ≥'strongly positive' (P

Cellular differentiation induces various morphological changes, including elongation, in mitochondria. Preimplantation embryos have round-shaped mitochondria, characteristic of undifferentiated cells. However, there is controversy regarding the precise mitochondrial morphology in blastocyst embryos, which are generated from two cell lineages: undifferentiated inner cell mass (ICM) and differentiated trophectoderm (TE). This study attempted to precisely determine mitochondrial morphology in these two blastocyst regions. Transmission electron microscopy analyses were conducted using more than 1000 mitochondria from blastocyst embryos. No significant differences were observed in the configuration of mitochondrial cristae and frequencies of hooded mitochondria, which are specific to embryos of livestock animals, between the ICM and TE. To accurately compare mitochondrial roundness between the ICM and TE, oblateness was calculated based on both the major and minor axes. Average oblateness was significantly greater in the TE than in the ICM (P < 0.01). These results indicate tissue-specific mitochondrial maturation with complete elongation in the TE at the blastocyst stage. Since mitochondrial elongation is closely associated with cellular metabolism and differentia-tion, the present study provides new insights for better understanding of early embryonic develop-ment in cattle. (c) 2021 Elsevier Inc. All rights reserved.

DNA methyltransferase inhibitors have improved the prognosis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, because these agents are easily degraded by cytidine deaminase (CDA), they must be administered intravenously or subcutaneously. Recently, two orally bioavailable DNA methyltransferase inhibitors, CC-486 and ASTX727, were approved. In previous work, we developed 5-O-trialkylsilylated decitabines that resist degradation by CDA. However, the effects of silylation of a deoxynucleotide analog and enzymatic cleavage of silylation have not been fully elucidated. Enteric administration of OR21 in a cynomolgus monkey model led to high plasma concentrations and hypomethylation, and in a mouse model, oral administration of enteric-coated OR21 led to high plasma concentrations. The drug became biologically active after release of decitabine (DAC) from OR21 following removal of the 5′-O-trisilylate substituent. Toxicities were tolerable and lower than those of DAC. Transcriptome and methylome analysis of MDS and AML cell lines revealed that OR21 increased expression of genes associated with tumor suppression, cell differentiation, and immune system processes by altering regional promoter methylation, indicating that these pathways play pivotal roles in the action of hypomethylating agents. OR21 induced cell differentiation via upregulation of the late cell differentiation drivers CEBPE and GATA-1. Thus, silylation of a deoxynucleotide analog can confer oral bioavailability without new toxicities. Both in vivo and in vitro, OR21 exerted antileukemia effects, and had a better safety profile than DAC. Together, our findings indicate that OR21 is a promising candidate drug for phase I study as an alternative to azacitidine or decitabine.

This study tested 15 direct compaction grades to identify the contribution of different grades of mannitol to the storage stability of the resulting tablets. After preparing the model tablets with different values of hardness, they were stored at 25 &deg, C, 75% relative humidity for 1 week. Then, measurement of the tablet properties was conducted on both pre- and post-storage tablets. The tablet properties were tensile strength (TS), friability, and disintegration time (DT). The experimental data were analyzed using a Kohonen self-organizing map (SOM). The SOM analysis successfully classified the test grades into three distinct clusters having different changes in the behavior of the tablet properties accompanying storage. Cluster 1 showed an obvious rise in DT induced by storage, while cluster 3 showed a substantial change in mechanical strength of the tablet including a reduction in the TS and a rise in friability. Furthermore, the data were analyzed using an Elastic net regression technique to investigate the general relationships between the powder properties of mannitol and the change behavior of the tablet properties. Consequently, we succeeded in identifying the crucial powder properties for the storage stability of the resulting tablets. This study provides advanced technical knowledge to characterize the effect of different direct compaction grades of mannitol on the storage stability of tablet properties.

The transcription factor CCAAT enhancer-binding protein β (C/EBPβ) is required for stress-induced granulopoiesis at the level of hematopoietic stem/progenitor cells (HSPCs); however, its role and mechanisms of action in HSPCs are unknown. In this study, we assessed the regulation and functions of C/EBPβ in HSPCs, especially under stress conditions. After 5-fluorouracil treatment or bone marrow transplantation, Cebpb−/− HSPCs exhibited impaired cell-cycle activation and myeloid differentiation at the early and late phases of regeneration, respectively, whereas at steady state, Cebpb deficiency did not affect HSPCs. C/EBPβ was upregulated in response to hematopoietic stress, especially in CD150high long term-hematopoietic stem cells (LT-HSCs). Intracellular flow cytometric analysis that detected distinct domains of C/EBPβ revealed that, among the 3 isoforms of C/EBPβ, liver-enriched inhibitory protein (LIP) was upregulated in LT-HSCs prior to liver-enriched activating protein (LAP)/LAP* during regeneration. Early upregulation of LIP promoted cell-cycle entry of LT-HSCs by positively regulating Myc and expanded the HSPCs pool. Subsequent myeloid differentiation of amplified HSPCs was mediated by LAP/LAP*, which were upregulated at a later phase of regeneration. Collectively, our findings show that stress-induced sequential upregulation of C/EBPβ isoforms is critical for fine-tuning the proliferation and differentiation of regenerating HSPCs.

The postnatal testicular development and actin distribution in the seminiferous epithelium were examined by light microscopy, using the testes of the Habu (Trimeresurus flavoviridis; snake) from 0-year-old to 3-year-old. At 0-year-old (about 1 month after birth), the testis was quite small in size, and the seminiferous epithelium was composed of only Sertoli cells and large spermatogonia. Actin immunoreactivity was observed in the peritubular myoid cells, but could not be detected in the seminiferous epithelium. At 1-year-old (about 10 months after birth), the testicular size increased to a great degree. In the seminiferous epithelium, spermatocytes newly appeared. Actin could still not be detected in the seminiferous epithelium. At 2-year-old (about 1 year and 10 months after birth), the testes continued to develop in size. In the seminiferous epithelium, elongate spermatids and round spermatids were frequently seen, in addition to Sertoli cells, spermatogonia and spermatocytes. Thus, active spermatogenesis was clearly recognized at this age. Moreover, the actin distribution in the seminiferous epithelium was observed at the site between Sertoli cells and spermatids, as well as that at adult stage. The immunoreactivity of actin in the peritubular myoid cells gradually increased from 0-year-old to 2-year-old. Conclusively, it seems likely that spermatogenesis in the Habu initiates at 2-year-old, accompanying with the appearance of actin in the seminiferous epithelium.

The molecular dynamics (MD) technique to accelerate simulation of phase transition to liquid-crystalline (LC) phases is demonstrated on the model LC system 4-octyl-4'-cyanobiphenyl (8CB) smectic A phase. Simulation of a phase transition to a smectic phase is challenging because an intrinsically long simulation time and large system size are required owing to the high order and low onset temperature. Acceleration of the simulated transition of 8CB to the smectic A phase was ultimately achieved by selectively weakening the intermolecular Lennard-Jones interaction of alkyl chains and then returning the scaled interaction to the unscaled one. The total time needed to form the smectic A phase using selectively scaled and returned molecular dynamics (ssrMD) was five times shorter than that when using unscaled MD. Formation of the smectic A phase occurred only when induced polarization from the antiparallel dipole dimer point charge was included in the simulation. The use of ssrMD presented herein is anticipated to accelerate the theoretical development of self-assembled organic materials containing both rigid and flexible moieties, including LC materials.

Background: Hypomyelinating leukodystrophy 3 (HLD3), previously characterized as a congenital diseases associated with oligodendrocyte myelination, is increasingly regarded as primarily affecting neuronal cells. Methods: We used N1E-115 cells as the neuronal cell model to investigate whether HLD3-associated mutant proteins of cytoplasmic aminoacyl-tRNA synthase complex-interacting multifunctional protein 1 (AIMP1) aggregate in organelles and affect neuronal differentiation. Results: 292CA frame-shift type mutant proteins harboring a two-base (CA) deletion at the 292th nucleotide are mainly localized in the lysosome where they form aggregates. Similar results are observed in mutant proteins harboring the Gln39-to-Ter (Q39X) mutation. Interestingly, the frame-shift mutant-specific peptide specifically interacts with actin to block actin fiber formation. The presence of actin with 292CA mutant proteins, but not with wild type or Q39X ones, in the lysosome is detectable by immunoprecipitation of the lysosome. Furthermore, expression of 292CA or Q39X mutants in cells inhibits neuronal differentiation. Treatment with ibuprofen reverses mutant-mediated inhibitory differentiation as well as the localization in the lysosome. Conclusions: These results not only explain the cell pathological mechanisms inhibiting phenotype differentiation in cells expressing HLD3-associated mutants but also identify the first chemical that restores such cells in vitro.

We sought to demonstrate the usefulness of the T

Double cyclometalation of planar, oligomeric phenylpyridines yielded dinuclear palladium(ii) complexes with novel out-of-plane anisotropy. An X-ray crystal structure analysis revealed that the complexes exhibit concave-convex geometry, and 1H NMR measurement evidenced the occurrence of stable out-of-plane anisotropy. The dipole moment and Pd-Pd interaction were investigated by theoretical calculations.

The admixture of a steroid ointment and a moisturizing cream is frequently prescribed to patients suffering from atopic dermatitis. For the mixing operation, a revolution/rotation-type hybrid mixer is widely used in pharmacy. The purpose of this study was to monitor the mixed state of the admixtures during the mixing process of the hybrid mixer. The key technology used in this study was magnetic resonance imaging (MRI). Two different commercial mometasone furoate-containing ointments were used as a test steroid ointment. After layering the moisturizing cream and the steroid ointment in an ointment bottle, the sample was mixed for a predetermined period using the hybrid mixer. According to MRI transverse relaxation time (T2) mapping for nondestructive monitoring, it was confirmed that the Flumeta® ointment-containing admixture became homogeneous by mixing for 60 s or more. As for the mometasone furoate ointment 0.1%-containing admixture, the mixed state, after becoming homogeneous, was separated into two layers again by the prolonged mixing process. From the 1H-NMR spectra of the phase-separated layers, re-separation was caused by removing aqueous components from the bottom of the samples. MRI is a powerful tool for monitoring the mixed state of the admixture during the mixing process. We believe that our findings offer profound insights into the clinical practice of the mixing operation using a hybrid mixer.

The purpose of the present study is to demonstrate the applicability of magnetic resonance imaging, especially T2 relaxation time mapping, for nondestructive monitoring of the dispersion state of nanoparticles (NPs) in concentrated suspensions. TiO2 15-nm-diameter NPs, for use in sunscreen lotion products, were examined as a test NP. First, this study investigated whether T2 is sensitive to the NP concentration. In experiments with pulsed nuclear magnetic resonance on TiO2 NP suspensions with different organic solvents (ethanol, acetone, and decamethylcyclopentasiloxane), the T2 of each solvent varied in the suspensions according to the NP concentration. This study also confirmed that T2 mapping was effective for visualizing differences in NP concentration. Subsequently, gravitational sedimentation of the test suspensions was investigated. T2 mapping exhibited better detection sensitivity to sedimentation occurring in concentrated suspensions than visual observation, as it enabled the detection of changes in NP distributions that could not be visible to the naked eye. In addition, measurements of backscattered light enabled the full understanding of the dispersion stability of the TiO2 NPs in each solvent. Finally, the present study evaluated the centrifuge sedimentation of a commercial TiO2 NP suspension. T2 mapping clearly showed the complicated sedimentation behavior induced by the centrifugation treatment. The simulated fluid flow was consistent with the particle distribution in the centrifuged sample; thus, the sedimentation was believed to have developed in accordance with the vorticity generated by the centrifugation.

All-atom molecular dynamics simulations were performed on 4-heptyl-4'-cyanobiphenyl (7CB) to study the mechanism of heat conduction in this nematic liquid crystal atomistically. To describe 7CB properly, the AMBER-type force field was optimized for the dihedral parameter of biphenyl and the Lennard-Jones parameters. The molecular dynamics calculation using the optimized force field well reproduced the experimental values of the isotropic-nematic phase transition temperature, density, and anisotropy of the thermal conductivity. Furthermore, the contributions of convection, intramolecular interaction, and intermolecular interaction to the thermal conductivity were determined by performing thermal conductivity decomposition analysis. According to the analysis, the contributions of convection, bond stretching, and bond bending interactions were higher in the direction parallel to the nematic director than that perpendicular to the director, which is the origin of the anisotropy in the nematic phase. This result indicates that the anisotropy is caused by well-aligned covalent bonds and high mobility parallel to the director. This quantitative description of the mechanism of heat conduction of 7CB is foreseen to provide new insights toward designing highly thermally conductive liquid-crystalline materials.

A Lewis base catalyst Trip-SMe (Trip = triptycenyl) for electrophilic aromatic halogenation using