Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory ...FLT3-ITD+ AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.
Trans‐4‐Hydroxy‐l‐proline (trans‐Hyp) is a valuable chiral building block for the synthesis of pharmaceutical intermediates. Bioconversion of l‐proline using recombinant strain with ...proline‐4‐hydroxylase (P4H) is a preferred biocatalytic process in the economical production of trans‐Hyp. In this study, a recombinant E. coli overexpressing hydroxylase (P4H), γ‐glutamyl kinase and glutamate‐semialdehyde dehydrogenase (ProBA) genes were constructed by knocking out the key genes in the metabolism. These key genes contained putA encoding proline dehydrogenase (PutA) in the l‐proline metabolism and other catalytic enzyme genes, sucAB encoding α‐ketoglutarate dehydrogenase (SucAB), aceAK encoding isocitratelyase (AceA) and isocitrate dehydrogenase kinase/phosphatase (AceK) in the TCA cycle. This recombinant strain coupled the synthetic pathway of trans‐Hyp with TCA cycle of the host strain. It inhibited the consumption of l‐proline completely and promoted the accumulation of 2‐oxoglutarate (2‐OG) as a co‐substrate, which realized the highest conversion of glucose to trans‐Hyp. A fed‐batch strategy was designed, capable of producing 31·0 g l−1 trans‐Hyp from glucose. It provided a theoretical basis for commercial conversion of glucose to trans‐Hyp.
Significance and Impact of the Study:Trans‐4‐Hydroxy‐l‐proline (trans‐Hyp) is a valuable chiral building block for the synthesis of pharmaceutical intermediates. Unsatisfactory microbial bioconversion resulted in a low yield of trans‐Hyp. In this study, we blocked the unwanted blunting pathways of host strain and make the cell growth couple with the trans‐Hyp synthesis from glucose. Finally, a recombinant Escherichia coli with short‐cut and efficient trans‐Hyp biosynthetic pathway was obtained. It provided a theoretical basis for commercial production of trans‐Hyp.
Significance and Impact of the Study:Trans‐4‐Hydroxy‐l‐proline (trans‐Hyp) is a valuable chiral building block for the synthesis of pharmaceutical intermediates. Unsatisfactory microbial bioconversion resulted in a low yield of trans‐Hyp. In this study, we blocked the unwanted blunting pathways of host strain and make the cell growth couple with the trans‐Hyp synthesis from glucose. Finally, a recombinant Escherichia coli with short‐cut and efficient trans‐Hyp biosynthetic pathway was obtained. It provided a theoretical basis for commercial production of trans‐Hyp.
An experiment to search for light sterile neutrinos is conducted at a reactor with a thermal power of 2.8 GW located at the Hanbit nuclear power complex. The search is done with a detector consisting ...of a ton of Gd-loaded liquid scintillator in a tendon gallery approximately 24 m from the reactor core. The measured antineutrino event rate is 1976 per day with a signal to background ratio of about 22. The shape of the antineutrino energy spectrum obtained from the eight-month data-taking period is compared with a hypothesis of oscillations due to active-sterile antineutrino mixing. No strong evidence of 3+1 neutrino oscillation is found. An excess around the 5 MeV prompt energy range is observed as seen in existing longer-baseline experiments. The mixing parameter sin^{2}2θ_{14} is limited up to less than 0.1 for Δm_{41}^{2} ranging from 0.2 to 2.3 eV^{2} with a 90% confidence level.
Subgingival microorganisms are potentially associated with periodontal diseases. However, changes in the subgingival microbiota during the progress of periodontal diseases are poorly understood. In ...this study, we analyzed bacterial communities in the subgingival paper point samples from 32 Korean individuals with no sign of disease, gingivitis, or periodontitis using 454 FLX Titanium pyrosequencing. A total of 256,113 reads representing 26 phyla, 433 genera, and 1,016 species were detected. Bacteroidetes, Fusobacteria, Synergistetes, and Spirochaetes were the abundant phyla in periodontitis subjects, whereas Firmicutes and Proteobacteria were identified as the dominant phyla in the gingivitis and healthy subjects, respectively. Although high levels of Porphyromonas, Fusobacterium, Fretibacterium, Rothia, Filifactor, and Treponema genera were observed in the periodontitis subjects, Streptococcus, Capnocytophaga, Leptotrichia, and Haemophilus genera were found at high frequency in the gingivitis subjects. Species including Porphyromonas gingivalis, Fusobacterium nucleatum, and Fretibacterium fastidiosum were significantly increased in periodontitis subjects. On the other hand, Streptococcus pseudopneumoniae, Haemophilus parainfluenzae, and Leptotrichia hongkongensis were preferentially observed in the gingivitis subjects. Intriguingly, the halophile Halomonas hamiltonii was revealed as a predominant species in the healthy subjects. Based on Fast UniFrac analysis, distinctive bacterial clusters were classified for the healthy, gingivitis, and periodontitis state. The current findings might be useful for understanding the pathogenesis, diagnosis, and treatment of periodontal diseases.
The key physics of the spin valve involves spin-polarized conduction electrons propagating between two magnetic layers such that the device conductance is controlled by the relative magnetization ...orientation of two magnetic layers. Here, we report the effect of a magnon valve which is made of two ferromagnetic insulators (YIG) separated by a nonmagnetic spacer layer (Au). When a thermal gradient is applied perpendicular to the layers, the inverse spin Hall voltage output detected by a Pt bar placed on top of the magnon valve depends on the relative orientation of the magnetization of two YIG layers, indicating the magnon current induced by the spin Seebeck effect at one layer affects the magnon current in the other layer separated by Au. We interpret the magnon valve effect by the angular momentum conversion and propagation between magnons in two YIG layers and conduction electrons in the Au layer. The temperature dependence of the magnon valve ratio shows approximately a power law, supporting the above magnon-electron spin conversion mechanism. This work opens a new class of valve structures beyond the conventional spin valves.
Carboxylated/oxidized diamond nanoparticles (nominal size 100 nm) exhibit exceptionally high affinity for proteins through both hydrophilic and hydrophobic forces. The affinity is so high that ...proteins in dilute solution can be easily captured by diamonds, simply separated by centrifugation, and directly analyzed by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS). No preseparation of the adsorbed molecules from diamonds is required for the mass spectrometric analysis. Compared to conventional MALDI-TOF-MS, an enhancement in detection sensitivity by more than 2 orders of magnitude is achieved for dilute solution containing cytochrome c, myoglobin, and albumin because of preconcentration of the probed molecules. The lowest concentration detectable is 100 pM for a 1-mL solution. Aside from the enhanced sensitivity, the overall performance of this technique does not show any sign of deterioration for highly contaminated protein solutions, and furthermore, no significant peak broadening and band shift were observed in the mass spectra. The promise of this new method for clinical proteomics research is demonstrated with an application to human blood serum.
Aims
We aimed to explore Yarrowia lipolytica carbonyl reductases as effective biocatalysts and to develop efficient asymmetric reduction systems for chiral alcohol synthesis.
Methods and Results
...Yarrowia lipolytica carbonyl reductase genes were obtained via homologous sequence amplification strategy. Two carbonyl reductases, YaCRI and YaCRII, were identified and characterized, and used to catalyse the conversion of 2‐hydroxyacetophenone (2‐HAP) to optically pure (S)‐1‐phenyl‐1,2‐ethanediol. Enzymatic assays revealed that YaCRI and YaCRII exhibited specific activities of 6·96 U mg−1 (99·8% e.e.) and 7·85 U mg−1 (99·9% e.e.), respectively, and showed moderate heat resistance at 40–50°C and acid tolerance at pH 5·0–6·0. An efficient whole‐cell two‐phase system was established using reductase‐expressing recombinant Escherichia coli. The conversion of 2‐HAP (20·0 g l−1) conversion with the solvent of dibutyl phthalate was approximately 70‐fold higher than in water. Furthermore, the two recombinant E. coli displayed biocatalyst activity and enantioselectivity towards several different carbonyl compounds, and E. coli BL21 (DE3)/pET‐28a‐yacrII showed a broad substrate spectrum.
Conclusions
A new whole‐cell recombinant E. coli‐based bioreduction system for enantiopure alcohol synthesis with high enantioselectivity at high substrate concentrations was developed.
Significance and Impact of the Study
We proposed a promising approach for the efficient preparation of enantiopure chiral alcohols.
Fast radio bursts (FRBs) are millisecond-duration radio transients of unknown physical origin observed at extragalactic distances
. It has long been speculated that magnetars are the engine powering ...repeating bursts from FRB sources
, but no convincing evidence has been collected so far
. Recently, the Galactic magnetar SRG 1935+2154 entered an active phase by emitting intense soft γ-ray bursts
. One FRB-like event with two peaks (FRB 200428) and a luminosity slightly lower than the faintest extragalactic FRBs was detected from the source, in association with a soft γ-ray/hard-X-ray flare
. Here we report an eight-hour targeted radio observational campaign comprising four sessions and assisted by multi-wavelength (optical and hard-X-ray) data. During the third session, 29 soft-γ-ray repeater (SGR) bursts were detected in γ-ray energies. Throughout the observing period, we detected no single dispersed pulsed emission coincident with the arrivals of SGR bursts, but unfortunately we were not observing when the FRB was detected. The non-detection places a fluence upper limit that is eight orders of magnitude lower than the fluence of FRB 200428. Our results suggest that FRB-SGR burst associations are rare. FRBs may be highly relativistic and geometrically beamed, or FRB-like events associated with SGR bursts may have narrow spectra and characteristic frequencies outside the observed band. It is also possible that the physical conditions required to achieve coherent radiation in SGR bursts are difficult to satisfy, and that only under extreme conditions could an FRB be associated with an SGR burst.
Linking topology in oligocarbazoles (see figure) has a strong influence on their electronic properties. 3(6),9′‐linked oligocarbazoles exhibit unusual suppression of electronic coupling between ...units, leading to localized excited states and very small reduction of triplet energies (compared to the monomer). Coupled with their excellent morphological stability, this makes them suitable as host materials for blue electrophosphorescence devices.
In a study involving patients with non–small-cell lung cancer with a
MET
exon 14 skipping mutation, the use of tepotinib (a selective MET inhibitor) was associated with a partial response in ...approximately half the patients. The main adverse event was peripheral edema.
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