Through a rigorous application of first‐principles simulations, it is endeavored to provide a systematic examination of how the crystal structure, electronic structure, density of states, optical ...properties, and superconducting transition temperature of ZrBeSi are influenced by variations in pressure. The research has shown that pressure can alter the electronic structure and density of states, with a tendency for expansion toward higher energy regions as pressure increases. By manipulating the pressure, both the absorption coefficient and energy loss are sensitive to pressure and exhibit sharp absorption and loss peaks in the UV wavelength region. In addition to the above, the effects of electron–phonon coupling are taken into account and further investigations of the superconducting transition temperature , which is found to be 0.564 K at 0 GPa, are subsequently delved into. Additionally, there exists a quadratic attenuation relationship between the temperature and pressure. Further studies reveal that the decrease of with increasing pressure is a result of the combined effects of the gradual increase in the phonon density of states’ frequency and the flattening of the density of states near the Fermi level. The findings of this study contribute to the understanding of the impact of pressure on the physical properties of materials.
Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for ...COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC
between 1.2 and 4.3 μM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.
Aberrated glucose metabolism is a key future of cancer cells. Unlike normal cells, tumor cells favor glycolysis even in the presence of sufficient oxygen. Pyruvate kinase (PK), a key glucose ...metabolic enzyme, converts phosphoenolpyruvate (PEP) to pyruvate by transferring the high-energy phosphate group to adenosine diphosphate (ADP) to produce adenosine triphosphate (ATP). Pyruvate kinase M2 (PKM2), one of the four isozyme of PK, which universally expressed in rapidly proliferating cells such as embryonic cells and cancer cells. Recent years, more and more research suggested PKM2 plays a crucial role in cancer progression through both metabolic and non-metabolic pathways. On the one hand, the middle product of glycolysis, such as amino acids, nucleotides, lipids is necessary to rapid growth of cancer cells. On the other hand, PKM2 supports tumor growth through regulating the expression of gene that involved in cell proliferation, migration and apoptosis. In this article, we review the recent advances to further understand the regulation and function of PKM2 in tumorigenesis. Given its multiple effects on cancer, PKM2 may be a potential target for cancer diagnosis and treatment.
•Pyruvate kinase M2 enzymatic activity is regulated by both post-translation and allosteric regulators.•The expression of Pyruvate kinase M2 is regulated by mutiple ways.•Pyruvate kinase M2 functions as pyruvate kinase, proteins kinase and tanscriptional coactivators.
SUMMARY
Floral patterns are unique to rice and contribute significantly to its reproductive success. SL1 encodes a C2H2 transcription factor that plays a critical role in flower development in rice, ...but the molecular mechanism regulated by it remains poorly understood. Here, we describe interactions of the SL1 with floral homeotic genes, SPW1, and DL in specifying floral organ identities and floral meristem fate. First, the sl1 spw1 double mutant exhibited a stamen‐to‐pistil transition similar to that of sl1, spw1, suggesting that SL1 and SPW1 may located in the same pathway regulating stamen development. Expression analysis revealed that SL1 is located upstream of SPW1 to maintain its high level of expression and that SPW1, in turn, activates the B‐class genes OsMADS2 and OsMADS4 to suppress DL expression indirectly. Secondly, sl1 dl displayed a severe loss of floral meristem determinacy and produced amorphous tissues in the third/fourth whorl. Expression analysis revealed that the meristem identity gene OSH1 was ectopically expressed in sl1 dl in the fourth whorl, suggesting that SL1 and DL synergistically terminate the floral meristem fate. Another meristem identity gene, FON1, was significantly decreased in expression in sl1 background mutants, suggesting that SL1 may directly activate its expression to regulate floral meristem fate. Finally, molecular evidence supported the direct genomic binding of SL1 to SPW1 and FON1 and the subsequent activation of their expression. In conclusion, we present a model to illustrate the roles of SL1, SPW1, and DL in floral organ specification and regulation of floral meristem fate in rice.
Significance Statement
The morphology of rice flowers is crucial for successful reproduction and grain yield. However, research on floral organ specification gene regulatory network (FOS‐GRN) in rice and other grass species is not as extensive as in Arabidopsis. In this study, we unveil the crucial role of the C2H2 zinc finger transcription factor SL1 in regulating flower organ development and floral meristem fate in rice. Our experimental evidence indicates that SL1 positively regulates the expression of SPW1, which, in turn, activates B‐class genes OsMADS2 and OsMADS4 to indirectly suppress DL expression, influencing the formation of floral organs. Additionally, we identify a cooperative role of SL1 and DL in terminating floral meristem fate.
Transforming growth factor beta (TGF‐β) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation‐associated responses. However, the ...antiviral activities and mechanisms of TGF‐β isoforms, including TGF‐β1, TGF‐β2 and TGF‐β3, remain unclear. Here, we demonstrated that all of the three TGF‐β isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF‐β isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF‐β isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF‐β/SMAD signalling pathway–dependent and TGF‐β/SMAD signalling pathway–independent manners. TGF‐β isoforms showed additional anti‐HCV activities when combined with each other. However, the elevated TGF‐β1 and TGF‐β2, not TGF‐β3, could also induce liver fibrosis with a high expression of type I collagen alpha‐1 and α‐smooth muscle actin in LX‐2 cells. Our results showed a new insight into TGF‐β isoforms in the HCV‐related liver disease progression.
Peroxisome proliferator-activated receptor (PPAR)-γ is involved in both normal physiological processes and pathology of various diseases. The purpose of this study was to explore the function and ...underlying mechanisms of PPAR-γ in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) proliferation and migration. In the present study, we found PPAR-γ expression was remarkably reduced in RA synovium patient compare with OA and normal, as well as it was low-expression in Adjuvant-induced arthritis (AA). Moreover, inhibition PPAR-γ expression by T0070907 (12.5 μM) or PPAR-γ siRNA could promote FLSs proliferation and expressions of c-Myc, Cyclin D1, MMP-1, and MMP-9 in AA FLSs, except for TIPM-1. These date indicate that up-regulation of PPAR-γ may play a critical role in RA FLSs. Interestingly, co-incubation FLSs with Pioditazone (25 μM) and over expression vector with pEGFP-N1-PPAR-γ reduced proliferation and expressions of c-Myc, Cyclin D1, MMP-1, and MMP-9 in AA FLSs, besides TIMP-1. Further study indicates that PPAR-γ may induce activation Wnt/β-catenin signaling. In short, these results indicate that PPAR-γ may play a pivotal role during FLSs activation and activation of Wnt/β-catenin signaling pathway.
Taking berberine (BBR) as the lead, 23 new BBR derivatives were synthesized and examined for their antiviral activities against four different genotype enterovirus 71 (EV71) strains with a cytopathic ...effect (CPE) assay. Structure-activity relationship (SAR) studies indicated that introduction of a suitable substituent at the 9-position might be beneficial for potency. Among them, compound
exhibited most potent activities with IC
values of 7.12⁻14.8 μM, similar to that of BBR. The effect of
was further confirmed in a dose-dependent manner both in RNA and protein level. The mechanism revealed that
could inhibit the activation of MEK/ERK signaling pathway. Meanwhile, it could suppress the EV71-induced autophagy by activating AKT and inhibiting the phosphorylation of JNK and PI3KIII proteins. We consider BBR derivatives to be a new family of anti-EV71 agents through targeting host components, with an advantage of broad-spectrum anti-EV71 potency.
Two new ursane‐type triterpenes, eburnealactones A and B (1 and 2), one new flavonoid, eburneatin A (6), and one new phenylethanoid glycoside, chiritoside D (7), along with 9 known compounds (3–5, ...8–13) were isolated from the whole plant of Primulina eburnea. Their structures were elucidated by comprehensive spectroscopic data analysis (IR, UV, NMR, and HR‐ESI‐MS). All the compounds were evaluated for their cytotoxic activities. Compound 1 showed significant cytotoxic activities against MKN‐45 cell lines and 5637 cell lines with the IC50 values of 9.57 μM and 8.30 μM, respectively. Compound 1 exhibited moderate cytotoxic activities against A549 and PATU8988T cell lines with the IC50 values of 30.70 μM and 38.22 μM, respectively. Compound 6 exhibited moderate cytotoxic activities against MKN‐45, HCT116, PATU8988T, 5637 and A‐673 cell lines with the IC50 values of 19.69 μM, 16.44 μM, 18.07 μM, 11.51 μM and 18.15 μM, respectively. Compound 5 showed moderate cytotoxic activities against A549 cell lines with the IC50 values of 24.06 μM.
Compaction layers are widely distributed in the Huang-Huai-Hai Plain, China, which restrict root growth and reduce yields. The adoption of subsoiling has been recommended to disrupt compacted soil ...layers and create a reasonable soil structure for crop development. In this paper, the effects of subsoiling depth (30, 35 and 40 cm), period interval (2 or 3 years) and combined pre-sowing tillage practice (rotary cultivation or ploughing) on soil condition improvement was studied on a tidal soil in the Huang-Huai-Hai Plain. Seven tillage patterns were designed by combining different subsoiling depths, period intervals and pre-sowing. The evaluation indicators for soil condition improvement were as follows: thickness of the plough layer and hard pan, soil bulk density, cone index, soil three-phase R values, alkali nitrogen content, crop yield, and economic benefits. The results showed that subsoiling can significantly improve the soil structure and physical properties. In all subsoiling treatments, the depth of 35 or 40 cm at a 2-year interval was the most significant. The thickness of the plough layer increased from 13.67 cm before the test to 21.54–23.45 cm in 2018. The thickness of the hard pan decreased from 17.68 cm before the test to 12.09–12.76 cm in 2018, a decrease of about 40.07%. However, the subsoiling combined pre-sowing tillage practice, that is, rotary cultivation or ploughing, was not significant for soil structure and physical properties. For all subsoiling treatments, the soil bulk density, cone index and soil three-phase R values of the 15–25 cm soil layer were significantly lower compared to single rotary cultivation. Subsoiling was observed to increase the soil alkaline nitrogen and water contents. The tillage patterns that had subsoiling at the depth of 35–40 cm at a 2-year interval combined with rotary cultivation had the highest alkali nitrogen and water contents, which increased by 31.08–34.23% compared with that of the single rotary cultivation. Subsoiling can significantly increase the yield both of wheat and corn, as well as the economic benefits. The treatment of subsoiling at the depth of 35 cm at an interval of 2 years combined with rotary cultivation had the highest annual yield and economic benefits. For this treatment, the annual yield and economic benefits increased by 14.55 and 62.87% in 2018, respectively. In conclusion, the tillage patterns that involved subsoiling at a depth of 35 cm at a 2-year interval along with rotary cultivation are suitable for the Huang-Huai-Hai Plain.
The construction of libraries of stereoisomers of natural products serves as an important approach to investigating the correlation between the stereostructure and biological activity. However, the ...total synthesis and isomerzation of polycyclic scaffolds with multiple chrial centers are rare. Spirooliganin (
1
), a new skeleton natural product isolated from the plant
Illicium oligandrum
, was structurally characterized by comprehensive analysis of NMR spectroscopic data and ECD which revealed an unprecedented 5-6-6-6-7 polycyclic framework with six chiral centers. Here we report a 17-step total synthesis to prepare a library of stereochemically diverse isomers of spirooliganin, including 16 diastereoisomers and 16 regioisomers. In addition to a regioselective hetero-Diels-Alder cycloaddition, the synthetic strategy involves a photo-induced stereoselective Diels-Alder reaction, which gives only the abnormal
trans
-fused product as rationalized by density functional theory calculations. Preliminary biological evaluation showed that spirooliganin and regioisomers
39
exhibited potent inhibition of Coxsackievirus B3. It also revealed the pharmacophore effect of the D-ring (16
R
,18
R
,24
R
, and 26
R
) for their antiviral activities.
Library construction of stereochemically diverse isomers to investigate the relationship between stereoconfiguration and anti-coxsackie virus B3 activity.
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