6-Diazo-5-oxo-L-norleucine (DON) is a potent glutamine antagonist with toxic side effects; in order to reduce these effects, multiple prodrugs have been designed. However, there are currently no ...reports of a DON prodrug with a defined mechanism to achieve high tumor selectivity. To improve the selective toxicity of DON to tumor cells while reducing systemic toxicity, a hypoxia-activated prodrug, termed HDON, was designed. HDON achieved remarkable tumor suppression of 76.4 ± 5.2% without leading to weight loss in an H22 murine liver cancer model with high hypoxia. Moreover, to augment the therapeutic efficacy of HDON, combretastatin A4 nanoparticles were used to aggravate tumor hypoxia of MC38 murine colon cancer and 4T1 murine breast cancer, activate HDON to DON, and stimulate a robust anti-tumor immune response while selectively killing in tumor cells in vivo, achieving significantly elevated tumor suppression rates of 98.3 ± 3.4% and 98.1 ± 3.1%, with cure rates of 80.0% and 20.0%, respectively.
•The geometric configurations of the major component molecules in natural ester insulating oils were constructed.•The kinematic viscosity values of 20 triglycerides at different temperatures were ...obtained using molecular dynamics.•The molecular descriptors were calculated, and those related to kinematic viscosity were selected and analyzed.•The kinematic viscosity prediction models for triglycerides were constructed based on sparse machine learning methods.
The high viscosity property of natural ester insulating oils can be improved by means of molecular structure modification. However, it is difficult to find the optimal molecular structure that meets the conditions in the vast chemical space by relying on macroscopic experiments. Herein, the kinematic viscosity prediction models of triglyceride molecules based on sparse machine learning methods are proposed in this paper. Firstly, the molecular dynamics technique is used to simulate the kinematic viscosity (-20℃ to 40℃) of the main 20 triglyceride molecules in natural ester insulating oil, which provides extensive characterization data for subsequent model training. Secondly, the molecular descriptors are calculated for each triglyceride molecule based on density functional theory (DFT). Thirdly, four sparse feature selection methods (Boruta, RFECV, Pearson correlation coefficient, and mutual information) are used to identify the most relevant molecular descriptors for the kinematic viscosity of natural ester insulating oil and further analysis is performed. Finally, quantitative structure–property relationship (QSPR) models are constructed using automated machine learning methods to achieve efficient and accurate prediction of kinematic viscosity (average R2 reached 0.96). This study provides certain mechanistic explanations from the perspective of molecular descriptors and provides a predictive model basis for the viscosity modification of natural ester molecules, which serves as a theoretical guide to improve the kinematic viscosity of natural ester insulating oil.
Abstract Background Adherence to a combination of healthy lifestyle factors has been related to a considerable reduction of cardiovascular risk in white populations; however, little is known whether ...such associations persist in nonwhite populations like the Asian population. Objectives This study aimed to examine the associations of a combination of modifiable, healthy lifestyle factors with the risks of ischemic cardiovascular diseases and estimate the proportion of diseases that could potentially be prevented by adherence to these healthy lifestyle patterns. Methods This study examined the associations of 6 lifestyle factors with ischemic heart disease and ischemic stroke (IS) in the China Kadoorie Biobank of 461,211 participants 30 to 79 years of age who did not have cardiovascular diseases, cancer, or diabetes at baseline. Low-risk lifestyle factors were defined as nonsmoking status or having stopped smoking for reasons other than illness, alcohol consumption of <30 g/day, a median or higher level of physical activity, a diet rich in vegetables and fruits and limited in red meat, a body mass index of 18.5 to 23.9 kg/m2 , and a waist-to-hip ratio <0.90 for men and <0.85 for women. Results During a median of 7.2 years (3.3 million person-years) of follow-up, this study documented 3,331 incident major coronary events (MCE) and 19,348 incident ISs. In multivariable-adjusted analyses, current nonsmoking status, light to moderate alcohol consumption, high physical activity, a diet rich in vegetables and fruits and limited in red meat, and low adiposity were independently associated with reduced risks of MCE and IS. Compared with participants without any low-risk factors, the hazard ratio for participants with ≥4 low-risk factors was 0.42 (95% confidence interval: 0.34 to 0.52) for MCE and 0.61 (95% confidence interval: 0.56 to 0.66) for IS. Approximately 67.9% (95% confidence interval: 46.5% to 81.9%) of the MCE and 39.1% (95% confidence interval: 26.4% to 50.4%) of the IS cases were attributable to poor adherence to healthy lifestyle. Conclusions Adherence to healthy lifestyle may substantially lower the burden of cardiovascular diseases in Chinese.
Surface modification techniques have been applied to generate titanium implant surfaces that promote osseointegration for the implants in cementless arthroplasty. However, its effect is not ...sufficient for osteoporotic bone. Strontium (Sr) promotes osteoblast proliferation and inhibits osteoclast proliferation and positively affects bone regeneration. The aim of this study was to confirm the effects of strontium-substituted hydroxyapatite (Sr-HA) coating via electrochemical deposition on implant’s osseointegration in the osteoporotic condition. Female Sprague Dawley rats were used for this study. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into four groups: group HA; group 5 % Sr-HA; group 10 % Sr-HA; and group 20 % Sr-HA. Afterward, all rats from groups HA, 5 % Sr-HA, 10 % Sr-HA, and 20 % Sr-HA received implants with hydroxyapatite coating containing 0, 5, 10, and 20 % Sr. Implants were inserted bilaterally in all animals until death at 12 weeks. The bilateral femurs of rats were harvested for evaluation. All treatment groups increased new bone formation around the surface of titanium rods and push-out force; group 20 % Sr-HA showed the strongest effects on new bone formation and biomechanical strength. Additionally, these are significant differences in bone formation and push-out force was observed between groups 5 % Sr-HA and 10 % Sr-HA. This finding suggests that Sr-HA coating can improve implant osseointegration, and the 20 % Sr coating exhibited the best properties for implant osseointegration among the tested coatings in osteoporosis rats.
To elucidate an etiology in a case with persistent oligohydramnios by prenatal diagnosis and actively treat the case to achieve good prognosis.
We performed whole exome sequencing (WES) of DNA from ...the fetus and parents. Serial amnioinfusions were conducted until birth. Pressors were required to maintain normal blood pressure. The infant angiotensin-converting enzyme (ACE) activity, angiotensin II (Ang II, a downstream product of ACE), and compensatory enzymes (CEs) activities were measured. Compensatory enzyme activities in plasma from age-matched healthy controls were also detected.
We identified a fetus with a severe ACE mutation prenatally. The infant was born prematurely without pulmonary dysplasia. Hypotension and anuria resolved spontaneously. He had almost no ACE activity, but his Ang II level and CE activity exceeded the upper limit of the normal range and the upper limit of the 95% confidence interval of controls, respectively. His renal function also largely recovered.
Fetuses with ACE mutations can be diagnosed prenatally through WES. Serial amnioinfusion permits the continuation of pregnancy in fetal ACE deficiency. Compensatory enzymes for defective ACE appeared postnatally. Renal function may be spared by preterm delivery; furthermore, for postnatal vasopressor therapy to begin, improving renal perfusion pressure before nephrogenesis has been completed.
Interploidy cross commonly results in complex chromosome number and structural variations. In our previous study, a progeny with segregated ploidy levels was produced by an interploidy cross between ...diploid female parent
×
clone TB03 and triploid male parent
×
'Yinzhong'. However, the chromosome compositions of aneuploid genotypes in the progeny were still unclear. In the present study, a microsatellite DNA allele counting-peak ratios (MAC-PR) method was employed to analyze allelic configurations of each genotype to clarify their chromosome compositions, while 45S rDNA fluorescence
hybridization (FISH) analysis was used to reveal the mechanism of chromosome number variation. Based on the MAC-PR analysis of 47 polymorphic simple sequence repeat (SSR) markers distributed across all 19 chromosomes of
, both chromosomal number and structural variations were detected for the progeny. In the progeny, 26 hypo-triploids, 1 hyper-triploid, 16 hypo-tetraploids, 10 tetraploids, and 5 hyper-tetraploids were found. A total of 13 putative structural variation events (duplications and/or deletions) were detected in 12 genotypes, involved in chromosomes 3, 6, 7, 14, 15, 16, and 18. The 46.2% (six events) structural variation events occurred on chromosome 6, suggesting that there probably is a chromosome breakpoint near the SSR loci of chromosome 6. Based on calculation of the allelic information, the transmission of paternal heterozygosity in the hypo-triploids, hyper-triploid, hypo-tetraploids, tetraploids, and hyper-tetraploids were 0.748, 0.887, 0.830, 0.833, and 0.836, respectively, indicating that the viable pollen gains of the male parent 'Yinzhong' were able to transmit high heterozygosity to progeny. Furthermore, 45S rDNA-FISH analysis showed that specific-chromosome segregation feature during meiosis and chromosome appointment in normal and fused daughter nuclei of telophase II of 'Yinzhong,' which explained that the formation of aneuploids and tetraploids in the progeny could be attributed to imbalanced meiotic chromosomal segregation and division restitution of 'Yinzhong,' The data of chromosomal composition and structural variation of each aneuploid in the full-sib progeny of TB03 × 'Yinzhong' lays a foundation for analyzing mechanisms of trait variation relying on chromosome or gene dosages in
.
2D materials with low‐symmetry exhibit anisotropic physical properties, making them promising candidates for various applications. However, the lack of matured synthesis methods in anisotropic 2D ...materials is still the main obstacle to their future applications. Given the mature synthesis method of transition metal dichalcogenides (TMDCs), manipulating anisotropy in 2D TMDCs becomes a promising way to tune or trigger functional properties. Herein, for the first time, a van der Waals symmetry engineering is reported to introduce in‐plane polarization in MoS2 through contact with low‐symmetric CrOCl. The emergence of asymmetric second harmonic generation pattern in MoS2/CrOCl heterojunction indicates the variation of lattice symmetry in MoS2. Furthermore, the theoretical simulation shows that such change stems from lattice‐mismatch‐induced uniaxial strain because of the strong interlayer interactions. The angle‐dependent Raman and photoluminescence spectra further identify that the uniaxial strain gives rise to the in‐plane polarization in MoS2. In addition, the polarized MoS2 exhibits excellent orientation‐sensitive electrical characteristics with a conductance anisotropy ratio of ≈1.5. More importantly, the strong linear polarization‐sensitive photodetection is realized, and the anisotropic ratio reached 1.25 with 532 nm. The results suggest that symmetric engineering potentially opens up a new field to endow high‐symmetry 2D materials with anisotropic functionalities.
In‐plane polarization in MoS2 is realized through contact with low‐symmetric CrOCl. The emergence of asymmetric second harmonic generation pattern in MoS2/CrOCl heterojunction indicates the variation of lattice symmetry in MoS2, which stems from lattice‐mismatch‐induced uniaxial strain because of the strong interlayer interactions. More importantly, the strong linear polarization‐sensitive photodetection is realized.
Sonodynamic therapy (SDT) is an innovative modality for cancer treatment. But the biological effect of SDT on oral squamous cell carcinoma has not been studied. Our previous study has shown that ...endo-Protoporphyrin IX based SDT (ALA-SDT) could induce apoptosis in human tongue squamous carcinoma SAS cells through mitochondrial pathway. Herein, we investigated the effect of exo- Protoporphyrin based SDT (PpIX-SDT) on SAS cells in vitro and in vivo. We demonstrated that PpIX-SDT increased the ratio of cells in the G
/M phase and induced 3-4 times more cell apoptosis compared to sonocation alone. PpIX-SDT caused cell membrane damage prior to mitochondria damage and upregulated the expression of Fas and Fas L, while the effect was suppressed if cells were pre-treated with p53 inhibitor. Additionally, we examined the SDT-induced cell apoptosis in two cell lines with different p53 status. The increases of p53 expression and apoptosis rate in wild-type p53 SAS cells were found in the SDT group, while p53-mutated HSC-3 cells did not show such increase. Our data suggest that PpIX-SDT suppress the proliferation of SAS cells via arresting cell cycle at G
/M phase and activating the extrinsic Fas-mediated membrane receptor pathway to induce apoptosis, which is regulated by p53.
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•Astrocytes participate in engulfing myelin debris after spinal cord injury in rats.•Astrocytes that engulf myelin debris tend to transform into A1 astrocytes.•A1/A2 and ...reactive/scar-forming astrocyte phenotypes are mutually complementary.
After spinal cord injury (SCI), the accumulation of myelin debris can serve as proinflammatory agents, hindering axon regrowth and exacerbating damage. While astrocytes have been implicated in the phagocytosis of myelin debris, the impact of this process on the phenotypic transformation of astrocytes and their characteristics following SCI in rats is not well understood. Here, we demonstrated that the conditioned medium of myelin debris can trigger apoptosis in rat primary astrocytes in vitro. Using a compressional SCI model in rats, we observed that astrocytes can engulf myelin debris through ATP-binding cassette transporter sub-family A member 1 (ABCA1), and these engulfed cells tend to transform into A1 astrocytes, as indicated by C3 expression. At 4 days post-injury (dpi), astrocytes rapidly transitioned into A1 astrocytes and maintained this phenotype from 4 to 28 dpi, while A2 astrocytes, characterized by S100, were only detected at 14 and 28 dpi. Reactive astrocytes, identified by Nestin, emerged at 4 and 7 dpi, whereas scar-forming astrocytes, marked by N-cadherin, were evident at 14 and 28 dpi. This study illustrates the distribution patterns of astrocyte subtypes and the potential interplay between astrocytes and myelin debris after SCI in rats. We emphasize that myelin debris can induce astrocyte apoptosis in vitro and promote the transformation of astrocytes into A1 astrocytes in vivo. These two classification methods are not mutually exclusive, but rather complementary.
Porcine reproductive and respiratory syndrome virus (PRRSV) has become widespread in China particularly the highly pathogenic porcine reproductive and respiratory syndromes (HP-PRRSV), NADC30, and ...NADC34 strains, and has posed a threat to the swine industry for over 20 years. To monitor genetic variation in PRRSV-2 GP3 strains in China, we analyzed 618 strains isolated between 1996 to 2023 and constructed phylogenetic trees. Additionally, 60 selected strains were used to analyze nucleotide and amino acid homology. PRRSV GP3 gene exhibited nucleotide identity ranging from 78.2% to 100.0% and amino acid similarity ranging from 74.9% to 99.6%. The GP3 gene in the 60 selected strains consisted of 254 amino acids, and amino acid mutations in the strains primarily occurred in B-cell epitopes, T-cell epitopes, and highly variable regions. The glycosylation sites of the strains used for amino acid sequence comparisons remained unaltered, except for the N29 site in the GD20220303-2022 strain. PRRSV-2 strains in China belong to lineages 1, 3, 5, and 8. Recombination analysis detected two recombination events, involving lineages 1 and 8. In conclusion, this study investigated multiple strains of the PRRSV-2 GP3 gene to explore the prevalence and genetic diversity of the GP3 gene in China from a gene family perspective. The results of the analyses provide a basis for clinical prevention strategies and vaccine development.Porcine reproductive and respiratory syndrome virus (PRRSV) has become widespread in China particularly the highly pathogenic porcine reproductive and respiratory syndromes (HP-PRRSV), NADC30, and NADC34 strains, and has posed a threat to the swine industry for over 20 years. To monitor genetic variation in PRRSV-2 GP3 strains in China, we analyzed 618 strains isolated between 1996 to 2023 and constructed phylogenetic trees. Additionally, 60 selected strains were used to analyze nucleotide and amino acid homology. PRRSV GP3 gene exhibited nucleotide identity ranging from 78.2% to 100.0% and amino acid similarity ranging from 74.9% to 99.6%. The GP3 gene in the 60 selected strains consisted of 254 amino acids, and amino acid mutations in the strains primarily occurred in B-cell epitopes, T-cell epitopes, and highly variable regions. The glycosylation sites of the strains used for amino acid sequence comparisons remained unaltered, except for the N29 site in the GD20220303-2022 strain. PRRSV-2 strains in China belong to lineages 1, 3, 5, and 8. Recombination analysis detected two recombination events, involving lineages 1 and 8. In conclusion, this study investigated multiple strains of the PRRSV-2 GP3 gene to explore the prevalence and genetic diversity of the GP3 gene in China from a gene family perspective. The results of the analyses provide a basis for clinical prevention strategies and vaccine development.
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