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Atherosclerotic coronary heart disease is a common cardiovascular disease with high morbidity and mortality. In recent years, the incidence of coronary heart disease has gradually become younger, and biomarkers for predicting coronary heart disease have demonstrated valuable clinical prospects. Several studies have established an association between coronary heart disease and intestinal flora metabolites, including trimethylamine oxide (TMAO), which has attracted widespread attention from researchers. Investigations have also shown that plasma levels of TMAO and its precursors can predict cardiovascular risk in humans; however, TMAO’s mechanism of action in causing coronary heart disease is not fully understood. This review examines TMAO’s generation, the mechanism through which it causes coronary heart disease, and the approaches used to treat TMAO-caused coronary heart disease to possible avenues for future research on coronary heart disease and find new concepts for the treatment of the condition.

ABSTRACTPopulation mobility plays an essential role in the diffusion of knowledge. To the best of our knowledge, the existing literature focuses on the migration of workers between regions. Still, we employ a temporary policy of human mobility restriction in China to estimate the effect of COVID-19 on innovation. We find that the number of application invention patents decreases remarkably 1.813 using RD design and remains declined even if we rule out the Spring Festival and the viral effects using RD-DID. Moreover, the mechanism research suggests that the lockdown causes a decline in the population mobility within Wuhan city and inflow from other cities and we rule out the mechanism that skilled labours flow out Wuhan. In addition, we further find that institutional innovations have a significant reduction, especially invention patents in universities. This study highlights the enormous negative impact of human mobility restrictions on innovation due to COVID-19.

In the present study, we investigated the effects of sourdough on the staling rate of bread from the perspectives of starch retrogradation during storage and gluten depolymerization in bread dough. Three sourdough types, which were fermented using Weissella cibaria, Latilactobacillus sakei, and Fructilactobacillus sanfranciscensisstrains, were added to bread dough at a 25% ratio. Compared with regular bread, sourdough bread (SDB) exhibited a lower hardness value and slower staling rate during a 7-day storage period. The relative crystallinities and enthalpies revealed that sourdough addition inhibited amylopectin recrystallization. Furthermore, sourdough-induced acid conditions promoted glutenin macropolymer depolymerization; and the dough containing sourdough (SD-D) showed a decrease in viscoelastic properties and changes on microstructure, reflecting a weakened gluten network structure. Among the three sourdough types, L. sakei-fermented sourdough exhibited the lowest staling rate; this might be owing to its higher gluten depolymerization degree, lower α-helix and intermolecular β-sheet contents, and decreased viscoelastic properties. Our study findings provide a theoretical basis for using sourdough fermentation with different strains to develop clean label bread and improve bread quality in the future.

Osmotic stress imposed by drought and high salinity inhibits plant growth and crop yield. However, our current knowledge on the mechanism by which plants sense osmotic stress is still limited. Here, we identify the transcriptional regulator SEUSS (SEU) as a key player in hyperosmotic stress response in Arabidopsis. SEU rapidly coalesces into liquid-like nuclear condensates when extracellular osmolarity increases. The intrinsically disordered region 1 (IDR1) of SEU is responsible for its condensation. IDR1 undergoes conformational changes to adopt more compact states after an increase in molecular crowding both in vitro and in cells, and two predicted α-helical peptides are required. SEU condensation is indispensable for osmotic stress tolerance, and loss of SEU dramatically compromises the expression of stress tolerance genes. Our work uncovers a critical role of biomolecular condensates in cellular stress perception and response and expands our understanding of the osmotic stress pathway.

Supplemental Digital Content is available in the text.

An analytical trajectory prediction method is put forward for skip re-entry of lifting vehicles. First, the 3-D analytical solutions of skip re-entry trajectory are developed, which are crucial to realize the analytical trajectory prediction. To facilitate the derivation, an auxiliary geocentric inertial frame is established to deal with the strong nonlinear problem caused by the Earth’s rotation. Thereafter, the analytical solutions of the downrange, crossrange, and velocity are approximated by the outer solutions of a two-time scale singular perturbation. The analytical solutions of the altitude and flight-path angle are developed using regular perturbation techniques which can decompose the strongly coupled and nonlinear system into a sequence of linear problems. Second, since the analytical solutions are with respect to the lift-to-drag ratio and bank angle, a method based on the EKF technique is proposed to estimate the lift-to-drag ratio and bank angle of the re-entry vehicle. Third, the analytical trajectory prediction schemes for the lifting re-entry vehicle with multiple bank reversals are put forward. The simulations show that the proposed analytical solutions are in good agreement with the numerical solutions, but the computation time of the analytical solutions is about two orders of magnitude less than that of the numerical solutions. In addition, the superior performance of the proposed analytical trajectory prediction method is well demonstrated by the simulation results.

A hostile tumor microenvironment is one of the major obstacles for the efficacy of chimeric antigen receptor modified T (CAR-T) cells, and combination treatment might be a potential way to overcome this obstacle. Poly(ADP-ribose) polymerase inhibitor (PARPi) has demonstrated tremendous potential in breast cancer. In this study, we explored the possible combination of the PAPRi olaparib with EGFRvIII-targeted CAR (806-28Z CAR) T cells in immunocompetent mouse models of breast cancer. The results indicated that the administration of olaparib could significantly enhance the efficacy of 806-28Z CAR-T cells in vivo. Interestingly, we observed that olaparib could suppress myeloid-derived suppressor cell (MDSC) migration and promote the survival of CD8+T cells in tumor tissue. Mechanistically, olaparib was shown to reduce the expression of SDF1α released from cancer-associated fibroblasts (CAFs) and thereby decreased MDSC migration through CXCR4. Taken together, this study demonstrated that olaparib could increase the antitumor activities of CAR-T cell therapy at least partially through inhibiting MDSC migration via the SDF1α/CXCR4 axis. These findings uncover a novel mechanism of PARPi function and provide additional mechanistic rationale for combining PARPi with CAR-T cells for the treatment of breast cancer.

The artificial bee colony (ABC) algorithm is a widely used algorithm in the field of function optimization problems. The traditional ABC algorithm has long search time, slow convergence speed and easy to fall into local optimum at the end of the search. In this paper, the design scheme and method of implementing parallel ABC algorithm are studied, which makes use of the characteristics of many data bits and easy expansion of data bits of the ternary optical computer (TOC). First, by analysing the traditional ABC algorithm, we can find the parallel parts and parallel design. Then the detailed algorithm implementation flow is given and the clock cycle of the algorithm is analysed. Finally, the correctness of the parallel scheme is verified by experiments. Compared with the ABC algorithm and parallel ABC algorithms based on computer (PABC), the ABC algorithm based on TOC (TOC-PABC) effectively shortens the search time, improves the optimization performance of complex multimodal function optimization problems and obtains a higher speedup.

Zhang et al. show that manipulating the splicing regulator ESRP1 to shift alternative splicing from splice isoform CD44v to CD44s leads to an induction of cancer stem cell properties.

Genetic variants among individuals have been associated with ineffective control of hypertension. Previous work has shown that hypertension has a polygenic nature, and interactions between these loci have been associated with variations in drug response. Rapid detection of multiple genetic loci with high sensitivity and specificity is needed for the effective implementation of personalized medicine for the treatment of hypertension. Here, we used a cationic conjugated polymer (CCP)–based multistep fluorescence resonance energy transfer (MS-FRET) technique to qualitatively analyze DNA genotypes associated with hypertension in the Chinese population. Assessment of 10 genetic loci using this technique successfully identified known hypertensive risk alleles in a retrospective study of whole-blood samples from 150 patients hospitalized with hypertension. We then applied our detection method in a prospective clinical trial of 100 patients with essential hypertension and found that personalized treatment of patients with hypertension based on results from the MS-FRET technique could effectively improve blood pressure control rate (94.0% versus 54.0%) and shorten the time duration to controlling blood pressure (4.06 ± 2.10 versus 5.82 ± 1.84 days) as compared with conventional treatment. These results suggest that CCP-based MS-FRET genetic variant detection may assist clinicians in rapid and accurate classification of risk in patients with hypertension and improve treatment outcomes.

Recently, type-II Dirac fermions characterized by strongly titled Dirac cones have been proposed. The new fermions exhibit unique physical properties different from the type-I Dirac fermions and thus attract tremendous attentions. To date, all type-II fermions are only found in the heavy compounds with strong spin obit coupling. Here, we propose that both type-I and type-II Dirac fermions can exist in the graphene embedding nitrogen line defects, and the types of Dirac fermions can be tuned by the size Wof graphene nanoribbons between the line defects. By comparison of the two types of Dirac fermions, their different physical properties and originations are revealed directly. Remarkably, the type-I Dirac points induce one Fermi arc corresponding to edge states along the armchair direction, while the type-II Dirac points induce two Fermi arcs corresponding to two sets of edge states along the zigzag direction. These results not only expand our views on the Dirac fermions in two-dimensional structures but also extend their applications in electronics.

Mutation or aberrant splicing can interrupt gene expression. Tumor suppressor Bax is one of the susceptible genes prone to microsatellite frameshifting mutations in coding regions. As a result, tumors exhibiting microsatellite instability (MSI) often present a “Bax-negative” phenotype. We previously reported that some Bax-negative cells in fact contain a functional Bax isoform (Bax?2), generated when unique alternative splicing “salvages” the shifted reading frame introduced by a microsatellite mutation. Here we compared Bax alternative splicing profiles in a range of cell lines and primary tumors with and without Bax microsatellite mutations. We found that MSI tumors exhibit a high Bax alternative splicing frequency, especially in exon 2, and produce a family of alternatively spliced isoforms that retain many important Bax functional domains. Surprisingly, these Bax?2 family isoforms can rescue Bax from all common microsatellite frameshift mutations. Production of Bax?2 requires specific cismutations, while transcomponents are not cell-type specific. Furthermore, all Bax?2 family isoforms are more potent cell death inducers than the parental Bax without directly targeting mitochondria. These results indicate that the Bax?2 family can potentially salvage Bax tumor suppressor expression otherwise lost to mutation.

Limited T-cell persistence restrains chimeric antigen receptor (CAR)-T-cell therapy in solid tumors. To improve persistence, T cells have been engineered to secrete proinflammatory cytokines, but other possible methods have been understudied. Runx3 has been considered a master regulator of T-cell development, cytotoxic T-lymphocyte (CTL) differentiation and tissue-resident memory T (Trm)-cell formation. A study using a transgenic mouse model revealed that overexpression of Runx3 promoted T-cell persistence in solid tumors. Here, we generated CAR-T cells overexpressing Runx3 (Run-CAR-T cells) and found that Run-CAR-T cells had long-lasting antitumor activities and achieved better tumor control than conventional CAR (Con-CAR)-T cells. We observed that more Run-CAR-T cells circulated in the peripheral blood and accumulated in tumor tissue, indicating that Runx3 coexpression improved CAR-T-cell persistence in vivo. Tumor-infiltrating Run-CAR-T cells showed less cell death with enhanced proliferative and effector activities. Consistently, in vitro studies indicated that AICD was also decreased in Run-CAR-T cells via downregulation of tumor necrosis factor (TNF) secretion. Further studies revealed that Runx3 could bind to the TNF promoter and suppress its gene transcription after T-cell activation. In conclusion, Runx3-armored CAR-T cells showed increased antitumor activities and could be a new modality for the treatment of solid tumors.

Supplemental Digital Content is available in the text

Preterm birth is the leading cause of neonatal deaths and is also associated with well-known infant morbidities. Although the effects of active smoking during pregnancy are recognized, evidence for the effects of passive smoking is mixed. In China, 3.2 of women and 48.9 of men are active smokers, which offers a unique opportunity for studying passive smoking and reproductive health in nonsmoking women. This cohort study was undertaken to examine the association between passive smoking and preterm birth by clinical subtypes.

Purpose: Death domain–associated protein (DAXX) is a multifunctional nuclear protein involved in apoptosis, transcription, deoxyribonucleic acid damage response, and tumorigenesis. However, the role of DAXX in breast cancer development and progression remains elusive. In this study, we examined the expression patterns and function of DAXX in human breast cancer samples and cell lines.Methods: Immunohistochemistry was used to analyze the expression and localization patterns of DAXX. Additionally, we investigated whether DAXX played an intrinsic role in the cellular response to damage induced by ultraviolet (UV) irradiation in MDA-MB-231 breast cancer cells (isolated at M D Anderson from a pleural effusion of a patient with invasive ductal carcinoma).Results: Our results showed that nucleus size, chromatin organization, and DAXX localization were altered in breast cancer tissues compared with those in control tissues. Compared with cytoplasmic and nuclear expression in benign breast tissues, DAXX was colocalized with promyelocytic leukemia in nuclei with a granular distribution. Endogenous DAXXmessenger ribonucleic acid levels were upregulated upon UV radiation in MDA-MB-231 cells. DAXX-deficient cells tended to be more sensitive to irradiation than control cells. Conversely, DAXX-overexpressing cells exhibited reduced phosphorylated histone H2AX (γ-H2AX) accumulation, increased cell survival, and resistance to UV-induced damage. The protective effects of DAXX may be related to the activation of the ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (ATM-CHK2)-cell division cycle 25c (CDC25c) signaling pathways in Gap2/Mitosis (G2/M) checkpoint and ultimately cell cycle arrest at G2/M phase.Conclusions: Taken together, these results suggested that DAXX may be an essential component in breast cancer initiation, malignant progression, and radioresistance.

Polymorphyism of the vitamin D receptor ( VDR) gene is reported to play a major role in variations of the genetic regulation of bone mass. The role of VDR polymorphisms within various ethnic populations is also undetermined. The purpose of the present study was to determine the frequencies of VDR genotypes in the Han and Kazak nationalities in China. We analyzed the polymorphism defined by the Bsm1 restriction enzyme using polymerase chain reaction–restriction fragment length polymorphism in 179 healthy postmenopausal Han women and 63 healthy postmenopausal Kazak women. The genotype frequencies of the VDR were calculated later using the Hardy–Weinberg equilibrium formula. The results showed that for women of Han nationality, the bb, Bb, and BB genotypes accounted for 90.5%, 9.5%, and 0%, respectively. In Kazak women, the respective frequencies were 38.1%, 55.56%, and 6.35%. We found that there was a significant difference between women of Han and Kazak nationality in terms of the frequency of distribution of VDR genotype ( P < 0.001). There was a similar distribution of VDR genotypes in Kazak women to that seen for the Caucasian population of the USA. The results of the present study provide further evidence on the different pathogeny of osteoporosis in various ethnic groups.

ABSTRACTDespite the success of CD20 antibody rituximab in immunotherapy, acquired resistance is one of the prime obstacles for the successful treatment of B-cell malignancies. There is an urgent need to intensify efforts against resistance in cancer treatment. Growing evidence indicated that lysosomes may form an “Achilles heel” for cancer cells by sensitizing them to death pathways. Here, we uncover an important role of CD20 in initiation of ceramide/lysosomal membrane permeabilization (LMP)-mediated cell death, showing that colocalization of CD20-TNFR1 after type II CD20 antibody ligation can stimulate de novoceramide synthesis by ceramide synthase and consequently induce remarkable lysosomal permeabilization (LMP) and lysosome-mediated cell death. Further studies show that the potent lysosome-mediated cell death induced by CD20 antibodies exhibits a profound killing effect against both rituximab-sensitive and -resistant (RR) lymphoma. Furthermore, engineering of rituximab by introducing a point mutation endows it with the ability to induce potent ceramide/LMP-mediated cell death in both RR lymphoma and primary B-cell malignancies from patients with rituximab-refractory, suggesting the potential clinical application to combat rituximab resistance.

The sequence allows to construct the required indoles from simple precursors, i.e.

A sequence of Knoevenagel reaction, NHC‐catalyzed Stetter reaction, and intramolecular cyclization is efficiently achieved.

Novel cyclopenta[b]pyrans (IV) are obtained via facile one‐pot multicomponent reaction.