Transient interactions modulate the affinity of NF-κB transcription factors for DNA.

The dimeric nuclear factor kappa B (NF-κB) transcription factors (TFs) regulate gene expression by binding to a variety of κB DNA elements with conserved G:C-rich flanking sequences enclosing a degenerate central region. Toward defining mechanistic principles of affinity regulated by degeneracy, we observed an unusual dependence of the affinity of RelA on the identity of the central base pair, which appears to be noncontacted in the complex crystal structures. The affinity of κB sites with A or T at the central position is ~10-fold higher than with G or C. The crystal structures of neither the complexes nor the free κB DNAs could explain the differences in affinity. Interestingly, differential dynamics of several residues were revealed in molecular dynamics simulation studies, where simulation replicates totaling 148 µs were performed on NF-κB:DNA complexes and free κB DNAs. Notably, Arg187 and Arg124 exhibited selectivity in transient interactions that orchestrated a complex interplay among several DNA-interacting residues in the central region. Binding and simulation studies with mutants supported these observations of transient interactions dictating specificity. In combination with published reports, this work provides insights into the nuanced mechanisms governing the discriminatory binding of NF-κB family TFs to κB DNA elements and sheds light on cancer pathogenesis of cRel, a close homolog of RelA.

METTL3-induced FGD5-AS1 contributes to the tumorigenesis and PD-1/PD-L1 checkpoint to enhance the resistance to paclitaxel of endometrial carcinoma.

Endometrial cancer (EC), a widely occurring cancer in the uterus, is among the top four most frequent malignancies in women. To improve approaches for combating this disease, it is essential to gain a more comprehensive comprehension of the intricate causes of EC. Accumulating evidence highlight the essential role of long non-coding RNA (LncRNA) in EC progression, while its biological and mechanical function has not been fully revealed. In this study, a LncRNA microarray analysis was performed using four pairs of paclitaxel (PTX) resistant EC cells, FGD5-AS1 was identified as a significantly upregulated gene. Biologically, it was found that FGD5-AS1 enhances chemoresistance of EC cells to PTX treatment and blocking immune escape via PD-1/PD-L1 checkpoint. Furthermore, FGD5-AS1 exerted an oncogene role in EC cells via promoting cell proliferation and migration. Mechanically, METTL3 could upregulate FGD5-AS1 expression via N6-methyladenosine (m6A) modification. The biological roles of METTL3 were exerted via modulating FGD5-AS1 expression in EC. Collectively, our research has shed light on the involvement of the METTL3/FGD5-AS1 axis in the development of PTX resistance in EC. This finding offers a new avenue for further exploration of the underlying mechanisms of chemoresistance in EC and provides valuable insights for the development of potential therapeutic targets in the treatment of EC.

NIGT1 represses plant growth and mitigates phosphate starvation signaling to balance the growth response tradeoff in rice.

Inorganic phosphate (Pi) availability is an important factor which affects the growth and yield of crops, thus an appropriate and effective response to Pi fluctuation is critical. However, how crops orchestrate Pi signaling and growth under Pi starvation conditions to optimize the growth defense tradeoff remains unclear. Here we show that a Pi starvation-induced transcription factor NIGT1 (NITRATE-INDUCIBLE GARP-TYPE TRANSCRIPTIONAL REPRESSOR 1) controls plant growth and prevents a hyper-response to Pi starvation by directly repressing the expression of growth-related and Pi-signaling genes to achieve a balance between growth and response under a varying Pi environment. NIGT1 directly binds to the promoters of Pi starvation signaling marker genes, like IPS1, miR827, and SPX2, under Pi-deficient conditions to mitigate the Pi-starvation responsive (PSR). It also directly represses the expression of vacuolar Pi efflux transporter genes VPE1/2 to regulate plant Pi homeostasis. We further demonstrate that NIGT1 constrains shoot growth by repressing the expression of growth-related regulatory genes, including brassinolide signal transduction master regulator BZR1, cell division regulator CYCB1;1, and DNA replication regulator PSF3. Our findings reveal the function of NIGT1 in orchestrating plant growth and Pi starvation signaling, and also provide evidence that NIGT1 acts as a safeguard to avoid hyper-response during Pi starvation stress in rice.

Evaluating the Performance of Different Large Language Models on Health Consultation and Patient Education in Urolithiasis.

OBJECTIVES: To evaluate the effectiveness of four large language models (LLMs) (Claude, Bard, ChatGPT4, and New Bing) that have large user bases and significant social attention, in the context of medical consultation and patient education in urolithiasis. MATERIALS AND METHODS: In this study, we developed a questionnaire consisting of 21 questions and 2 clinical scenarios related to urolithiasis. Subsequently, clinical consultations were simulated for each of the four models to assess their responses to the questions. Urolithiasis experts then evaluated the model responses in terms of accuracy, comprehensiveness, ease of understanding, human care, and clinical case analysis ability based on a predesigned 5-point Likert scale. Visualization and statistical analyses were then employed to compare the four models and evaluate their performance. RESULTS: All models yielded satisfying performance, except for Bard, who failed to provide a valid response to Question 13. Claude consistently scored the highest in all dimensions compared with the other three models. ChatGPT4 ranked second in accuracy, with a relatively stable output across multiple tests, but shortcomings were observed in empathy and human caring. Bard exhibited the lowest accuracy and overall performance. Claude and ChatGPT4 both had a high capacity to analyze clinical cases of urolithiasis. Overall, Claude emerged as the best performer in urolithiasis consultations and education. CONCLUSION: Claude demonstrated superior performance compared with the other three in urolithiasis consultation and education. This study highlights the remarkable potential of LLMs in medical health consultations and patient education, although professional review, further evaluation, and modifications are still required.

Water quality improvement performance of two urban constructed water quality treatment wetland engineering landscaping in Hangzhou, China.

For typical wastewater treatment processes of urban sewage, plants are often noneffective to improve water qualities of lightly polluted domestic sewage, and urban constructed water quality treatment (WQT) wetlands designed with engineering landscape methods are utilized to optimize both water qualities and landscape values in recent years. The research determines the effects of two typical ecological engineering landscaping projects of urban constructed WQT wetlands by analysing their effects of wastewater quality improvements. Differences of water quality indicators (WQI) respectively among different treatment stages of wetlands includes surface flow wetland, vertical flow wetland, floating wetland islands etc., which have been measured and compared. Evaluation of urban constructed WQT wetlands engineering landscaping has been concluded based on comparisons among hydrological indicators and water quality indicators, i.e. pH, DO, NH3-N, CODCr, TP. Removal effects of individual indicators, includes NH3-N, CODCr and TP during different treatment stages have been quantitatively analysed. In accordance with quantitative analysis, benefits and deficiencies of practical landscape design of urban constructed WQT wetlands are concluded. By adapting proper principles in engineering landscaping, environmental and economic benefits can be achieved to create sustainable landscapes of urban constructed WQT wetlands.

Actinomycin D causes oocyte maturation failure by inhibiting chromosome separation and spindle assembly†.

Actinomycin D (ActD) has been considered as one of the most effective and safe chemotherapeutic medications for treating a number of cancers. Although ActD has been used in the treatment of gynecological tumors and pediatric tumors for more than 50 years, the toxic effects of ActD on mammalian oocytes remain unknown. In this study, the influence of ActD on mouse and human oocyte maturation and the possible mechanisms were investigated. Notably, ActD inhibited oocyte maturation and arrested oocytes at the metaphase I (MI) stage in a dose-dependent manner. In addition, ActD arrested oocyte maturation when the oocytes were treated at different successive stages, including the germinal vesicle (GV), germinal vesicle breakdown, and MI stages. In ActD-treated oocytes, disordered chromosome condensation and irregular spindle assembly occurred, resulting in incomplete chromosome segregation and oocytes arresting at the MI phase; these results possibly occurred because ActD triggered the formation of reactive oxygen species, resulting in DNA damage and decreased ATP in mouse GV oocytes. Besides, in vivo treatment with ActD also inhibited mouse oocyte maturation. Similar effects were seen in human oocytes. Collectively, our results indicated that ActD exposure disrupted oocyte maturation by increasing DNA damage, which is a finding that might help with optimizing future methods for female fertility preservation before undergoing chemotherapy.

A structure model explaining the binding between a ubiquitous unconventional G-protein (OsYchF1) and a plant-specific C2-domain protein (OsGAP1) from rice.

The unconventional G-protein OsYchF1 plays regulatory roles in plant defense and abiotic stress responses. We have previously resolved the crystal structures of OsYchF1 and its plant-specific regulator, OsGAP1, and determined the residues on OsGAP1 that are essential for its binding to OsYchF1. In this study, we employed site-directed mutagenesis to identify four critical residues on the TGS domain of OsYchF1 that are critical for its binding to OsGAP1. We also generated a docking model of the OsYchF1 : OsGAP1 complex to dissect the molecular basis of their interactions. Our finding not only reveals the roles of the key interacting residues controlling the binding between OsYchF1 and OsGAP1, but also provides a working model on the potential regulatory mechanism mediated by a TGS domain, particularly in the class of GTPase of the OBG family.

Role of Ninth Type-III Domain of Fibronectin in the Mediation of Cell-Binding Domain Adsorption on Surfaces with Different Chemistries.

The orientation and conformation of adhesive proteins after adsorption play a central role in cell-binding bioactivity. Fibronectin (Fn) holds two peptide sequences that favor cell adhesion: the Arg-Gly-Asp (RGD) loop on the tenth type-III domain (Fn-III10) and the Pro-His-Ser-Arg-Asn (PHSRN) synergy site on the ninth type-III domain (Fn-III9). Herein, adsorption of Fn fragments (Fn-III10 and Fn-III9-10) on self-assembled monolayers (SAMs) carrying various functional groups (-COOH, -NH2, -CH3, and -OH) was investigated by the Monte Carlo method and molecular dynamics simulation in order to understand its mediation effect on cell adhesion. The results demonstrated that Fn-III9 could enhance the stiffness of the Fn molecule and further fix the adsorption orientation. The RGD site of the Fn fragment appeared to be deactivated on hydrophobic surfaces (CH3-SAM) because of the binding of adjacent nonpolar residues on surfaces, whereas charged surfaces (COOH-SAM and NH2-SAM) and hydrophilic surfaces (OH-SAM) were conducive to the formation of cell-binding-favorable orientation for Fn fragments. The cell adhesion capability of Fn fragments was highly improved on positively charged surfaces (NH2-SAM) and hydrophilic surfaces because of the advantageous steric structure and orientation of both RGD and PHSRN sites. This work provides an insight into the interplay at the atomic scale between protein adsorption and surface chemistry for designing biologically responsive substrate surfaces.

Chemokine Receptor Type 4 Regulates Migration and Invasion of Trophectoderm Cell in the Human Blastocyst.

Chemokine receptor type 4 (CXCR4) has been suggested to regulate cell migration and invasion in human somatic cells. However, its role in human oocytes and embryos has not been investigated directly. Here we show that CXCR4 mRNA was initially expressed at the 4-cell stage, and its expression gradually increased until the blastocyst stage, whereas its protein was detectable only after the 8-cell stage. In addition, CXCR4 mRNA and protein were expressed in the inner cell mass (ICM) and trophectoderm (TE) cell of the blastocyst. Furthermore, we collected embryos from women whose embryos had undergone successful implantation (SI) and those whose embryos had failed implantation (FI) in their fresh cycles. TE cells from the FI group had reduced CXCR4 mRNA expression relative to those from the SI group but not in the ICM. Through ICM replacement, we constructed mouse blastocysts in which Cxcr4 was specifically knocked down in TE cells to simulate the CXCR4 expression profile of human blastocysts from the FI group. In this case, we found that the implantation rate significantly decreased after transfer of reconstructed embryos. Bioinformatic analysis indicated that CXCR4 can induce cell apoptosis and migration mediated by Rho signaling. This hypothesis was confirmed by invasion and migration experiments, using a human trophoblast cell line. The present study is the first to explore the characteristics of CXCR4 expression using human oocytes and embryos and suggests that CXCR4 is required upstream of TE cell apoptosis and migration. CXCR4 expression is a potential biomarker to predict implantation competence during assisted reproductive technologies.

Role of Sirt3 in mitochondrial biogenesis and developmental competence of human in vitro matured oocytes.

STUDY QUESTION: Does Sirt3 dysfunction result in poor developmental outcomes for human oocytes after in vitro maturation (IVM)? SUMMARY ANSWER: Inefficient Sirt3 expression induced decreased mitochondrial DNA copy number and biogenesis, and therefore impaired the developmental competence of human IVM oocytes. WHAT IS KNOWN ALREADY: Cytoplasmic immaturity in IVM oocytes may lead to reduced developmental competence. Mitochondrial dysfunction results in the accumulation of free radicals and leads to DNA mutations, protein damage, telomere shortening and apoptosis. SIRT3 (in the Sirtuin protein family) has emerged as a mitochondrial fidelity protein that directs energy generation and regulates reactive oxygen species scavenging proteins. STUDY DESIGN, SIZE, DURATION: In vivo matured metaphase II (IVO-MII) oocytes and IVM-MII oocytes were donated by 324 infertile patients undergoing assisted reproductive technology cycles (12 patients for 60 IVO oocytes, and 312 patients for 403 IVM oocytes). Five oocytes each in the germinal vesicle (GV), IVM and IVO groups were compared with respect to mRNA levels for Sirt1-7 mRNA, and five samples at each developmental stage were analysed for Sirt3 mRNA. IVM-MII oocytes were injected with in vitro transcribed mRNA (n = 59) or small interfering RNA (siRNA) (n = 78). In human and mouse, IVM, mRNA-injection IVM, and siRNA-injection IVM groups (n = 5 each) were analysed for mitochondrial DNA copy number and abundance of Sirt3 and Pgc1α (an inducer of mitochondrial biogenesis) mRNAs. Human blastocysts in the IVO (n = 12), IVM (n = 9), mRNA-injection IVM (n = 13) and siRNA-injection IVM (n = 6) groups were used to generate embryonic stem cells (ESCs). In addition, 587 IVO-MII and 1737 IVM-MII oocytes from 83 mice were collected to compare the preliminary human oocyte data with another species. PARTICIPANTS/MATERIALS, SETTING, METHODS: mRNA abundance was analysed by single-cell real-time PCR. Karyotyping of human embryos was performed with an array comparative genomic hybridization method, and that of ESCs by cytogenetic analysis. The function of the Sirt3 gene was investigated using siRNA and in vitro transcribed mRNA injection. Markers of ESCs were identified using immunofluorescence. MAIN RESULTS AND THE ROLE OF CHANCE: A retrospective analysis revealed a higher spontaneous abortion rate (P < 0.01) and decrease in high quality embryo rate (P < 0.01) in patients with IVM versus controlled ovarian stimulation (COS) cycles. A decrease in abundance of Sirt3 mRNA (P < 0.01) and mitochondrial biogenesis (P < 0.05) were identified in human IVM compared with IVO oocytes. The developmental potential of human IVM-MII oocytes to the blastocyst stage was significantly reduced when Sirt3 mRNA was inhibited by siRNA (P < 0.05 versus IVM-MII group) but could be up-regulated by injection of Sirt3 mRNAs. Compared with IVO-MII group, comparable generation efficiency of human ESCs can be obtained using blastocysts from IVM-MII oocytes with Sirt3 mRNA injection. Sirt3 mRNA was significantly increased in mouse zygotes after IVF (P < 0.001 versus MII oocytes) but gradually declined until the blastocyst stage. In mice, lower Sirt3 mRNA levels were observed IVM-MII oocytes and preimplantation embryos compared with in vivo controls, and mitochondrial biogenesis and the developmental efficiency from oocytes to blastocyst were affected by the abundance of Sirt3 mRNA in accordance with human. Therefore a similar role for Sirt3 mRNA in IVM-MII oocytes was observed in mouse and human. LIMITATIONS, REASONS FOR CAUTION: The couples in the study had a variety of different simple and complex factors causing infertility. Additional studies with a larger number of oocytes are required to confirm the present results owing to the limited number of human oocytes in the present study. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study investigating a role of the Sirt3 gene in mitochondrial biogenesis and the developmental competence of human IVM-MII oocytes. The observation may help to improve clinical application of the IVM procedure. STUDY FUNDING/COMPETING INTERESTS: This work was supported in part by the National Natural Science Foundation of Key Program (31230047), Ministry of Science and Technology of China Grants (973 program; 2014CB943203), the National Natural Science Foundation of General Program (31371521 and 81571400), Beijing Nova Program (xxjh2015011), and Specialized Research Fund for the Doctoral Program of Higher Education (20120001130008) and the National Natural Science Foundation of Young Scholar (31501201). The authors have declared that no conflict of interest exists.

Feasibility of coded vibration in a vibro-ultrasound system for tissue elasticity measurement.

The ability of various methods for elasticity measurement and imaging is hampered by the vibration amplitude on biological tissues. Based on the inference that coded excitation will improve the performance of the cross-correlation function of the tissue displacement waves, the idea of exerting encoded external vibration on tested samples for measuring its elasticity is proposed. It was implemented by integrating a programmable vibration generation function into a customized vibro-ultrasound system to generate Barker coded vibration for elasticity measurement. Experiments were conducted on silicone phantoms and porcine muscles. The results showed that coded excitation of the vibration enhanced the accuracy and robustness of the elasticity measurement especially in low signal-to-noise ratio scenarios. In the phantom study, the measured shear modulus values with coded vibration had an R(2 )= 0.993 linear correlation to that of referenced indentation, while for single-cycle pulse the R(2) decreased to 0.987. In porcine muscle study, the coded vibration also obtained a shear modulus value which is more accurate than the single-cycle pulse by 0.16 kPa and 0.33 kPa at two different depths. These results demonstrated the feasibility and potentiality of the coded vibration for enhancing the quality of elasticity measurement and imaging.

Rho GDIalpha Modulates Rabbit Trophoblast Stem Cell Survival and Migration.

Trophoblast stem cells differentiate into different trophoblast cell populations that are indispensable for successful pregnancy through interactions with the maternal uterine decidua. Rho GTPases play an important role in the regulation of trophoblast stem cell (TSC) self-renewal and differentiation; however, the role of Rho GDP-dissociation inhibitors (Rho GDIs) remains unclear. Here we report that overexpression of Rho GDIalpha resulted in rapid apoptosis of TSCs, while its knockdown promoted proliferation. Moreover, Rho GDIalpha knockdown also enhanced TSC invasion. Collectively, these results establish a potential mechanism whereby TSCs can balance growth and apoptosis, and thus ensure normal fetal development.

Dynamic curvature topography for evaluating the anterior corneal surface change with Corvis ST.

BACKGROUND: The measurement of dynamic parameters, such as the length of applanation and the amplitude of deformation, is significant for evaluating corneal properties. Most of the corneal properties (related to shape) including the anterior corneal curvature and the thickness of cornea can be easily measured using some existing techniques. However, they only provide the static or pseudo-dynamic analysis. Based on Corvis ST images, the dynamic features after corneal boundaries detection and parameter estimation will be helpful for corneal analysis. MATERIAL: The study included 40 eyes in normal group (ranging from 19 to 45 years old) and 30 eyes in keratoconus group (ranging from 16 to 40 years old). These eyes were examined by Corvis ST and for each one a sequence of 140 images was obtained. Besides, 11 subjects of each group were also tested by Pentacam. METHODS: By analyzing the video from the Corvis ST imaging, the fully dynamic curvature topography is proposed to evaluate the response of the anterior corneal surface to the air puff. The new method not only quantitatively measures the intact variation of anterior corneal surface but also provides an intuitive way to observe the dynamic change of the anterior corneal surface in the whole air stream process. The proposed method consists of three main steps: cornea segmentation, curvature estimation and integrated visualization. An automatic segmentation method based on the combination of prior knowledge with phase symmetry and asymmetry theory is firstly presented to detect the corneal boundaries. The Landau-new method is then used to estimate the anterior corneal surface. The corneal dynamic topography is finally obtained by combining the dynamic parameters with the original Corvis ST video, which is an improvement of the fusion technique proposed by Li et al. RESULTS AND CONCLUSION: By comparing the segmentation results with manual method and built-in method of Corvis ST, the accuracy and robustness of our proposed segmentation method is demonstrated. The correctness of the estimated corneal anterior curvatures is also evaluated by comparing it with that of Pentacam which is considered to be able to provide the first-class measurement currently. The dynamic topography may be used to distinguish the dynamic behavior of normal corneas from that of keratoconus.

Assessment of ocular biomechanics using dynamic ultra high-speed Scheimpflug imaging in keratoconic and normal eyes.

PURPOSE: To introduce several new ocular biomechanical parameters for comparison between keratoconic and normal eyes using an analysis method based on corneal dynamic deformation video recorded by corneal visualization Scheimpflug technology (Corvis ST; Oculus Optikgeräte GmbH, Wetzlar, Germany). METHODS: This comparative study comprised 52 keratoconic eyes of 43 patients with keratoconus and 52 normal eyes of 52 controls. An analysis method (PolyU [Labview 2009; National Instrument, Austin, TX]) was developed to introduce several new ocular biomechanical parameters and to compare the difference between keratoconic and normal eyes. The repeatability of the new parameters measurement was evaluated and compared with the Corvis ST measurement. Receiver operating characteristic curves were used to establish a cutoff value for the new biomechanical parameters. RESULTS: Intraclass correlation coefficients of the deformation amplitude, peak distance, corneal concave radius of curvature, maximum deformation area, maximum corneal inward velocity and outward velocity (Vin, max and Vout, max) were high in both the keratoconic and normal eyes (all intraclass correlation coefficients > 0.75). The measurement agreement of the PolyU analysis method and Corvis ST was good. Most of the biomechanical parameters of patients with keratoconus were significantly different from those of the controls. In the receiver operating characteristic analysis, the Vin, max was the best predictive parameter with an area under the curve of 0.79. CONCLUSIONS: The corneal deformation video recorded by the Corvis ST provides useful information for the study of ocular biomechanics. Most of the new ocular biomechanical parameters were significantly different between keratoconic and normal eyes. Further research is needed to develop more comprehensive clinical applications with these new ocular biomechanical parameters.

Surface hydrophobization of hydrogels via interface dynamics-induced network reconfiguration.

Effective and easy regulation of hydrogel surface properties without changing the overall chemical composition is important for their diverse applications but remains challenging to achieve. We report a generalizable strategy to reconfigure hydrogel surface networks based on hydrogel-substrate interface dynamics for manipulation of hydrogel surface wettability and bioadhesion. We show that the grafting of hydrophobic yet flexible polymeric chains on mold substrates can significantly elevate the content of hydrophobic polymer backbones and reduce the presence of polar groups in hydrogel surface networks, thereby transforming the otherwise hydrophilic hydrogel surface into a hydrophobic surface. Experimental results show that the grafted highly dynamic hydrophobic chains achieved with optimal grafting density, chain length, and chain structure are critical for such substantial hydrogel surface network reconfiguration. Molecular dynamics simulations further reveal the atomistic details of the hydrogel network reconfiguration induced by the dynamic interface interactions. The hydrogels prepared using our strategy show substantially enhanced bioadhesion and transdermal delivery compared with the hydrogels of the same chemical composition but fabricated via the conventional method. Our findings provide important insights into the dynamic hydrogel-substrate interactions and are instrumental to the preparation of hydrogels with custom surface properties.

Structures of NF-κB p52 homodimer-DNA complexes rationalize binding mechanisms and transcription activation.

The mammalian NF-κB p52:p52 homodimer together with its cofactor Bcl3 activates transcription of κB sites with a central G/C base pair (bp), while it is inactive toward κB sites with a central A/T bp. To understand the molecular basis for this unique property of p52, we have determined the crystal structures of recombinant human p52 protein in complex with a P-selectin(PSel)-κB DNA (5'-GGGGTGACCCC-3') (central bp is underlined) and variants changing the central bp to A/T or swapping the flanking bp. The structures reveal a nearly two-fold widened minor groove in the central region of the DNA as compared to all other currently available NF-κB-DNA complex structures, which have a central A/T bp. Microsecond molecular dynamics (MD) simulations of free DNAs and p52 bound complexes reveal that free DNAs exhibit distinct preferred conformations, and p52:p52 homodimer induces the least amount of DNA conformational changes when bound to the more transcriptionally active natural G/C-centric PSel-κB, but adopts closed conformation when bound to the mutant A/T and swap DNAs due to their narrowed minor grooves. Our binding assays further demonstrate that the fast kinetics favored by entropy is correlated with higher transcriptional activity. Overall, our studies have revealed a novel conformation for κB DNA in complex with NF-κB and pinpoint the importance of binding kinetics, dictated by DNA conformational and dynamic states, in controlling transcriptional activation for NF-κB.

Integrated bulk and scRNA sequence identified anoikis-related diagnostic biomarkers and potential association with immune infiltration in type A aortic dissection.

Type-A aortic dissection (TAAD) is common life-threatening cardiovascular diseases with high-morbidity and mortality but the concrete etiology of disease remains unclear, which might disturb or delay the early diagnosis for TAAD. Anoikis is a special form of programmed cell-death (PCD) induced by detachment of anchorage-dependent cells from the extracellular matrix (ECM) or neighboring cells, and has been widely applied to identify anoikis-related biomarkers for the prediction and prognosis in oncological fields. However, the specific roles of anoikis-related genes (ARGs) in TAAD remain unclear. In this study, we first identified and validated eight diagnostic ARGs for TAAD based on multiple RNA-sequence datasets, including CHEK2, HIF1A, HK2, HMGA1, SERPINA1, PTPN1, SLC2A1 and VEGFA. The comprehensive functional annotation was evaluated by the integrated functional enrichments analysis. We identified the activation of inflammatory-related pathways, metabolic reprogramming and angiogenesis, and the inhibition of cardiovascular development pathways in TAAD. Immune cell infiltration (ICI) analysis further demonstrated that innate immune-cells were more dominant than adaptive immune-cells in TAAD tissues, especially in macrophages, monocytes, activated-DC, NKT cells and CD56+dim NK cells. The cellular landscape was further validated by single-cell RNA sequence technology with significant associations with anoikis in TAAD patients. Four vital ARGs (HIF1A, HMGA1, SERPINA1 and VEGFA) were ultimately identified along with the changes of differentiation trajectory, and major expressions were conformably concentrated on Macro1-3, Mono1-2 and Mono4 subtypes. These findings provide a promising diagnostic biomarker for the accurately diagnosing the disease and would be helpful to further explore the potential pathogenesis with anoikis process for TAAD.

Radiotherapy plus immune checkpoint inhibitor in prostate cancer.

The immune checkpoint inhibitor (ICI) is a promising strategy for treating cancer. However, the efficiency of ICI monotherapy is limited, which could be mainly attributed to the tumor microenvironment of the "cold" tumor. Prostate cancer, a type of "cold" cancer, is the most common cancer affecting men's health. Radiotherapy is regarded as one of the most effective prostate cancer treatments. In the era of immune therapy, the enhanced antigen presentation and immune cell infiltration caused by radiotherapy might boost the therapeutic efficacy of ICI. Here, the rationale of radiotherapy combined with ICI was reviewed. Also, the scheme of radiotherapy combined with immune checkpoint blockades was suggested as a potential option to improve the outcome of patients with prostate cancer.

Association between polymorphisms of the cytokine and cytokine receptor genes and immune response to hepatitis B vaccination in a Chinese Han population.

The immune response to hepatitis B vaccination varies among individuals. It has been reported that polymorphisms in cytokine and cytokine receptor genes are associated with these individual differences. The aim of the current study was to investigate the association between polymorphisms of the Th1/Th2 cytokine and cytokine receptor genes and the response to hepatitis B vaccination in a Chinese Han population. A total of 10 single nucleotide polymorphisms distributed in 6 genes (TNFRSF1A, IL12A, IL12B, IFNG, IL4, and IL10) were genotyped in 214 high-responders [hepatitis B surface antibody (anti-HBs) ≥1,000 mIU/ml] and 107 low-responders (anti-HBs: 10-99 mIU/ml). The minor CTCTAA allele of rs17860508 in the IL12B gene was associated with a low response to hepatitis B vaccination (P = 0.039, odds ratio = 1.41, 95% confidence interval = 1.00-1.99). In addition, a significant gene-gene interaction was found: the frequency of the combined genotypes IL12A rs2243115 TT and IL12B rs17860508 CTCTAA/CTCTAA was significantly higher in the low-response group than in the high-response group (P = 0.008, odds ratio = 2.19, 95% confidence interval = 1.23-3.93). These findings suggest that polymorphisms in the IL12A and IL12B genes might play an important role jointly in determining the response to hepatitis B vaccination.

How to synchronously slow down starch digestion and retrogradation: A structural analysis study.

Digestibility and retrogradation properties of starch are important for the nutrition and quality of starch-based foods. In this study, a new idea on the synchronous delay the starch digestion and retrogradation was proposed, and the regulation mechanism was explored from perspectives of structural evolution using 13C NMR, XRD and SAXS techniques as well as the molecular dynamics simulations. Results showed that the chestnut starch treated with hot extrusion and 8% catechins (HE-8% CA)## could reach highest anti-retrogradation rate (AR 76.63%) and lowest rapidly digestible starch content (RDS 64.55%) at day 24. The starch digestion was slowed down by increasing single/double helix, V-type crystallinity and compactness of aggregates, while retrogradation process was suppressed by inhibiting the packing of short-range ordered structure into long-range ordered structure. The hydrogen bonding and van der Waals forces were the main driving force for the interactions between flavonoid polyphenols and starch molecules. Overall, this study is instructive for further investigations on the synchronous modulation of functional properties of starch.