Dietary complex probiotic supplementation changed the composition of intestinal short-chain fatty acids and improved the average daily gain of weaned piglets.

Probiotics are a group of active microorganisms that form colonies within the body and alter the composition of the flora in a specific area to provide benefits to the host. In this study, a total of 96 Duroc × Landrace × Yorkshire weaned piglets with an initial body weight (BW) of 8.56 ± 0.53 kg were employed in a randomized complete block design for a 28-day experiment. Pigs were randomly divided into two treatment groups: the control group (CON) and the complex probiotic group (CON + 0.2% probiotics), respectively. The study found that through the 28-day experiment, the average daily gain (ADG) of the complex probiotic group was significantly higher than that of the CON (p < 0.05). However, compared with the CON, the feed conversion efficiency significantly decreased on days 0-14 (p < 0.05). The addition of dietary complex probiotic significantly increased the villus height (VH) of duodenum and ileum, acetate, propionate, butyrate, and total short-chain fatty acids (SCFAs) in feces, and decreased fecal methyl mercaptans, acetic acid, and CO2 (p < 0.05). It concluded that feeding weaned piglets 0.2% complex probiotic increased the VH of duodenum and ileum, as well as changed the content of SCFAs in feces. This ultimately led to an increase in ADG.

Role of Emerin in regulating fibroblast differentiation and migration at the substrate of stiffness coupled topology.

In hypertrophic scars, the differentiation and migration of fibroblasts are influenced by the extracellular matrix microenvironment, which includes factors such as stiffness, restraint, and tensile force. These mechanical stresses incite alterations in cell behavior, accompanied by cytoskeletal protein reorganization. However, the role of nucleo-skeletal proteins in this context remains underexplored. In this study, we use a polyacrylamide hydrogel (PAA) to simulate the mechanical stress experienced by cells in scar tissue and investigate the impact of Emerin on cell behavior. We utilize atomic force microscopy (AFM) and RNA interference technology to analyze cell differentiation, migration, and stiffness. Our findings reveal that rigid substrates and cellular restriction elevate Emerin expression and diminish differentiation. Conversely, reducing Emerin expression leads to attenuated cell differentiation, where stiffness and constraining factors exert no notable influence. Furthermore, a softening of cells and an enhanced migration rate are also markedly observed. These observations indicate that variations in nuclear skeletal proteins, prompted by diverse matrix microenvironments, play a pivotal role in the pathogenesis of hypertrophic scars (HSs). This research offers novel insights and a reference point for understanding scar fibrosis formation mechanisms and preventing fibrosis.

Dietary Citrus Flavonoids Improved Growth Performance and Intestinal Microbiota of Weaned Piglets via Immune Function Mediated by TLR2/NF-κB Signaling Pathway.

This study investigated the effects of citrus flavonoids (CF) and compared to antibiotics on piglet growth and gut health. Weaned piglets were fed either a basal diet (CON) or a basal diet supplemented with 75 mg/kg chlortetracycline (CTC), 20 mg/kg CF (CF1), 40 mg/kg CF (CF2), or 80 mg/kg CF (CF3). The CF group, especially CF3, exhibited improved growth performance; reduced diarrhea; significantly higher levels of serum growth factors, immunoglobulins, and anti-inflammatory cytokines; and significantly lower levels of pro-inflammatory factors and markers of intestinal barrier damage (P < 0.05). The intestinal mucosa proteins ZO-1 and occludin increased, while NF-κB and TLR2 decreased, correlating with CF dosage (P < 0.05). Furthermore, CF promoted a favorable balance in the gut microbiota, with an increased relative abundance of Bacteroidetes and Prevotella and decreased taxa Tenericutes and Clostridiales. Overall, CF enhanced piglet growth and gut health by modulating the TLR2/NF-κB pathway, offering a natural antibiotic alternative. The optimal dose of CF was 80 mg/kg.

Multi-Objective Optimization of Laser Cleaning Quality of Q390 Steel Rust Layer Based on Response Surface Methodology and NSGA-II Algorithm.

To improve the laser cleaning surface quality of rust layers in Q390 steel, a method of determining the optimal cleaning parameters is proposed that is based on response surface methodology and the second-generation non-dominated sorting genetic algorithm (NSGA-II). It involves constructing a mathematical model of the input variables (laser power, cleaning speed, scanning speed, and repetition frequency) and the objective values (surface oxygen content, rust layer removal rate, and surface roughness). The effects of the laser cleaning process parameters on the cleaning surface quality were analyzed in our study, and accordingly, NSGA-II was used to determine the optimal process parameters. The results indicate that the optimal process parameters are as follows: a laser power of 44.99 W, cleaning speed of 174.01 mm/min, scanning speed of 3852.03 mm/s, and repetition frequency of 116 kHz. With these parameters, the surface corrosion is effectively removed, revealing a distinct metal luster and meeting the standard for surface treatment before welding.

Research progress on the types, functions, biosynthesis, and metabolic regulation of ginkgo terpenoids.

Ginkgo biloba L. is a relict plant endemic to China that is commonly considered a "living fossil". It contains unique medicinal compounds that play important roles in its response to various stresses and help maintain human health. Ginkgo terpenoids are known to be important active ingredients but have received less attention than flavonoids. Hence, this review focuses on recent progress in research on the pharmacological effects of ginkgo terpenoid and the bioactivities of different terpenoid monomers. Many key structural genes, enzyme-encoding genes, transcription factors, and noncoding RNAs involved in the ginkgo terpenoid pathway were identified. Finally, many external factors (ecological factors, hormones, etc.) that regulate the biosynthesis and metabolism of terpenoids were proposed. All these findings improve the understanding of the biosynthesis, accumulation, and medicinal functions of terpenoids. Finally, this review includes an in-depth discussion regarding the limitations of terpenoid-related studies and potential future research directions.

Sexually Dimorphic Response to Hepatic Injury in Newborn Suffering from Intrauterine Growth Restriction.

Intrauterine growth restriction (IUGR), when a fetus does not grow as expected, is associated with a reduction in hepatic functionality and a higher risk for chronic liver disease in adulthood. Utilizing early developmental plasticity to reverse the outcome of poor fetal programming remains an unexplored area. Focusing on the biochemical profiles of neonates and previous transcriptome findings, piglets from the same fetus are selected as models for studying IUGR. The cellular landscape of the liver is created by scRNA-seq to reveal sex-dependent patterns in IUGR-induced hepatic injury. One week after birth, IUGR piglets experience hypoxic stress. IUGR females exhibit fibroblast-driven T cell conversion into an immune-adapted phenotype, which effectively alleviates inflammation and fosters hepatic regeneration. In contrast, males experience even more severe hepatic injury. Prolonged inflammation due to disrupted lipid metabolism hinders intercellular communication among non-immune cells, which ultimately impairs liver regeneration even into adulthood. Additionally, Apolipoprotein A4 (APOA4) is explored as a novel biomarker by reducing hepatic triglyceride deposition as a protective response against hypoxia in IUGR males. PPARα activation can mitigate hepatic damage and meanwhile restore over-expressed APOA4 to normal in IUGR males. The pioneering study offers valuable insights into the sexually dimorphic responses to hepatic injury during IUGR.

Rapid-Response Water-Shrink Films with High Output Work Density Based on Polyethylene Oxide and α-Cyclodextrin for Autonomous Wound Closure.

Conventional wound closure methods, including sutures and tissue adhesives, present significant challenges for self-care treatment, particularly in the context of bleeding wounds. Existing stimuli-responsive contractile materials designed for autonomous wound closure frequently lack sufficient output work density to generate the force needed to bring the wound edges into proximity or necessitate stimuli that are not compatible with the human body. Here, semi-transparent, flexible, and water-responsive shrinkable films, composed of poly(ethylene oxide) and α-cyclodextrin, are reported. These films exhibit remarkable stability under ambient conditions and demonstrate significant contraction (≈50%) within 6 s upon exposure to water, generating substantial contractile stress (up to 6 MPa) and output work density (≈1028 kJ m-3), which is 100 times larger than that of conventional hydrogel and 25 times larger than that of skeletal muscles. Remarkably, upon hydration, these films are capable of lifting objects 10 000 times their own weight. Leveraging this technology, water-shrink tapes, which, upon contact with water, effectively constrict human skin and autonomously close bleeding wounds in animal models within 10 seconds, are developed further. This work offers a novel approach to skin wound management, showing significant potential for emergency and self-care scenarios.

Self-assembled metal-phenolic network nanoparticles for delivery of a cisplatin prodrug for synergistic chemo-immunotherapy.

Despite cisplatin's pivotal role in clinically proven anticancer drugs, its application has been hampered by severe side effects and a grim prognosis. Herein, we devised a glutathione (GSH)-responsive nanoparticle (PFS-NP) that integrates a disulfide bond-based amphiphilic polyphenol (PP-SS-DA), a dopamine-modified cisplatin prodrug (Pt-OH) and iron ions (Fe3+) through coordination reactions between Fe3+ and phenols. After entering cells, the responsively released Pt-OH and disulfide bonds eliminate the intracellular GSH, in turn disrupting the redox homeostasis. Meanwhile, the activated cisplatin elevates the intracellular H2O2 level through cascade reactions. This is further utilized to produce highly toxic hydroxyl radicals (˙OH) catalyzed by the Fe3+-based Fenton reaction. Thus, the amplified oxidative stress leads to immunogenic cell death (ICD), promoting the maturation of dendritic cells (DCs) and ultimately activating the anti-tumor immune system. This innovative cisplatin prodrug nanoparticle approach offers a promising reference for minimizing side effects and optimizing the therapeutic effects of cisplatin-based drugs.

Solving Engineering Optimization Problems Based on Multi-Strategy Particle Swarm Optimization Hybrid Dandelion Optimization Algorithm.

In recent years, swarm intelligence optimization methods have been increasingly applied in many fields such as mechanical design, microgrid scheduling, drone technology, neural network training, and multi-objective optimization. In this paper, a multi-strategy particle swarm optimization hybrid dandelion optimization algorithm (PSODO) is proposed, which is based on the problems of slow optimization speed and being easily susceptible to falling into local extremum in the optimization ability of the dandelion optimization algorithm. This hybrid algorithm makes the whole algorithm more diverse by introducing the strong global search ability of particle swarm optimization and the unique individual update rules of the dandelion algorithm (i.e., rising, falling and landing). The ascending and descending stages of dandelion also help to introduce more changes and explorations into the search space, thus better balancing the global and local search. The experimental results show that compared with other algorithms, the proposed PSODO algorithm greatly improves the global optimal value search ability, convergence speed and optimization speed. The effectiveness and feasibility of the PSODO algorithm are verified by solving 22 benchmark functions and three engineering design problems with different complexities in CEC 2005 and comparing it with other optimization algorithms.

Extracellular vesicles of Bacteroides uniformis induce M1 macrophage polarization and aggravate gut inflammation during weaning.

Weaning process is commonly associated with gastrointestinal inflammation and dysbiosis of the intestinal microbes. In particular, the impact of gut bacteria and extracellular vesicles on the etiology of intestinal inflammation during weaning is not well understood. We have uncovered a potential link between gut inflammation and the corresponding variation of macrophage bacterial sensing and pro-inflammatory polarization during the weaning process of piglets through single-cell transcriptomic analyses. We conducted a comprehensive analysis of bacterial distribution across the gastrointestinal tract and pinpointed Bacteroides uniformis enriching in piglets undergoing weaning. Next, we found out that exposure to B. uniformis-derived extracellular vesicles (BEVs) exacerbated gut inflammation in a murine colitis model while recruiting and polarizing intestinal macrophages toward a pro-inflammatory phenotype. BEVs modulated the function of macrophages cultured in vitro by suppressing the granulocyte-macrophage colony-stimulating factor/signal transducer and activator of transcription 5/arginase 1 pathway, thereby affecting polarization toward an M1-like state. The effects of BEVs were verified both in the macrophage clearance murine model and by using an adoptive transfer assay. Our findings highlight the involvement of BEVs in facilitating the polarization of pro-inflammatory macrophages and promoting gut inflammation during weaning.

Antigen specific VNAR screening in whitespotted bamboo shark (Chiloscyllium plagiosum) with next generation sequencing.

IgNAR exhibits significant promise in the fields of cancer and anti-virus biotherapies. Notably, the variable regions of IgNAR (VNAR) possess comparable antigen binding affinity with much smaller molecular weight (∼12 kDa) compared to IgNAR. Antigen specific VNAR screening is a changeling work, which limits its application in medicine and therapy fields. Though phage display is a powerful tool for VNAR screening, it has a lot of drawbacks, such as small library coverage, low expression levels, unstable target protein, complicating and time-consuming procedures. Here we report VANR screening with next generation sequencing (NGS) could effectively overcome the limitations of phage display, and we successfully identified approximately 3000 BAFF-specific VNARs in Chiloscyllium plagiosum vaccinated with the BAFF antigen. The results of modelling and molecular dynamics simulation and ELISA assay demonstrated that one out of the top five abundant specific VNARs exhibited higher binding affinity to the BAFF antigen than those obtained through phage display screening. Our data indicates NGS would be an alternative way for VNAR screening with plenty of advantages.

Flavonoids, gut microbiota, and host lipid metabolism.

Flavonoids are widely distributed in nature and have a variety of beneficial biological effects, including antioxidant, anti-inflammatory, and anti-obesity effects. All of these are related to gut microbiota, and flavonoids also serve as a bridge between the host and gut microbiota. Flavonoids are commonly used to modify the composition of the gut microbiota by promoting or inhibiting specific microbial species within the gut, as well as modifying their metabolites. In turn, the gut microbiota extensively metabolizes flavonoids. Hence, this reciprocal relationship between flavonoids and the gut microbiota may play a crucial role in maintaining the balance and functionality of the metabolism system. In this review, we mainly highlighted the biological effects of antioxidant, anti-inflammatory and antiobesity, and discussed the interaction between flavonoids, gut microbiota and lipid metabolism, and elaborated the potential mechanisms on host lipid metabolism.

Nutrition strategies to control post-weaning diarrhea of piglets: From the perspective of feeds.

Post-weaning diarrhea (PWD) is a globally significant threat to the swine industry. Historically, antibiotics as well as high doses of zinc oxide and copper sulfate have been commonly used to control PWD. However, the development of bacterial resistance and environmental pollution have created an interest in alternative strategies. In recent years, the research surrounding these alternative strategies and the mechanisms of piglet diarrhea has been continually updated. Mechanically, diarrhea in piglets is a result of an imbalance in intestinal fluid and electrolyte absorption and secretion. In general, enterotoxigenic Escherichia coli (ETEC) and diarrheal viruses are known to cause an imbalance in the absorption and secretion of intestinal fluids and electrolytes in piglets, resulting in diarrhea when Cl- secretion-driven fluid secretion surpasses absorptive capacity. From a perspective of feedstuffs, factors that contribute to imbalances in fluid absorption and secretion in the intestines of weaned piglets include high levels of crude protein (CP), stimulation by certain antigenic proteins, high acid-binding capacity (ABC), and contamination with deoxynivalenol (DON) in the diet. In response, efforts to reduce CP levels in diets, select feedstuffs with lower ABC values, and process feedstuffs using physical, chemical, and biological approaches are important strategies for alleviating PWD in piglets. Additionally, the diet supplementation with additives such as vitamins and natural products can also play a role in reducing the diarrhea incidence in weaned piglets. Here, we examine the mechanisms of absorption and secretion of intestinal fluids and electrolytes in piglets, summarize nutritional strategies to control PWD in piglets from the perspective of feeds, and provide new insights towards future research directions.

The role of hydrogen in the prevention and treatment of coronary atherosclerotic heart disease.

Coronary atherosclerotic heart disease (CHD) is a primary cardiovascular disease caused by atherosclerosis (AS), which is characterized by chronic inflammation and lipid oxidative deposition. Molecular hydrogen (H2) is an effective anti-inflammatory agent and has potential to ameliorate glycolipid metabolism disorders, which is believed to exert beneficial effects on the prevention and treatment of CHD. It is suggested that H2 reduces inflammation in CHD by regulating multiple pathways, including NF-κB inflammatory pathway, pyroptosis, mitophagy, endoplasmic reticulum (ER) stress, and Nrf2 antioxidant pathway. Additionally, H2 may improve glycolipid metabolism by mediation of PI3K and AMPK signalling pathways, contributing to inhibition of the occurrence and development of CHD. This review elaborates pathogenesis of CHD and evaluates the role of H2 in CHD. Moreover, possible molecular mechanisms have been discussed and speculated, aiming to provide more strategies and directions for subsequent studies of H2 in CHD.

Dietary tryptophan improves growth and intestinal health by promoting the secretion of intestinal ß-defensins against enterotoxigenic Escherichia coli F4 in weaned piglets.

Adequate dietary L-tryptophan (Trp) governs intestinal homeostasis in piglets. However, the defensive role of Trp in the diet against enterotoxigenic Escherichia coli F4 (K88) in pigs is still poorly understood. Here, sixty (6.15 ± 1.52 kg, 24-day-old, Duroc × Landrace × Yorkshire) weaned piglets were used for an E. coli F4 attack test in a 2 × 2 factorial design. The growth (ADG, ADFI, GH), immune factors (IL-10, IgA, IgG, IgM), Trp metabolite 5-HT, intestinal morphology (jejunal and colonic VH), mRNA expression of ß-defensins (jejunal BD-127, BD-119, ileal BD-1, BD-127), and abundance of beneficial microorganisms in the colon (Prevotella 9, Lactobacillus, Phascolarctobacterium, Faecalibacterium) were higher in the piglets in the HT (High Trp) and HTK (High Trp, K88) groups than in the LT (Low Trp) and LTK (Low Trp, K88) groups (P<.05), while FCR, diarrhea rate, diarrhea index, serum Trp, Kyn, IDO, D-LA, ET, and abundance of harmful microorganisms in the colon (Spirochaetes, Fusobacteria, Prevotella, Christensenellaceae R7) were lower in the HT and HTK groups than in the LT and LTK groups (P<.05). High Trp reduced the expression of virulence genes (K88 and LT) after E. coli F4 attack (P<.05). The IL-6, TNF-α was lower in the HTK group than in the LT, LTK group (P<.05). In short, a diet containing 0.35% Trp protected piglets from enterotoxigenic E. coli F4 (K88) via Trp metabolism promoting BD expression in the intestinal mucosa, which improved growth and intestinal health.

Exploration of a noninvasive radiomics classifier for breast cancer tumor microenvironment categorization and prognostic outcome prediction.

RATIONALE AND OBJECTIVES: Breast cancer progression and treatment response are significantly influenced by the tumor microenvironment (TME). Traditional methods for assessing TME are invasive, posing a challenge for patient care. This study introduces a non-invasive approach to TME classification by integrating radiomics and machine learning, aiming to predict the TME status using imaging data, thereby aiding in prognostic outcome prediction. MATERIALS AND METHODS: Utilizing multi-omics data from The Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA), this study employed CIBERSORT and MCP-counter algorithms analyze immune infiltration in breast cancer. A radiomics classifier was developed using a random forest algorithm, leveraging quantitative features extracted from intratumoral and peritumoral regions of Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) scans. The classifer's ability to predict diverse TME states were and their prognostic implications were evaluated using Kaplan-Meier survival curves. RESULTS: Three distinct TME states were identified using RNA-Seq data, each displaying unique prognostic and biological characteristics. Notably, patients with increased immune cell infiltration showed significantly improved prognoses (P < 0.05). The classifier, comprising 24 radiomic features, demonstrated high predictive accuracy (AUC of training set = 0.960, 95 % CI: 0.922, 0.997; AUC of testing set = 0.853, 95 % CI: 0.687, 1.000) in differentiating these TME states. Predictions from the classifier also correlated significantly with overall patient survival (P < 0.05). CONCLUSION: This study offers a detailed analysis of the complex TME states in breast cancer and presents a reliable, noninvasive radiomics classifier for TME assessment. The classifer's accurate prediction of TME status and its correlation with prognosis highlight its potential as a tool in personalized breast cancer treatment, paving the way for more individualized and less invasive therapeutic strategies.

Understanding the consumer-citizen gap in Chinese public attitudes toward farm animal welfare.

Individuals of the general public can perform both consumer and citizen roles in farm animal welfare, and attitudes toward farm animal welfare may differ between these roles. However, scant research is available regarding this distinction, especially in developing countries such as China. The present study aimed to explore consumer-citizen gaps in Chinese public attitudes toward farm animal welfare across three dimensions and across demographic characteristics. A 36-item scale was designed, and completed by 5284 Chinese participants in a large-scale cross-sectional survey. Consumer-citizen gaps in attitudes toward farm animal welfare across three dimensions and demographic characteristics were analyzed using the Wilcoxon signed-rank test, and effects of demographic characteristics on attitudes were further explored by linear regression analysis. A significant consumer-citizen gap was found in overall attitudes, although the consumer role was only slightly more positive than the citizen role. The consumer-citizen gap is driven by differences in both cognitive attitudes and behavioral attitudes. The gap is most pronounced in cognitive attitudes, where the consumer role is significantly more positive, and smaller in behavioral attitudes, where the citizen role is significantly more positive. The consumer-citizen gap varies significantly among different demographic groups, including gender, age, education, monthly household income, area of residence, and occupation. Additionally, education, monthly household income, and area of residence have significant effects on attitudes in the dual role, whereas gender only affect consumer-role attitudes significantly. The findings provide evidence that consumer-citizen gaps in Chinese public attitudes toward farm animal welfare exist, and this distinction is mainly determined by demographic characteristics.

IgA-mediated control of host-microbial interaction during weaning reaction influences gut inflammation.

The mechanisms of how host-microbe mutualistic relationships are established at weaning contingently upon B-cell surveillance remain inadequately elucidated. We found that CD138+ plasmacyte (PC)-mediated promotion of IgA response regulates the symbiosis between Bacteroides uniformis (B. uniformis) and the host during the weaning period. The IgA-skewed response of CD138+ PCs is essential for B. uniformis to occupy a defined gut luminal niche, thereby fostering stable colonization. Furthermore, B. uniformis within the natural gut niche was perturbed in the absence of IgA, resulting in exacerbated gut inflammation in IgA-deficient mice and weaned piglets. Thus, we propose that the priming and maintenance of intestinal IgA response from CD138+ PCs are required for host-microbial symbiosis, whereas the perturbation of which would enhance inflammation in weaning process.

Realizing high-efficiency third harmonic generation via accidental bound states in the continuum.

The bound states in the continuum (BICs) have attracted much attention in designing metasurface due to their high Q-factor and effectiveness in suppressing radiational loss. Here we report on the realization of the third harmonic generation (THG) at a near-ultraviolet wavelength (343 nm) via accidental BICs in a metasurface. The absolute conversion efficiency of the THG reaches 1.13 × 10-5 at a lower peak pump intensity of 0.7 GW/cm2. This approach allows the generation of an unprecedentedly high nonlinear conversion efficiency with simple structures.

Real-world outcomes of first-line maintenance therapy for recurrent or metastatic cervical cancer: A multi-center retrospective study.

BACKGROUND: Maintenance therapy (MT) for recurrent or metastatic cervical cancer remains non-standardized. This study assessed MT effectiveness using a comprehensive approach and identifies prognosis factors inpatients with recurrent or metastatic cervical cancer. METHODS: From January 2019 and December 2021, over 6000 patients from six Chinese institutions were retrospectively examined. Patients had recurrent/metastatic cervical cancer and underwent first-line chemotherapy with or without MT. We calculated overall and progression-free survival using Kaplan-Meier analysis, comparing via log-rank test, and conducted Cox regression for prognostic factors. RESULTS: Overall, 274 patients were stratified into an MT group (n = 77) and a non-MT group (n = 197). The 3-year OS rates were 52.5 % and 28.0 % for the MT and non-MT groups, respectively. The MT group had significantly enhanced median OS (37 vs. 21 months; HR, 0.43; 95 % CI, 0.30-0.61; P < 0.001) and PFS (21 vs. 14 months; HR, 0.65; 95 % CI, 0.47-0.90; P = 0.014) compared with the non-MT group. No significant differences in efficacy were observed among the various MT regimens, whether PD-1 monoclonal antibody, targeted therapeutic agents, or a combination of both. Extended PFS and OS were observed in patients receiving > 8 MT cycles. Multivariate analyses revealed that oligometastasis, MT, exclusive prior surgery (as opposed to combined surgery and radiotherapy), and extended interval before recurrence were independent OS predictors (P = 0.045, P < 0.001, P = 0.010, and P = 0.005, respectively); oligometastasis, concurrent radiotherapy, MT, and extended interval before recurrence were independent PFS predictors (P = 0.004, P = 0.007, P = 0.009, and P = 0.003). CONCLUSIONS: The MT integration markedly extended PFS and OS in patients diagnosed with recurrent or metastatic cervical cancer.