A Multi-Agent RL Algorithm for Dynamic Task Offloading in D2D-MEC Network with Energy Harvesting.

Delay-sensitive task offloading in a device-to-device assisted mobile edge computing (D2D-MEC) system with energy harvesting devices is a critical challenge due to the dynamic load level at edge nodes and the variability in harvested energy. In this paper, we propose a joint dynamic task offloading and CPU frequency control scheme for delay-sensitive tasks in a D2D-MEC system, taking into account the intricacies of multi-slot tasks, characterized by diverse processing speeds and data transmission rates. Our methodology involves meticulous modeling of task arrival and service processes using queuing systems, coupled with the strategic utilization of D2D communication to alleviate edge server load and prevent network congestion effectively. Central to our solution is the formulation of average task delay optimization as a challenging nonlinear integer programming problem, requiring intelligent decision making regarding task offloading for each generated task at active mobile devices and CPU frequency adjustments at discrete time slots. To navigate the intricate landscape of the extensive discrete action space, we design an efficient multi-agent DRL learning algorithm named MAOC, which is based on MAPPO, to minimize the average task delay by dynamically determining task-offloading decisions and CPU frequencies. MAOC operates within a centralized training with decentralized execution (CTDE) framework, empowering individual mobile devices to make decisions autonomously based on their unique system states. Experimental results demonstrate its swift convergence and operational efficiency, and it outperforms other baseline algorithms.

Clinical efficacy and risk factors for suction curettage and hysteroscopy in patients with type I and II cesarean scar pregnancy.

OBJECTIVE: To investigate the clinical efficacy and evaluate risk factors for suction curettage (SC) and hysteroscopy in the treatment of type I and II cesarean scar pregnancy (CSP). METHODS: This was a retrospective study including 100 women diagnosed with type I/II CSP. Patients were treated with either ultrasound-guided SC (SC group) or hysteroscopy resection (surgery group). The success rates, mean operation time, hospitalization duration, hospitalization cost, risk factors, adverse events, and complications were analyzed. RESULTS: The success rate of the SC and surgery groups were 85% and 100%, respectively, and the difference was statistically significant (P = 0.032). There was one case of type I CSP and eight cases of type II CSP that failed SC treatment. No failed cases were found in the surgery group. Analysis of the causes of treatment failure revealed that diameter of the gestational sac was a risk factor for SC failure (odds ratio, 19.66 [95% confidence interval {CI}, 1.70-227.72], P = 0.017). Comparing the clinical outcomes between the SC and surgery groups, although the mean operation time of the SC group was significantly shorter than the surgery group (15 [CI, 15-20] vs. 30 [CI, 27-40], P = 0.001), the cost and duration of hospitalization were significantly lower in the surgery group than that in the SC group. No significant differences were observed for adverse events and complications between the two groups (P > 0.05). CONCLUSION: Hysteroscopy is an effective and economical method for treating type I/II CSP. Moreover, SC is not recommended for patients with type I/II CSP with a gestation age ≥8 weeks.

Efficient Bifunctional Photoelectric Integrated Cathode for Solar Energy Conversion and Storage.

The integrated photoelectric battery serves as a compact and energy-efficient form for direct conversion and storage of solar energy compared to the traditional isolated PV-battery systems. However, combining efficient light harvesting and electrochemical energy storage into a single material is a great challenge. Here, a bifunctional lead phytate-cesium lead bromide (PbPA-CsPbBr3) cathode is explored for the solid-state batteries in terms of CsPbBr3 in situ grown on the PbPA framework. Specifically, CsPbBr3 nanocrystals generate electron-hole pairs under sunlight, the holes contribute to the lithium desorption of the discharged PbPA, and the electrons participate in the formation of the cathode interfacial film through oxygen reduction. The obtained solid-state photoelectric lithium-metal battery achieved a photoconversion efficiency of 0.72%, outperforming other systems under the same lighting conditions. The reasonable cathode design and its application in integrated solid-state batteries provide an efficient way for solar energy utilization.

Physiological and lipidomic response of exogenous choline chloride alleviating salt stress injury in Kentucky bluegrass (Poa pratensis).

Introduction: Choline participates in plant stress tolerance through glycine betaine (GB) and phospholipid metabolism. As a salt-sensitive turfgrass species, Kentucky bluegrass (Poa pratensis) is the main turfgrass species in cool-season areas. Methods: To improve salinity tolerance and investigate the effects of choline on the physiological and lipidomic responses of turfgrass plants under salinity stress conditions, exogenous choline chloride was applied to Kentucky bluegrass exposed to salt stress. Results: From physiological indicators, exogenous choline chloride could alleviate salt stress injury in Kentucky bluegrass. Lipid analysis showed that exogenous choline chloride under salt-stress conditions remodeled the content of phospholipids, glycolipids, and lysophospholipids. Monogalactosyl diacylglycerol, digalactosyl diacylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and lysophosphatidylcholine content were increased and phosphatidic acid content were decreased in plants after exogenous choline chloride under salt treatment. Plant leaf choline content increased, but GB was not detected in exogenous choline chloride treatment plants under nonstress or salt-stress conditions. Discussion: GB synthesis pathway related genes showed no clear change to choline chloride treatment, whereas cytidyldiphosphate-choline (CDP-choline) pathway genes were upregulated by choline chloride treatment. These results reveal that lipid remodeling through choline metabolism plays an important role in the salt tolerance mechanism of Kentucky bluegrass. Furthermore, the lipids selected in this study could serve as biomarkers for further improvement of salt-sensitive grass species.

Association of ambient PM1 exposure with maternal blood pressure and hypertensive disorders of pregnancy in China.

Evidence concerning PM1 exposure, maternal blood pressure (BP), and hypertensive disorders of pregnancy (HDP) is sparse. We evaluated the associations using 105,063 participants from a nationwide cohort. PM1 concentrations were evaluated using generalized additive model. BP was measured according to the American Heart Association recommendations. Generalized linear mixed models were used to assess the PM1-BP/HDP associations. Each 10 µg/m3 higher first-trimester PM1 was significantly associated with 1.696 mmHg and 1.056 mmHg higher first-trimester SBP and DBP, and with 11.4% higher odds for HDP, respectively. The above associations were stronger among older participants (> 35 years) or those educated longer than 17 years or those with higher household annual income (> 400,000 CNY). To conclude, first-trimester PM1 were positively associated with BP/HDP, which may be modified by maternal age, education level, and household annual income. Further research is warranted to provide more information for both health management of HDP and environmental policies enactment.

TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.

The transcription factor p63 guards genome integrity in the female germline, and its mutations have been reported in patients with premature ovarian insufficiency (POI). However, the precise contribution of the TP63 gene to the pathogenesis of POI needs to be further determined. Here, in 1,030 Chinese patients with POI, we identified 6 heterozygous mutations of the TP63 gene that impaired the C-terminal transactivation-inhibitory domain (TID) of the TAp63α protein and resulted in tetramer formation and constitutive activation of the mutant proteins. The mutant proteins induced cell apoptosis by increasing the expression of apoptosis-inducing factors in vitro. We next introduced a premature stop codon and selectively deleted the TID of TAp63α in mice and observed rapid depletion of the p63+/ΔTID mouse oocytes through apoptosis after birth. Finally, to further verify the pathogenicity of the mutation p.R647C in the TID that was present in 3 patients, we generated p63+/R647C mice and also found accelerated oocyte loss, but to a lesser degree than in the p63+/ΔTID mice. Together, these findings show that TID-related variants causing constitutive activation of TAp63α lead to POI by inducing oocyte apoptosis, which will facilitate the genetic diagnosis of POI in patients and provide a potential therapeutic target for extending female fertility.

Influence of group B streptococcus and vaginal cleanliness on the vaginal microbiome of pregnant women.

BACKGROUND: The vaginal microbiome plays a critical role in the health of pregnant women and their newborns. Group B Streptococcus (GBS) and vaginal cleanliness significantly affect the vaginal microecosystem and are closely associated with vaginal diseases. AIM: To explore the effects of GBS status and vaginal cleanliness on vaginal microecosystems. METHODS: We collected 160 vaginal swabs from pregnant women and divided them into the following four groups based on GBS status and vaginal cleanliness: GBS-positive + vaginal cleanliness I-II degree, GBS-negative + vaginal cleanliness I-II degree, GBS-positive + vaginal cleanliness III-IV degree, and GBS-negative + vaginal cleanliness III-IV degree. Samples were subjected to 16S rRNA gene amplicon sequencing. RESULTS: Alpha diversity analysis showed that the Shannon index did not significantly differ between the four groups. We identified significant variation in taxa abundance between the GBS-positive and GBS-negative groups and between the vaginal cleanliness I-II degree and III-IV degree groups. Principal coordinate analysis and non-metric multidimensional scaling analysis further confirmed the microbial diversity of the four groups. Moreover, the linear discriminant analysis demonstrated that Lactobacillus jensenii and Actinobacteria were strongly associated with GBS-positive status, and Lactobacillus iners, Lactobacillaceae, Lactobacillus, Lactobacillales, Bacilli and Firmicutes were closely correlated with GBS-negative status. CONCLUSION: GBS status and vaginal cleanliness significantly affect vaginal microbiome differences in pregnant women. Our findings provide instructional information for clinical antibiotic treatment in pregnant women with different GBS statuses and vaginal cleanliness degrees.

Transcription-replication conflicts in primordial germ cells necessitate the Fanconi anemia pathway to safeguard genome stability.

Preserving a high degree of genome integrity and stability in germ cells is of utmost importance for reproduction and species propagation. However, the regulatory mechanisms of maintaining genome stability in the developing primordial germ cells (PGCs), in which rapid proliferation is coupled with global hypertranscription, remain largely unknown. Here, we find that mouse PGCs encounter a constitutively high frequency of transcription-replication conflicts (TRCs), which lead to R-loop accumulation and impose endogenous replication stress on PGCs. We further demonstrate that the Fanconi anemia (FA) pathway is activated by TRCs and has a central role in the coordination between replication and transcription in the rapidly proliferating PGCs, as disabling the FA pathway leads to TRC and R-loop accumulation, replication fork destabilization, increased DNA damage, dramatic loss of mitotically dividing mouse PGCs, and consequent sterility of both sexes. Overall, our findings uncover the unique source and resolving mechanism of endogenous replication stress during PGC proliferation, provide a biological explanation for reproductive defects in individuals with FA, and improve our understanding of the monitoring strategies for genome stability during germ cell development.

The eight-year long-term follow-up on the effectiveness of the quadrivalent human papillomavirus vaccine in Chinese women 20-45 years of age.

The quadrivalent human papillomavirus (4vHPV) vaccine has shown confirmative effectiveness in preventing HPV-related diseases among women and men around the globe. The phase III, randomized, double-blind efficacy study (Base study, NCT00834106) conducted in China showed 100% efficacy against HPV 16/18-related cervical intraepithelial neoplasia and efficacy against HPV persistent infection for 78 months. Participants aged 20-45 years who received three doses of 4vHPV vaccine or placebo during the base study were selected and invited for this long-term follow-up (LTFU) study to assess the long-term effectiveness of the 4vHPV vaccine in preventing HPV-related diseases. A total of 368 participants were included in this LTFU study with a median follow-up of 94 months. Among 27 participants (Vaccine vs. Placebo: 8 vs. 19) who underwent colposcopy and biopsy due to cervical cytological abnormalities or HPV infection, no HPV-16/18-related cases of cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), or vaginal intraepithelial neoplasia (VaIN) was observed in the vaccine group while two HPV-16-related cases (CIN1/VaIN) were observed in the placebo group. There were another two HPV-related cases (non-vaccine HPV types) found in the placebo group. Consistent with the findings from global studies that suggested long-term efficacy of 4vHPV vaccine, our study showed continued protective effect of 4vHPV vaccine against HPV-related precancerous diseases through a median follow-up time of 94 months with the longest follow-up time of 125 months after completing three doses of vaccination among Chinese women 20-45 years of age.

Mesenchymal stem cells combined with autocrosslinked hyaluronic acid improve mouse ovarian function by activating the PI3K-AKT pathway in a paracrine manner.

BACKGROUND: Declining ovarian function in advance-aged women and in premature ovarian insufficiency (POI) patients seriously affects quality of life, and there is currently no effective treatment to rescue ovarian function in clinic. Stem cell transplantation is a promising therapeutic strategy for ovarian aging, but its clinical application is limited due to the low efficiency and unclear mechanism. Here, a novel combination of umbilical cord-mesenchymal stem cells (UC-MSCs) and autocrosslinked hyaluronic acid (HA) gel is explored to rescue ovarian reserve and fecundity in POI and naturally aging mice. METHODS: To investigate HA prolonged the survival after UC-MSCs transplantation, PCR and immunofluorescence were performed to track the cells on day 1, 3, 7 and 14 after transplantation. The effects of HA on UC-MSCs were analyzed by CCK8 assay, RNA-sequencing and 440 cytokine array. In vivo experiments were conducted to evaluate the therapeutic effects of UC-MSCs combined with HA transplantation in 4-vinylcyclohexene diepoxide (VCD)-induced POI mice and naturally aging mice model. Ovarian function was analyzed by ovarian morphology, follicle counts, estrous cycle, hormone levels and fertility ability. To investigate the mechanisms of stem cell therapy, conditioned medium was collected from UC-MSCs and fibroblast. Both in vitro ovarian culture model and 440 cytokine array were applied to assess the paracrine effect and determine the underlying mechanism. Hepatocyte growth factor (HGF) was identified as an effective factor and verified by HGF cytokine/neutralization antibody supplementation into ovarian culture system. RESULTS: HA not only prolongs the retention of UC-MSCs in the ovary, but also boosts their secretory function, and UC-MSCs promote follicular survival by activating the PI3K-AKT pathway through a paracrine mechanism both in vitro and in vivo. More importantly, HGF is identified as the key functional cytokine secreted by MSCs. CONCLUSIONS: The results show that HA is an excellent cell scaffold to improve the treatment efficiency of UC-MSCs for ovarian aging under both physiological and pathological conditions, and the therapeutic mechanism is through activation of the PI3K-AKT pathway via HGF. These findings will facilitate the clinical application of MSCs transplantation for ovarian disorders.

HGF Secreted by Mesenchymal Stromal Cells Promotes Primordial Follicle Activation by Increasing the Activity of the PI3K-AKT Signaling Pathway.

Primordial follicle activation is fundamental for folliculogenesis and for the maintenance of fertility. An effective therapeutic strategy for patients with premature ovarian insufficiency (POI) is to promote the activation of residual primordial follicles. The secretome of human umbilical cord mesenchymal stromal cells (hUC-MSC-sec) contains several components that might promote the activation of primordial follicles. In the present study, we revealed that treatment with the hUC-MSC-sec significantly increased the proportion of activated primordial follicles in mouse ovaries both in vitro and in vivo. The activating effects of hUC-MSC-sec on primordial follicles were attributed to the activation of the PI3K-AKT signaling pathway by hepatocyte growth factor (HGF). While the effect of the hUC-MSC-sec was attenuated by the neutralizing antibodies against HGF, application of exogenous HGF alone also promoted the activation of primordial follicles. Furthermore, we demonstrated that HGF promoted the expression of KITL in granulosa cells by binding with the HGF receptor c-Met, thereby increasing the activity of the PI3K-AKT signaling pathway to activate primordial follicles. Taken together, our findings demonstrate that hUC-MSC-sec promotes primordial follicle activation through the functional component HGF to increase the PI3K-AKT signaling activity, highlighting the application of the hUC-MSC-sec or HGF for the treatment of POI patients.

The effects of Cl-PFESAs exposure on blood lipids - A community-based large population study in Guangzhou.

Numerous epidemiological studies have investigated the lipid interference effects of legacy PFASs, however, no studies on PFAS alternatives and blood lipids have been published. In this study, we explored the association between Cl-PFESAs, a typical PFASs alternative in China, and blood lipid profiles in 1336 Guangzhou community residents using linear and non-linear regression models. The results showed a deleterious effect of Cl-PFESAs and blood lipids: adjusted estimates (ß) for TC, TG, LDL-C and HDL-C per natural log unit increase of 6:2 Cl-PFESA were 0.029 (95% CI: 0.020, 0.038), 0.075 (95% CI: 0.049, 0.101), 0.035 (95% CI: 0.021, 0.049) and -0.071 (95% CI: -0.084, -0.058), respectively. The association between Cl-PFESAs and dyslipidemia was also positively significant (P < 0.05). Furthermore, a non-linear relationship was observed in Cl-PFESAs and serum lipid levels using a restricted cubic splines (RCS) model. In summary, our research suggested a negative impact of Cl-PFESAs on blood lipid patterns and a possible non-linear association.

Defect Engineering in Metal‒Organic Frameworks as Futuristic Options for Purification of Pollutants in an Aqueous Environment.

Clean water scarcity is becoming an increasingly important worldwide issue. The water treatment industry is demanding the development of novel effective materials. Defect engineering in nanoparticles is among the most revolutionary of technologies. Because of their high surface area, structural diversity, and tailorable ability, Metal‒Organic Frameworks (MOFs) can be used for a variety of purposes including separation, storage, sensing, drug delivery, and many other issues. The application in wastewater treatment associated with water stable MOF‒based materials has been an emerging research topic in recent decades. Defect engineering is a sophisticated technique used to manufacture defects and to change the geometric framework of target compounds. Since MOFs have a series of designable structures and active sites, tailoring properties in MOFs by defect engineering is a novel concept. Defect engineering can excavate hidden active sites in MOFs, which can lead to better performance in many fields. Therefore, this technology will open new opportunities in water purification processes. However, there has been little effort to comprehensively discuss this topic. In this review, we provide an overview of the development of defect engineered MOFs for water purification processes. Furthermore, we discuss the potential applications of defect engineered materials.

Stem Cell Transplantation Improves Ovarian Function through Paracrine Mechanisms.

The ovary serves as the source of oocytes for the maintenance of female fertility and is a major supplier of sex hormones for endocrine homeostasis. Various circumstances such as genetic defects, autoimmune disorders, natural aging and environmental toxins can damage the ovaries leading to diminished ovarian function, and there are currently no effective treatment regimens for such loss of function. Stem cells show promise for treating many refractory diseases, and stem cell transplantation has been shown to be effective and safe as a new therapeutic method for ovarian injuries and ovarian aging in both animal models and women with premature ovarian insufficiency. However, the specific mechanisms that underlie the observed positive outcomes of improving ovarian function are not well understood. Evidence is mounting that stem cell-derived conditioned medium, exosomes, and trophic growth factors can also inhibit ovarian damage and alleviate the age-related fertility decline in female mice, indicating that stem cells exert the paracrine effects. Further studies to elucidate the cellular and molecular mechanisms, including signaling pathways, for improving ovarian function and promoting the secretory capacity of stem cells will fill the bench-to-bedside gap of stem cell therapy in the clinic. Furthermore, in-depth analyses of the stem cell secretome and identification of the key effective components will underlie a new paradigm in cell-free therapeutic strategies for ovarian insufficiency and ovarian aging.

Serum levels of per- and polyfluoroalkyl substances alternatives and blood pressure by sex status: Isomers of C8 health project in China.

Several in vitro and in vivo studies have demonstrated the toxicity of perfluoroalkyl and polyfluoroalkyl substances (PFASs) alternatives, however, relevant epidemiological findings remain to be performed. In addition, the association between PFASs alternatives and blood pressure has not been explored. To address this gap, we quantified serum levels of alternatives and legacy PFAS in 1273 healthy Chinese, aged 34-94 years, from "isomers of C8 health project". Our results showed that an increase of serum PFASs levels was correlated with elevated blood pressure and higher prevalence of hypertension: per natural log unit (ng/mL) increase of 6:2 chlorinated polyfluorinated ether sulfonic acids (Cl-PFESA) elevated 1.31 (95%CI: 0.13, 2.50) mmHg of diastolic pressure (DBP). Adjusted odds ratios (aORs) for hypertension with per natural log increase of 6:2 and 8:2 Cl-PFESA were 2.57 (95%CI: 1.86, 3.56) and 1.18 (95%CI: 1.06, 1.32), respectively. When stratified by sex, the effects of PFASs alternatives on increased blood pressure and hypertension were stronger in women. Meanwhile, the association between 6:2 Cl-PFESA (aOR = 6.81; 95%CI: 3.54, 13.09) and hypertension was stronger than perfluorooctanoic acid (PFOA) (aOR = 2.32, 95%CI: 1.38, 3.91) in women. In conclusion, our pilot study demonstrates that serum concentrations of PFASs alternatives are positively associated with blood pressure. Moreover, women seem to be more susceptible, and alternatives exhibited stronger effects than legacy PFASs.

Adsorption behaviour and mechanism of the PFOS substitute OBS (sodium p-perfluorous nonenoxybenzene sulfonate) on activated carbon.

Perfluorooctane sulfonate (PFOS) was listed as a persistent organic pollutant by the Stockholm Convention. As a typical alternative to PFOS, sodium p-perfluorous nonenoxybenzene sulfonate (OBS) has recently been detected in the aquatic environment which has caused great concern. For the first time, the adsorption behaviour and mechanism of OBS on activated carbon (AC) with different physical and chemical properties were investigated. Decreasing the particle size of AC can accelerate its adsorption for OBS, while AC with too small particle size was not conducive to its adsorption capacity due to the destruction of its pore structure during the mechanical crushing process. Intra-particle diffusion had a lesser effect on the adsorption rate of AC with smaller particle size, higher hydrophilicity and larger pore size. Reactivation of AC by KOH can greatly enlarge their pore size and surface area, greatly increasing their adsorption capacities. The adsorption capacity of two kinds of R-GAC exceeded 0.35 mmol g-1, significantly higher than that of other ACs. However, increasing the hydrophilicity of AC would decrease their adsorption capacities. Further investigation indicated that a larger pore size and smaller particle size can greatly enhance the adsorptive removal of OBS on AC in systems with other coexisting PFASs and organic matter due to the reduction of the pore-blocking effect. The spent AC can be successfully regenerated by methanol, and it can be partly regenerated by hot water and NaOH solution. The percentage of regeneration for the spent AC was 70.4% with 90°C water temperature and up to 95% when 5% NaOH was added into the regeneration solution. These findings are very important for developing efficient adsorbents for the removal of these newly emerging PFASs from wastewater and understanding their interfacial behaviour.

Novel insights into the competitive adsorption behavior and mechanism of per- and polyfluoroalkyl substances on the anion-exchange resin.

Per- and polyfluoroalkyl substances (PFASs) are widely used and co-exist in various aquatic environments, but their co-removal is not clear. In this study, the competitive adsorption behavior and mechanism of six traditional and emerging PFASs on anion-exchange resin IRA67 in the bisolute and mixed systems were studied. The adsorption equilibrium of the long-chain PFASs was at least 96 h whereas 48 h was required for the short-chain PFASs. When the PFASs were co-removed in the bisolute system, their competition was not obvious at low PFAS concentration of 0.01597 mmol/L due to the relatively adequate adsorption sites. When the concentrations of PFASs were increased to 0.07666 mmol/L, the removal of perfluorobutanoic acid (PFBA) and perfluorobutane sulfonate (PFBS) decreased by 77.78% and 72.09%, respectively. The competitive experiments showed that the adsorbed short-chain PFASs could be replaced by the long-chain ones, which was closely related to their hydrophobicity, backbone and functional groups. With the increase of solution pH from 3 to 7, the polyamine groups on the resin IRA67 were transferred to the base forms and the effective adsorption sites decreased, resulting in a more obvious competitive replacement behavior. This study suggested that the PFASs with long chain could be more effectively removed from the coexisting PFASs solution by the anion-exchange resins, and the short-chain PFASs in water may be removed when high dosage of anion-exchange resins is applied or the solution pH is decreased.

Effect of periconceptional folic acid supplementation on the risk of neural tube defects associated with a previous spontaneous abortion or maternal first-trimester fever.

STUDY QUESTION: Does maternal periconceptional no folic acid supplementation have an increased risk of neural tube defects (NTDs) associated with previous spontaneous abortion or first-trimester fever? SUMMARY ANSWER: Maternal periconceptional no folic acid supplementation can increase the risk of NTDs associated with previous spontaneous abortion or first-trimester fever, independent of known confounding factors. WHAT IS KNOWN ALREADY: Maternal periconceptional folic acid deficiency can increase the risk of NTDs. However, whether an interaction between periconceptional no folic acid supplementation and history of spontaneous abortion or first-trimester fever may have an increased risk of NTDs remains unknown. STUDY DESIGN, SIZE, DURATION: A population-based case-control study was performed including 104 nuclear families with offspring with NTDs and 100 control families with normal offspring between 1993 and 2002. PARTICIPANTS/MATERIALS, SETTING, METHODS: We investigated the potential interaction between periconceptional no folic acid use and a maternal history of spontaneous abortion or first-trimester fever in the risk for NTDs. Information on exposure factors was obtained at the onset of pregnancy, and pregnancy outcomes were collected during the first week after delivery or at the time of termination of the pregnancy. A multivariate logistic regression analysis was performed. MAIN RESULTS AND THE ROLE OF CHANCE: The interaction between periconceptional no folic acid use and a maternal history of spontaneous abortion markedly increased the risk of NTDs (adjusted odds ratio (aOR) 18.68, 95% CI, 4.43-78.76) after adjusting for potential confounding factors. The interaction coefficient was found to be 2.08, higher than 1, indicating that there is a significant interaction between two factors. Mothers who did not take periconceptional folic acid and had first-trimester fever had an increased risk of NTDs (aOR 21.81, 95% CI, 8.81-80.73). However, the interaction coefficient was found to be 0.62, less than 1, indicating that there is no significant interaction between two factors. LIMITATIONS, REASONS FOR CAUTION: A potential limitation was that the interval between the previous spontaneous abortion and the beginning of the subsequent pregnancy could not be estimated accurately, but was at least 1 year or more. WIDER IMPLICATIONS OF THE FINDINGS: We emphasize that a previous spontaneous abortion may represent a first occurrence of NTDs rather than be the cause of NTDs. Our findings indicate that mothers with a history of spontaneous abortion are ideal candidates for periconceptional folic acid supplementation. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by National Natural Science Foundation of China (41871360) and Danone Nutrition Center for Dietary Nutrition Research and Education Foundation (DIC2015-05). There are no competing interests to declare.

Proteomic analysis of the effects of cell culture density on the metastasis of breast cancer cells.

Cancer cell progression and proliferation increase cell density, resulting in changes to the tumour site, including the microenvironment. What is not known is if increased cell density influences the aggressiveness of cancer cells, especially their proliferation, migration, and invasion capabilities. In this study, we found that dense cell culture enhances the aggressiveness of the metastatic cancer cell lines, 4T1 and ZR-75-30, by increasing their proliferation, migration, and invasion capabilities. However, a less metastatic cell line, MCF-7, did not show an increase in aggressiveness, following dense cell culture conditions. We conducted a differential proteomic analysis on 4T1 cells cultured under dense or sparse conditions and identified an increase in expression for proteins involved in migration, including focal adhesion, cytoskeletal reorganization, and transendothelial migration. In contrast, 4T1 cells grown under sparse conditions had higher expression levels for proteins involved in metabolism, including lipid and phospholipid binding, lipid and cholesterol transporter activity, and protein binding. These results suggest that the high-density tumour microenvironment can cause a change in cellular behaviour, leading towards more aggressive cancers. SIGNIFICANCE OF THE STUDY: Metastasis of cancer cells is an obstacle to the clinical treatment of cancer. We found that dense cultures made metastatic cancer cells more potent in terms of proliferation, migration, and invasion. The proteomic and bioinformatic analyses provided some valuable clues for further intensive studies about the effects of cell density on cancer cell aggressiveness, which were associated with events such as pre-mRNA splicing and RNA transport, focal adhesion and cytoskeleton reorganization, ribosome biogenesis, and transendothelial migration, or associated with proteins, such as JAM-1 and S100A11. This investigation gives us new perspectives to investigate the metastasis mechanisms related to the microenvironment of tumour sites.