History of tuberculosis disease is associated with genetic regulatory variation in Peruvians.

A quarter of humanity is estimated to have been exposed to Mycobacterium tuberculosis (Mtb) with a 5-10% risk of developing tuberculosis (TB) disease. Variability in responses to Mtb infection could be due to host or pathogen heterogeneity. Here, we focused on host genetic variation in a Peruvian population and its associations with gene regulation in monocyte-derived macrophages and dendritic cells (DCs). We recruited former household contacts of TB patients who previously progressed to TB (cases, n = 63) or did not progress to TB (controls, n = 63). Transcriptomic profiling of monocyte-derived DCs and macrophages measured the impact of genetic variants on gene expression by identifying expression quantitative trait loci (eQTL). We identified 330 and 257 eQTL genes in DCs and macrophages (False Discovery Rate (FDR) < 0.05), respectively. Four genes in DCs showed interaction between eQTL variants and TB progression status. The top eQTL interaction for a protein-coding gene was with FAH, the gene encoding fumarylacetoacetate hydrolase, which mediates the last step in mammalian tyrosine catabolism. FAH expression was associated with genetic regulatory variation in cases but not controls. Using public transcriptomic and epigenomic data of Mtb-infected monocyte-derived dendritic cells, we found that Mtb infection results in FAH downregulation and DNA methylation changes in the locus. Overall, this study demonstrates effects of genetic variation on gene expression levels that are dependent on history of infectious disease and highlights a candidate pathogenic mechanism through pathogen-response genes. Furthermore, our results point to tyrosine metabolism and related candidate TB progression pathways for further investigation.

Urinary eicosanoid levels in early life and risk of atopic disease in childhood.

BACKGROUND: Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs), and leukotrienes with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. This study aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. METHODS: This study quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) (age 1 year, n = 450) and VDAART (Vitamin D Antenatal Asthma Reduction Trial) (age 3 years, n = 575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of type-2 inflammation, applying false discovery rate of 5% (FDR5%) multiple testing correction. RESULTS: In both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P < FDR5%) and type-2 inflammation (P < .05). In VDAART, lower PGE2 and PGI2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P < FDR5%). For wheeze/asthma, analyses in COPSAC2010 showed that lower isoprostanes and PGF2 eicosanoids and higher PGD2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (P < .05), whereas analyses in VDAART showed that lower PGE2 and higher TXA2 eicosanoids at age 3 years associated with an increased risk at 6 years (P < FDR5%). CONCLUSIONS: This study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.

High-Fidelity Sensitive Tracing Circulating Tumor Cell Telomerase Activity.

Dynamic tracing of intracellular telomerase activity plays a crucial role in cancer cell recognition and correspondingly in earlier cancer diagnosis and personalized precision therapy. However, due to the complexity of the required reaction system and insufficient loading of reaction components into cells, achieving a high-fidelity determination of telomerase activity is still a challenge. Herein, an Aptamer-Liposome mediated Telomerase activated poly-Molecular beacon Arborescent Nanoassembly(ALTMAN) approach was described for direct high-fidelity visualization of telomerase activity. Briefly, intracellular telomerase activates molecular beacons, causing their hairpin structures to unfold and produce fluorescent signals. Furthermore, multiple molecular beacons can self-assemble, forming arborescent nanostructures and leading to exponential amplification of fluorescent signals. Integrating the enzyme-free isothermal signal amplification successfully increased the sensitivity and reduced interference by leveraging the skillful design of the molecular beacon and the extension of the telomerase-activated TTAGGG repeat sequence. The proposed approach enabled ultrasensitive visualization of activated telomerase exclusively with a prominent detection limit of 2 cells·µL-1 and realized real-time imaging of telomerase activity in living cancer cells including blood samples from breast cancer patients and urine samples from bladder cancer patients. This approach opens an avenue for establishing a telomerase activity determination and in situ monitoring technique that can facilitate both telomerase fundamental biological studies and cancer diagnostics.

Vitrification preservation of good-quality blastocysts for more than 5 years reduces implantation and live birth rates.

STUDY QUESTION: Does vitrification cryopreservation of embryos for more than 5 years affect the pregnancy outcomes after frozen embryo transfer (FET)? SUMMARY ANSWER: Vitrification cryopreservation of good-quality blastocysts for more than 5 years is associated with a decrease in the implantation rate (IR) and live birth rate (LBR). WHAT IS KNOWN ALREADY: Previous studies have predominantly focused on embryos cryopreserved for relatively short durations (less than 5 years), yet the impact of extended cryopreservation duration on pregnancy outcomes remains a controversial issue. There is a relative scarcity of data regarding the efficacy and safety of storing embryos for 5 years or longer. STUDY DESIGN, SIZE, DURATION: This retrospective study involved 36 665 eligible vitrified-thawed embryo transfer cycles from 1 January 2016 to 31 December 2022, at a single fertility center in China. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were divided into three groups according to embryo storage time: Group 1 consisted of 31 565 cycles, with storage time of 0-2 years; Group 2 consisted of 4458 cycles, with a storage time of 2-5 years; and Group 3 included 642 cycles, with storage time exceeding 5 years. The main outcome measures were IR and LBR. Secondary outcome variables included rates of biochemical pregnancy, multiple pregnancy, ectopic pregnancy, and miscarriage, as well as neonatal outcomes. Reproductive outcomes were analyzed as binary variables. Multivariate logistic regression analysis was used to explore the effect of preservation time on pregnancy outcomes after correcting for confounding factors. In addition, we also assessed neonatal outcomes, such as large for gestational age (LGA) and small for gestational age (SGA). MAIN RESULTS AND THE ROLE OF CHANCE: IRs in the three groups (0-2, 2-5, and >5 years) were 37.37%, 39.03%, and 35.78%, respectively (P = 0.017), and LBRs in the three groups were 37.29%, 39.09%, and 34.91%, respectively (P = 0.028). After adjustment for potential confounding factors, compared with the 0-2 years storage group, prolonged embryo vitrification preservation time (2-5 years or >5 years) did not affect secondary outcomes such as rates of biochemical pregnancy, multiple pregnancy, ectopic pregnancy, and miscarriage (P > 0.05). But cryopreservation of embryos for more than 5 years reduced the IR (adjusted odds ratio (aOR) 0.82, 95% CI 0.69-0.97, P = 0.020) and LBR (aOR 0.76, 95% CI 0.64-0.91, P = 0.002). Multivariate stratified analysis also showed that prolonging the cryopreservation time of blastocysts (>5 years) reduced the IR (aOR 0.78, 95% CI 0.62-0.98, P = 0.033) and LBR (aOR 0.68, 95% CI 0.53-0.87, P = 0.002). However, no effect on cleavage embryos was observed (P > 0.05). We further conducted stratified analyses based on the number and quality of frozen blastocysts transferred, and the results showed that the FET results after transfers of good-quality blastocysts in the >5 years storage group were negatively affected. However, the storage time of non-good-quality blastocysts was not significantly associated with pregnancy outcomes. Regarding the neonatal outcomes (of singletons), embryo vitrification preservation time had no effect on preterm birth rates, fetal birth weight, or neonatal sex ratios. However, as the storage time increased, rates of SGA (5.60%, 4.10%, and 1.18%) decreased, while rates of LGA (5.22%, 6.75%, and 9.47%) increased (P < 0.05). After adjusting for confounding factors, the increase in LGA and the decrease in SGA were significantly correlated with the duration of storage time. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective study using data from a single fertility center, even though the data had been adjusted, our findings still need to be validated in further studies. WIDER IMPLICATIONS OF THE FINDINGS: With the full implementation of the two-child policy in China, there may be more patients whose embryos have been frozen for a longer time in the future. Patients should be aware that the IR and LBR of blastocysts are negatively affected when the cryopreservation time is longer than 5 years. Couples may therefore consider shortening the time until FET treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Nature Science Foundation of China (No. 82101672), Science and Technology Projects in Guangzhou (No. 2024A03J0180), General Guidance Program for Western Medicine of Guangzhou Municipal Health Commission (No. 20231A011096), and the Medical Key Discipline of Guangzhou (2021-2023). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Visible Light-Mediated Late-Stage Thioetherification of Mercaptopurine Derivatives.

We disclose herein a novel and general radical approach to alkylthiopurines, encompassing 4 types of thiopurines, as well as their corresponding ribosides. This strategy is achieved through visible light-mediated late-stage functionalization of the sulfur atoms of mercaptopurines. The in situ-generated disulfide was proposed as the pivotal neutral intermediate for this transformation. We present herein a novel photo-mediated homolytic C-S bond formation for the preparation of alkylthiopurines and alkylthiopurine nucleosides. Despite the presence of reactive sites for the Minisci reaction, chemoselective S-alkylation remained the predominant pathway. This method allows for the late-stage introduction of a broad spectrum of alkyl groups onto the sulfur atom of unprotective mercaptopurine derivatives, encompassing 2-, 6-, and 8-mercaptopurine rings. Organoborons serve as efficient and eco-friendly alkylating reagents, providing advantages in terms of readily availability, stability, and reduced toxicity. Further derivatization of the thioetherified nucleosides, together with anti-tumor assays, led to the discovery of potent anti-tumor agents with an IC50 value reaching 6.1 µM (Comp. 31 for Jurkat).

Efficient hydrodeoxygenation of lignin-derived phenolic compounds over bifunctional catalyst comprising H4PMo11VO40 coupled with Ni/C.

In the catalytic transformation of bio-oil into liquid fuels having alkanes via hydrodeoxygenation (HDO), the acid and metal sites in the catalyst are pivotal for promoting the HDO of lignin-derived phenolic compounds. This study introduces a novel bifunctional catalyst comprising phosphomolybdenum-vanadium heteropolyacids (H4PMo11VO40) coupled with Ni/C. The HDO reaction of the model compound guaiacol was carried out under reaction conditions of 230 °C, revealing the superior performance of H4PMo11VO40 with Ni/C catalysts compared to the conventional acids, even at low dosage. The Keggin structure of H4PMo11VO40 provided a solid catalyst with strong acidic and redox properties, alongside advantages such as ease of synthesis, cost-effectiveness, and tunable acid and redox properties at the molecular level. Characterization of Ni/C and the prepared acid demonstrated favorable pore structure with a mesopore volume of 0.281 cm3/g and an average pore size of 3.404 nm, facilitating uniform distribution and catalytic activity of Ni-metal. Incorporating acid enhances the acidic sites, fostering synergistic interactions between metal and acidic sites within the catalyst, thereby significantly enhancing HDO performance. Guaiacol conversion at 230 °C reached 100%, with a cyclohexane selectivity of 89.3%. This study presents a promising pathway for converting lignin-derived phenolic compounds.

Novel [68Ga/177Lu]Ga/Lu-AZ-093 as PSMA-Targeting Agent for Diagnosis and Radiotherapy.

Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously, [68Ga]Ga-P16-093, containing a Ga(III) chelator, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), displayed excellent PSMA-targeting properties and showed a high tumor uptake and retention useful for diagnosis in prostate cancer patients. Recently, [177Lu]Lu-PSMA-617 has been approved by the U.S. food and drug administration (FDA) for the treatment of prostate cancer patients. Derivatives of PSMA-093 using AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), as the chelator, were designed as alternative agents forming complexes with both diagnostic and therapeutic radiometals, such as gallium-68 (log K = 22.18) or lutetium-177 (log K = 21.85). The aim of this study is to evaluate AAZTA-Gly-O-(methylcarboxy)-Tyr-Phe-Lys-NH-CO-NH-Glu (designated as AZ-093, 1) leading to a gallium-68/lutetium-177 theranostic pair as potential PSMA targeting agents. Synthesis of the desired precursor, AZ-093, 1, was effectively accomplished. Labeling with either [68Ga]GaCl3 or [177Lu]LuCl3 in a sodium acetate buffer solution (pH 4-5) at 50 °C in 5 to 15 min produced either [68Ga]Ga-1 or [177Lu]Lu-1 with high yields and excellent radiochemical purities. Results of in vitro binding studies, cell uptake, and retention (using PSMA-positive prostate carcinoma cells line, 22Rv1-FOLH1-oe) were comparable to that of [68Ga]Ga-P16-093 and [177Lu]Lu-PSMA-617, respectively. Specific cellular uptake was determined with or without the competitive blocking agent (2 µM of "cold" PSMA-11). Cellular binding and internalization showed a time-dependent increase over 2 h at 37 °C in the PSMA-positive cells. The cell uptakes were completely blocked by the "cold" PSMA-11 suggesting that they are competing for the same PSMA binding sites. In the mouse model with implanted PSMA-positive tumor cells, both [68Ga]Ga-1 and [177Lu]Lu-1 displayed excellent uptake and retention in the tumor. Results indicate that [68Ga]Ga/[177Lu]Lu-1 (68Ga]Ga/[177Lu]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.

A sonographic endometrial thickness <7 mm in women undergoing in vitro fertilization increases the risk of placenta accreta spectrum.

BACKGROUND: The prevalence of placenta accreta spectrum, a potentially life-threatening condition, has exhibited a significant global rise in recent decades. Effective screening methods and early identification strategies for placenta accreta spectrum could enable early treatment and improved outcomes. Endometrial thickness plays a crucial role in successful embryo implantation and favorable pregnancy outcomes. Extensive research has been conducted on the impact of endometrial thickness on assisted reproductive technology cycles, specifically in terms of pregnancy rates, live birth rates, and pregnancy loss rates. However, limited knowledge exists regarding the influence of endometrial thickness on placenta accreta spectrum. OBJECTIVE: This study aimed to evaluate the association between preimplantation endometrial thickness and the occurrence of placenta accreta spectrum in women undergoing assisted reproductive technology cycles. STUDY DESIGN: A total of 4637 women who had not undergone previous cesarean delivery and who conceived by in vitro fertilization or intracytoplasmic sperm injection-embryo transfer treatment and subsequently delivered at the Third Affiliated Hospital of Guangzhou Medical University between January 2008 and December 2020 were included in this study. To explore the relationship between endometrial thickness and placenta accreta spectrum, we used smooth curve fitting, threshold effect, and saturation effect analysis. Multivariate logistic regression analysis was performed to evaluate the independent association between endometrial thickness and placenta accreta spectrum while adjusting for potential confounding factors. Propensity score matching was performed to reduce the influence of bias and unmeasured confounders. Furthermore, we used causal mediation effect analysis to investigate the mediating role of endometrial thickness in the relationship between gravidity and ovarian stimulation protocol and the occurrence of placenta accreta spectrum. RESULTS: Among the 4637 women included in this study, pregnancies with placenta accreta spectrum (159; 3.4%) had significantly thinner endometrial thickness (non-placenta accreta spectrum, 10.08±2.04 mm vs placenta accreta spectrum, 8.88±2.21 mm; P<.001) during the last ultrasound before embryo transfer. By using smooth curve fitting, it was found that changes in endometrial thickness had a significant effect on the incidence of placenta accreta spectrum up to a thickness of 10.9 mm, beyond which the effect plateaued. Then, the endometrial thickness was divided into the following 4 groups: ≤7, >7 to ≤10.9, >10.9 to ≤13, and >13 mm. The absolute rates of placenta accreta spectrum in each group were 11.91%, 3.73%, 1.35%, and 2.54%, respectively. Compared with women with an endometrial thickness from 10.9 to 13 mm, the odds of placenta accreta spectrum increased from an adjusted odds ratio of 2.27 (95% confidence interval, 1.33-3.86) for endometrial thickness from 7 to 10.9 mm to an adjusted odds ratio of 7.15 (95% confidence interval, 3.73-13.71) for endometrial thickness <7 mm after adjusting for potential confounding factors. Placenta previa remained as an independent risk factor for placenta accreta spectrum (adjusted odds ratio, 11.80; 95% confidence interval, 7.65-18.19). Moreover, endometrial thickness <7 mm was still an independent risk factor for placenta accreta spectrum (adjusted odds ratio, 3.91; 95% confidence interval, 1.57-9.73) in the matched cohort after PSM. Causal mediation analysis revealed that approximately 63.9% of the total effect of gravidity and 18.6% of the total effect of ovarian stimulation protocol on placenta accreta spectrum were mediated by endometrial thickness. CONCLUSION: The findings of our study indicate that thin endometrial thickness is an independent risk factor for placenta accreta spectrum in women without previous cesarean delivery undergoing assisted reproductive technology treatment. The clinical significance of this risk factor is slightly lower than that of placenta previa. Furthermore, our results demonstrate that endometrial thickness plays a significant mediating role in the relationship between gravidity or ovarian stimulation protocol and placenta accreta spectrum.

Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway.

Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Through the integration and analysis of transcriptomic data from various CD databases, we found that the expression of AQP9 was significantly increased in anti-TNF therapy-resistant specimens. The response to anti-TNF therapy in the CD mouse model was significantly enhanced by specifically inhibiting AQP9. Further experiments found that the blockade of AQP9, which is dominantly expressed in macrophages, decreased inflamed macrophage functions and cytokine expression. Mechanistic studies revealed that AQP9 transported glycerol into macrophages, where it was metabolized to LPA, which was further metabolized to LPA, resulting in the activation of the LPAR2 receptor and downstream hippo pathway, finally promoting the expression of cytokines, especially IL23 and IL1ß⊡ Taken together, the expansion of AQP9+ macrophages is associated with resistance to anti-TNF therapy in Crohn's disease. These findings indicated that AQP9 could be a potential target for enhancing anti-TNF therapy in Crohn's disease.

Cytokinetic engineering enhances the secretory production of recombinant human lysozyme in Komagataella phaffii.

BACKGROUND: Human lysozyme (hLYZ) is a natural antibacterial protein with broad applications in food and pharmaceutical industries. Recombinant production of hLYZ in Komagataella phaffii (K. phaffii) has attracted considerable attention, but there are very limited strategies for its hyper-production in yeast. RESULTS: Here through Atmospheric and Room Temperature Plasma (ARTP)-based mutagenesis and transcriptomic analysis, the expression of two genes MYO1 and IQG1 encoding the cytokinesis core proteins was identified downregulated along with higher hLYZ production. Deletion of either gene caused severe cytokinesis defects, but significantly enhanced hLYZ production. The highest hLYZ yield of 1,052,444 ± 23,667 U/mL bioactivity and 4.12 ± 0.11 g/L total protein concentration were obtained after high-density fed-batch fermentation in the Δmyo1 mutant, representing the best production of hLYZ in yeast. Furthermore, O-linked mannose glycans were characterized on this recombinant hLYZ. CONCLUSIONS: Our work suggests that cytokinesis-based morphology engineering is an effective way to enhance the production of hLYZ in K. phaffii.

Sleep Deprivation Induces Gut Damage via Ferroptosis.

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.

Exploring the effects of Hippo signaling pathway on rumen epithelial proliferation.

BACKGROUND: The current understanding to the mechanism of rumen development is limited. We hypothesized that the Hippo signaling pathway controlled the proliferation of rumen epithelium (RE) during postnatal development. In the present study, we firstly tested the changes of the Hippo signaling pathway in the RE during an early growing period from d5 to d25, and then we expanded the time range to the whole preweaning period (d10-38) and one week post weaning (d45). An in vitro experiment was also carried out to verify the function of Hippo signaling pathway during RE cell proliferation. RESULTS: In the RE of lambs from d5 to d25, the expression of baculoviral IAP repeat containing (BIRC3/5) was increased, while the expressions of large tumor suppressor kinase 2 (LATS2), TEA domain transcription factor 3 (TEAD3), axin 1 (AXIN1), and MYC proto-oncogene (MYC) were decreased with rumen growth. From d10 to d38, the RE expressions of BIRC3/5 were increased, while the expressions of LATS2 and MYC were decreased, which were similar with the changes in RE from d5 to d25. From d38 to d45, different changes were observed, with the expressions of LATS1/2, MOB kinase activator 1B (MOB1B), and TEAD1 increased, while the expressions of MST1 and BIRC5 decreased. Correlation analysis showed that during the preweaning period, the RE expressions of BIRC3/5 were positively correlated with rumen development variables, while LAST2 was negatively correlated with rumen development variables. The in vitro experiment validated the changes of LATS2 and BIRC3/5 in the proliferating RE cells, which supported their roles in RE proliferation during preweaning period. CONCLUSIONS: Our results suggest that the LATS2-YAP1-BIRC3/5 axis participates in the RE cell proliferation and promotes rumen growth during the preweaning period.

Epithelial cells derived exosomal miR-203a-3p facilitates stromal inflammation of type IIIA chronic prostatitis/chronic pelvic pain syndrome by targeting DUSP5 and increasing MCP-1 generation.

Increased proinflammatory cytokines and infiltration of inflammatory cells in the stroma are important pathological features of type IIIA chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS-A), and the interaction between stromal cells and other cells in the inflammatory microenvironment is closely related to the inflammatory process of CP/CPPS-A. However, the interaction between stromal and epithelial cells remains unclear. In this study, inflammatory prostate epithelial cells (PECs) released miR-203a-3p-rich exosomes and facilitated prostate stromal cells (PSCs) inflammation by upregulating MCP-1 expression. Mechanistically, DUSP5 was identified as a novel target gene of miR-203a-3p and regulated PSCs inflammation through the ERK1/2/MCP-1 signaling pathway. Meanwhile, the effect of exosomes derived from prostatic fluids of CP/CPPS-A patients was consistent with that of exosomes derived from inflammatory PECs. Importantly, we demonstrated that miR-203a-3p antagomirs-loaded exosomes derived from PECs targeted the prostate and alleviated prostatitis by inhibiting the DUSP5-ERK1/2 pathway. Collectively, our findings provide new insights into underlying the interaction between PECs and PSCs in CP/CPPS-A, providing a promising therapeutic strategy for CP/CPPS-A.

Accuracy of MRI-Based Radiomics in Diagnosis of Placenta Accreta Spectrum: A PRISMA Systematic Review and Meta-Analysis.

BACKGROUND Placenta accreta syndrome (PAS) can lead to severe obstetric bleeding, and can be life-threatening. This study aimed to assess the precision of radiomics features derived from magnetic resonance imaging (MRI) for diagnosing PAS. MATERIAL AND METHODS A comprehensive search was conducted in the databases PubMed, Embase, Web of Science, and the Cochrane library from inception to October 2023. We included diagnostic accuracy studies utilizing radiomics-MRI in PAS patients, with histopathology serving as the reference standard. The overall diagnostic odds ratio (DOR), sensitivity, specificity, and area under the curve (AUC) were computed to gauge the diagnostic accuracy of MRI-based radiomic features in PAS patients. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies 2. Statistical analyses were carried out using Stata 14.2, MetaDiSc 1.4, and Review Manager 5.3 software. RESULTS Seven studies involving 672 patients were incorporated. The aggregated DOR, sensitivity, specificity, and AUC for radiomics in detecting PAS were 78% (confidence interval32, 191), 87% (76%, 93%), 92% (89%, 94%), and 0.93 (0.91-0.95), respectively. The meta-analysis revealed notable heterogeneity among the included studies, with no evidence of a threshold effect. Subgroup analysis demonstrated that, in comparison to manual segmentation and validation groups with ≤100 cases and internal validation datasets, automated segmentation, validation groups with >100 cases, and external validation datasets exhibited superior diagnostic performance . CONCLUSIONS Our findings indicate that MRI-based radiomic features perform well in assessing the diagnostic risk of PAS during prenatal diagnosis. This noninvasive and convenient tool may prove valuable in facilitating the identification of PAS.

Mediating effect of menopausal symptoms between the lifestyle and depressive symptoms.

PURPOSE: This study aimed to explore relationship between lifestyle and depressive symptoms and evaluated the mediating effect of menopausal symptoms. METHODS: This was a secondary analysis of a survey in Hunan Province, China. We selected 3190 women aged 40 to 55 into final analyses. Menopausal and depressive symptoms were assessed by the Kupperman Menopausal Index and the 9-item Patient Health Questionnaire, respectively. A self-administered questionnaire was used to collect demographic and lifestyle information. RESULTS: The prevalence of depressive symptoms was 19.5%. After adjusting for demographic variables, passive smoking, drinking, and intensity of physical activity were positively associated with depressive symptoms. Frequency of exercise was a protective factor for depressive symptoms (AOR = 0.783, 95%CI: 0.446-0.991). Excess or restricted sleep duration was associated with higher probability of having depressive symptoms (AOR = 1.746, 95% CI: 1.324-2.304). Menopausal symptoms partially mediated the relationship between lifestyle and depressive symptoms. CONCLUSION: Findings highlighted the importance of menopausal symptoms in the relationship between the lifestyle and depressive symptoms, and provided a possibility that active lifestyle might improve depression symptoms among women at perimenopause through changes in sex hormones.

Whole-genome resequencing reveals diversity and selective signals in the Wuxue goat.

Animal genetic resources are crucial for ensuring global food security. However, in recent years, a noticeable decline in the genetic diversity of livestock has occurred worldwide. This decline is pronounced in developing countries, where the management of these resources is insufficient. In the current study, we performed whole genome sequencing for 20 Wuxue (WX) and five Guizhou White (GW) goats. Additionally, we utilized the published genomes of 131 samples representing five different goat breeds from various regions in China. We investigated and compared the genetic diversity and selection signatures of WX goats. Whole genome sequencing analysis of the WX and GW populations yielded 120 425 063 SNPs, which resided primarily in intergenic and intron regions. Population genetic structure revealed that WX exhibited genetic resemblance to GW, Chengdu Brown, and Jintang Black and significant differentiation from the other goat breeds. In addition, three methods (nucleotide diversity, linkage disequilibrium decay, and runs of homozygosity) showed moderate genetic diversity in WX goats. We used nucleotide diversity and composite likelihood ratio methods to identify within-breed signatures of positive selection in WX goats. A total of 369 genes were identified using both detection methods, including genes related to reproduction (GRID2, ZNF276, TCF25, and SPIRE2), growth (HMGA2 and GJA3), and immunity (IRF3 and SRSF3). Overall, this study explored the adaptability of WX goats, shedding light on their genetic richness and potential to thrive in challenges posed by climatic changes and diseases. Further investigations are warranted to harness these insights to enhance more efficient and sustainable goat breeding initiatives.

Factors Affecting the Situational Awareness of Armored Vehicle Occupants.

In the field of armored vehicles, up to 70% of accidents are associated with low levels of situational awareness among the occupants, highlighting the importance of situational awareness in improving task performance. In this study, we explored the mechanisms influencing situational awareness by simulating an armored vehicle driving platform with 14 levels of experimentation in terms of five factors: experience, expectations, attention, the cueing channel, and automation. The experimental data included SART and SAGAT questionnaire scores, eye movement indicators, and electrocardiographic and electrodermal signals. Data processing and analysis revealed the following conclusions: (1) Experienced operators have higher levels of situational awareness. (2) Operators with certain expectations have lower levels of situational awareness. (3) Situational awareness levels are negatively correlated with information importance affiliations and the frequency of anomalous information in non-primary tasks. (4) Dual-channel cues lead to higher levels of situational awareness than single-channel cues. (5) Operators' situational awareness is lower at high automation levels.

ACEK Biosensor for the Minute-Scale Quantification of Breast Cancer ctDNA.

Circulating tumor DNA (ctDNA) appears as a valuable liquid biopsy biomarker in the early diagnosis, treatment, and prognosis of cancer. Here, a biosensing method derived from the AC electrokinetics (ACEK) effect was constructed in this study for the simple, efficient, and rapid method of detection of ctDNA. In the proof-of-concept experiment, ctDNA from the PIK3CA E542K mutant in breast cancer was quantified by detecting a normalized capacitance change rate using a forked-finger gold electrode as the sensing electrode in combination with the ACEK effect. We compared two formats for the construction of the approach by employing varied immobilization strategies; one is to immobilize the DNA capture probe on the electrode surface by Au-S bonding, while the other immobilizes the probe on a self-assembled membrane on the electrode surface by amide bonding. Both formats demonstrated ultrafast detection speed by completing the ctDNA quantification within 1 min and a linear range of 10 fM-10 pM was observed. Meanwhile, the immobilization via the self-assembled membrane yielded improved stability, sensitivity, and specificity than its Au-S bonding counterpart. A detection limit of 1.94 fM was eventually achieved using the optimized approach. This research provides a label-free and minute-scale universal method for the detection of various malignant tumors. The ctDNA biosensors based on the ACEK effect improved according to the probe type or electrode structure and have potential applications in tumor drug efficacy prediction, drug resistance monitoring, screening of high-risk groups, differential diagnosis, monitoring of tiny residual lesions, and prognosis determination.

Dietary supplements: clinical cholesterol-lowering efficacy and potential mechanisms of action.

This review aims to analyse the efficacy of dietary supplements in reducing plasma cholesterol levels. Focusing on evidence from meta-analyses of randomised controlled clinical trials, with an emphasis on potential mechanisms of action as supported by human, animal, and cell studies. Certain dietary supplements including phytosterols, berberine, viscous soluble dietary fibres, garlic supplements, soy protein, specific probiotic strains, and certain polyphenol extracts could significantly reduce plasma total and low-density lipoprotein (LDL) cholesterol levels by 3-25% in hypercholesterolemic patients depending on the type of supplement. They tended to be more effective in reducing plasma LDL cholesterol level in hypercholesterolemic individuals than in normocholesterolemic individuals. These supplements worked by various mechanisms, such as enhancing the excretion of bile acids, inhibiting the absorption of cholesterol in the intestines, increasing the expression of hepatic LDL receptors, suppressing the activity of enzymes involved in cholesterol synthesis, and activating the adenosine monophosphate-activated protein kinase signalling pathway.