Impacts of cascade hydropower development on aquatic environment in middle and lower reaches of Jinsha River, China: a review.

The middle and lower reaches of the Jinsha River, which is the upper reach of the Yangtze River in China, play crucial roles in the water security of people living in the middle and lower reaches of the Yangtze River. The construction of 11 dams in this region has significantly altered the aquatic environment. Although researchers have investigated the effects of cascade hydropower station development in the middle and lower reaches of the Jinsha River based on factors such as flow, sediment, and fish, the overall impact of this station on the aquatic environment remains unclear. Therefore, the purpose of this study is to comprehensively investigate the effects of cascade hydropower station development on the aquatic environment based on three factors: river, aquatic organism, and ecosystem factors. In terms of river factors, the development of cascade hydropower stations increases runoff in the dry season and decreases it in the flood season, leading to sediment deposition and water temperature stratification in cascade reservoirs, and changes in water quality. In terms of aquatic organism factors, cascade hydropower development not only changes the species composition but also reduces biodiversity. Effects of ecosystem factors including the ecological flow, value, and landscape as well as sustainability are summarized, with results indicating positive and negative impacts on river ecosystems. Finally, recommendations for future research on the effects of cascade hydropower development on the aquatic environment of rivers are provided.

Identification of the novel HLA-DPB1*21:01:02 allele using nanopore sequencing technology.

HLA-DPB1*21:01:02 differs from HLA-DPB1*21:01:01 by one single nucleotide substitution at position 435 C>T in exon 3.

A Spatiotemporally Controlled Gene-Regulation Strategy for Combined Tumor Therapy Based on Upconversion Hybrid Nanosystem.

The lack of precise spatiotemporal gene modulation and therapy impedes progress in medical applications. Herein, a 980 nm near-infrared (NIR) light-controlled nanoplatform, namely URMT, is developed, which can allow spatiotemporally controlled photodynamic therapy and trigger the enzyme-activated gene expression regulation in tumors. URMT is constructed by engineering an enzyme-activatable antisense oligonucleotide, which combined with an upconversion nanoparticle (UCNP)-based photodynamic nanosystem, followed by the surface functionalization of triphenylphosphine (TPP), a mitochondria-targeting ligand. URMT allows for the 980 nm NIR light-activated generation of reactive oxygen species, which can induce the translocation of a DNA repair enzyme (namely apurinic/apyrimidinic endonuclease 1, APE1) from the nucleus to mitochondria. APE1 can recognize the basic apurinic/apyrimidinic (AP) sites in DNA double-strands and perform cleavage, thereby releasing the functional single-strands for gene regulation. Overall, an augmented antitumor effect is observed due to NIR light-controlled mitochondrial damage and enzyme-activated gene regulation. Altogether, the approach reported in this study offers high spatiotemporal precision and shows the potential to achieve precise and specific gene regulation for targeted tumor treatment.

A review of reinforcement learning for natural language processing and applications in healthcare.

IMPORTANCE: Reinforcement learning (RL) represents a pivotal avenue within natural language processing (NLP), offering a potent mechanism for acquiring optimal strategies in task completion. This literature review studies various NLP applications where RL has demonstrated efficacy, with notable applications in healthcare settings. OBJECTIVES: To systematically explore the applications of RL in NLP, focusing on its effectiveness in acquiring optimal strategies, particularly in healthcare settings, and provide a comprehensive understanding of RL's potential in NLP tasks. MATERIALS AND METHODS: Adhering to the PRISMA guidelines, an exhaustive literature review was conducted to identify instances where RL has exhibited success in NLP applications, encompassing dialogue systems, machine translation, question-answering, text summarization, and information extraction. Our methodological approach involves closely examining the technical aspects of RL methodologies employed in these applications, analyzing algorithms, states, rewards, actions, datasets, and encoder-decoder architectures. RESULTS: The review of 93 papers yields insights into RL algorithms, prevalent techniques, emergent trends, and the fusion of RL methods in NLP healthcare applications. It clarifies the strategic approaches employed, datasets utilized, and the dynamic terrain of RL-NLP systems, thereby offering a roadmap for research and development in RL and machine learning techniques in healthcare. The review also addresses ethical concerns to ensure equity, transparency, and accountability in the evolution and application of RL-based NLP technologies, particularly within sensitive domains such as healthcare. DISCUSSION: The findings underscore the promising role of RL in advancing NLP applications, particularly in healthcare, where its potential to optimize decision-making and enhance patient outcomes is significant. However, the ethical challenges and technical complexities associated with RL demand careful consideration and ongoing research to ensure responsible and effective implementation. CONCLUSIONS: By systematically exploring RL's applications in NLP and providing insights into technical analysis, ethical implications, and potential advancements, this review contributes to a deeper understanding of RL's role for language processing.

Candida tropicalis ZD-3 prevents excessive fat deposition by regulating ileal microbiota and bile acids enterohepatic circulation in broilers.

Introduction: Evidence suggests that the dietary intake of Candida tropicalisZD-3 (ZD-3) has various health benefits, but the treatment mechanisms and effects remain unclear. The aim of this study investigates the effect of ZD-3 on reducing fat deposition in broilers and the underlying mechanism. Methods: 180 one-day-old, yellow-feathered broilers were randomly divided into three groups: control (CON) group fed a basal diet, an active Candida tropicalis ZD-3 (ZD) group supplemented with ZD, and a heat-inactivated Candida tropicalis ZD-3 (HZD) group supplemented with HZD. The experiment lasted for 28 d. Results: The ZD and HZD treatments significantly reduced the abdominal fat index (p < 0.05), decreased TG levels in serum and liver (p < 0.05), altered the ileal microbial composition by reducing the Firmicutes to Bacteroidetes (F/B) ratio. Additionally, the ZD and HZD treatments reduced liver cholesterol by decreasing ileal FXR-FGF19 signaling and increasing liver FXR-SHP signaling (p < 0.05). The ZD and HZD treatments also changed liver PC and TG classes lipid composition, regulating liver lipid metabolism by promoting TG degradation and modulating the signal transduction of the cell membrane. Discussion: Overall, ZD-3 was effective in improving lipid metabolism in broilers by regulating the ileal microbial composition and BAs enterohepatic circulation. This study provides a theoretical basis for the development and application of ZD-3 for the regulation of lipid metabolism in broilers.

Bibliometric analysis of research on retinoic acid in the field of kidney disorders.

Retinoic acid is an active metabolite with significant physiological functions in human development, immunity, vision, and skin health. In recent years, research on retinoic acid in the field of kidney disorders has been increasing gradually. Yet, there is a lack of systematic bibliometric analysis of retinoic acid research in the kidney domain. This study included 1,368 articles published between 1998 and 2023 on treating kidney diseases with retinoic acid. Using the bibliometric analysis software VOSviewer and CiteSpace, we analyzed data on publication trends, contributing countries and institutions, journals and cocited journals, authors and cocited authors, cocited references, research hotspots, and frontiers. On the basis of the results of the bibliometric analysis, we identified the research efforts and their developmental trends, providing the groundwork for future research on retinoic acid.

Subphenotypes of platelet count trajectories in sepsis from multi-center ICU data.

Although thrombocytopenia on admission to the ICU is associated with increased in-hospital mortality in septic patients, the role of longitudinally measured platelet counts, which are dynamically changing, is unclear. We aimed to identify patterns of dynamic platelet count trajectories and evaluate their association with outcomes and thrombocytopenia in septic patients. We tested the longitudinal platelet trajectory patterns of sepsis patients within the first four days of ICU admission in the MIMIC-IV database and their association with 28-day mortality, and independently validated our findings in the eICU-CRD database. Statistical methods used included multivariate regression, propensity score analysis, doubly robust estimation, gradient boosting model, and inverse probability weighting to ensure the robustness of our findings. A total of 22,866 septic patients were included in our study. The trajectory analysis categorizes patients into ascending (AS), stable (ST), or descending (DS) patterns. The risk of 28-day mortality was increased in the DS patients (OR = 2.464, 95%CI 1.895-3.203, p < 0.001) and ST patients (OR = 1.302, 95%CI 1.067-1.589, p = 0.009) compared to AS patients. The AS patients had lower ICU length of stay (2.36 vs. 4.32, p < 0.001) and 28-day maximum SOFA scores (5.00 vs. 6.00, p < 0.001) than the DS patients, but had more ventilator-free days within 28 days than the DS group (26.00 vs. 24.00, p < 0.001). The mediating effect of thrombocytopenia was significant (p < 0.001 for the average causal mediation effect (ACME)). Longitudinal platelet trajectory was associated with risk-adjusted 28-day mortality among patients with sepsis and was proportionally mediated through thrombocytopenia.

Integrated Multi-Omics Analysis Reveals Mountain-Cultivated Ginseng Ameliorates Cold-Stimulated Steroid-Resistant Asthma by Regulating Interactions among Microbiota, Genes, and Metabolites.

Steroid-resistant asthma (SRA), resisting glucocorticoids such as dexamethasone (DEX), is a bottleneck in the treatment of asthma. It is characterized by a predominantly neutrophilic inflammatory subtype and is prone to developing into severe refractory asthma and fatal asthma. Currently, there is a lack of universally effective treatments for SRA. Moreover, since cold stimulation does increase the risk of asthma development and exacerbate asthma symptoms, the treatment of cold-stimulated SRA (CSRA) will face greater challenges. To find effective new methods to ameliorate CSRA, this study established a CSRA mouse model of allergic airway inflammation mimicking human asthma for the first time and evaluated the alleviating effects of 80% ethanol extract of mountain-cultivated ginseng (MCG) based on multi-omics analysis. The results indicate that cold stimulation indeed exacerbated the SRA-related symptoms in mice; the DEX individual treatment did not show a satisfactory effect; while the combination treatment of DEX and MCG could dose-dependently significantly enhance the lung function; reduce neutrophil aggregation; decrease the levels of LPS, IFN-γ, IL-1ß, CXCL8, and IL-17; increase the level of IL-10; alleviate the inflammatory infiltration; and decrease the mucus secretion and the expression of MUC5AC. Moreover, the combination of DEX and high-dose (200 mg/kg) MCG could significantly increase the levels of tight junction proteins (TJs), regulate the disordered intestinal flora, increase the content of short-chain fatty acids (SCFAs), and regulate the abnormal gene profile and metabolic profile. Multi-omics integrated analysis showed that 7 gut microbes, 34 genes, 6 metabolites, and the involved 15 metabolic/signaling pathways were closely related to the pharmacological effects of combination therapy. In conclusion, integrated multi-omics profiling highlighted the benefits of MCG for CSRA mice by modulating the interactions of microbiota, genes, and metabolites. MCG shows great potential as a functional food in the adjuvant treatment of CSRA.

Intravenous immunoglobulin improves live birth rates in patients with unexplained recurrent pregnancy loss.

This real-world study aimed to assess the clinical efficacy and safety of intravenous immunoglobulin (IVIG) in treating unexplained recurrent pregnancy loss (uRPL) patients. A total of 238 patients with uRPL were enrolled in this retrospective study. According to the treatment, patients were assigned into treatment group (n=184, receiving IVIG+low molecular weight heparin [LMWH]) and control group (n=54, only LMWH). The primary outcome was the live birth rates (LBR) after 24 weeks of gestation. In addition, we performed subgroup analyses to assess the LBR in uRPL patients with age (≥30 years or <30 years), body mass index (BMI, 18-24 kg/m2 or ≥24 kg/m2), number of previous pregnancy losses (2 or ≥3), gestational week of first medication, and IVIG medication regimen during pregnancy. The LBR showed a significant increase after IVIG treatment compared to the control group (77.7 % vs. 53.7 %, P=0.001). Multivariable logistic regression indicated that IVIG was associated with increased LBR (aOR=4.383, 95 %CI 2.024-9.489). Besides, we observed a significantly lower incidence of decreased platelet count (1.6 % vs. 7.4 %, P=0.049) in the treatment group. Subgroup analyses showed that IVIG treatment was associated with improved LBR in uRPL patients with age of <30 years (aOR=4.012, 95 %CI 1.428-11.266), previous pregnancy losses ≥3 times (aOR=17.327, 95 %CI 2.525-118.921), and BMI of 18-24 kg/m2 (aOR=8.914, 95 %CI 2.985-26.618). IVIG treatment significantly improves the LBR in uRPL patients. These findings from real-world data provide evidence for the safety and efficacy of IVIG as a viable treatment for uRPL patients in clinical practice.

RNA-binding proteins potentially regulate alternative splicing of immune/inflammatory-associated genes during the progression of generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is a rare but severe form of psoriasis. However, the pathogenesis of GPP has not been fully elucidated. Although RNA-binding proteins (RBPs) and the alternative splicing (AS) process are essential for regulating post-transcriptional gene expression, their roles in GPP are still unclear. We aimed to elucidate the regulatory mechanisms to identify potential new therapeutic targets. Here, We analyzed an RNA sequencing (RNA-seq) dataset (GSE200977) of peripheral blood mononuclear cells (PBMCs) of 24 patients with GPP, psoriasis vulgaris (PV), and healthy controls (HCs) from the Gene Expression Omnibus (GEO) database. We found that the abnormal alternative splicing (AS) events associated with GPP were mainly "alt3p/alt5p", and 15 AS genes were differentially expressed. Notably, the proportions of different immune cell types were correlated with the expression levels of regulatory alternatively spliced genes (RASGs): significant differences were observed in expression levels of DTD2, NDUFAF3, NBPF15, and FBLN7 in B cells and ARFIP1, IPO11, and RP11-326L24.9 in neutrophils in the GPP samples. Furthermore, We identified 32 differentially expressed RNA-binding proteins (RBPs) (18 up-regulated and 14 down-regulated). Co-expression networks between 14 pairs of differentially expressed RBPs and RASGs were subsequently constructed, demonstrating that these differentially expressed RBPs may affect the progression of GPP by regulating the AS of downstream immune/inflammatory-related genes such as LINC00989, ENC1 and MMP25-AS1. Our results were innovative in revealing the involvement of inflammation-related RBPs and RASGs in the development of GPP from the perspective of RBP-regulated AS.

Probing rotaxane dynamics with 19F NMR/MRI: Unveiling the roles of mechanical bond and steric hindrance.

BACKGROUND: Deciphering the molecular dynamics (MD) of rotaxanes is crucial for designing and refining their applications in molecular devices. This study employed fluorine-19 nuclear magnetic resonance (19F NMR) and magnetic resonance imaging (MRI) to unveil the interplay between mechanical bonds and steric hindrance in a series of fluorinated rotaxanes. RESULTS: 1H/19F NMR revealed stable "Z"-shaped wheel conformations minimizing steric clashes and favoring π-π interactions with the axle. Utilizing fluorines and axle protons as reporters, 1H/19F relaxation rates and solid-state 19F NMR studies demonstrated that mechanical bond primarily governs wheel motion, while steric hindrance dictates axle movement. Intriguingly, mechanical bond mainly affects local axle groups, leaving distant ones minimally impacted. MD simulations corroborated these findings. Temperature-dependent 19F NMR indicated that energy input enhances rotational motion and wheel conformational transitions. Furthermore, the drastic increase in 19F relaxation rates upon mechanical bond formation and steric hindrance enables sensitive and selective 19F MRI visualization of MD changes. SIGNIFICANCE: This study, by elucidating the roles of internal and external factors on rotaxane molecular dynamics using 19F NMR/MRI, offers valuable insights that can advance the field of rotaxane-based molecular devices.

Preimplantation genetic testing for complex chromosomal rearrangements: clinical outcomes and potential risk factors.

Objective: Complex chromosome rearrangements (CCR) are rare structural abnormalities involving at least three breakpoints, categorized into three types based on their structure: type A (three-way rearrangements), type B (double two-way translocations), and type C (exceptional CCR). However, thus far, limited data exists on preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) in CCR carriers. This study aims to evaluate the clinical outcomes and influencing factors of PGT-SR in couples with CCR. Methods: Fifteen couples with unique CCR recruited from 793 couples following PGT-SR between January 2017 and May 2023. In addition, a total of 54 CCR cases, 39 previously reported as well as 15 newly added, were included in the analysis of factors associate with normal/balanced embryos. Results: A total of 100 blastocysts were biopsied and analyzed in 15 CCR couples after 17 PGT-SR cycles, with 16.0% being euploid, 78.0% aneuploid and 6.0% mosaic. 11 normal/balanced embryos and one mosaic embryo were transferred, resulting in eight live births. Furthermore, based on the combined data from 54 CCR carriers, the proportion of normal/balanced embryos was 10.8%, with a significant decrease observed among female carriers compared to male heterozygotes (6.5% vs. 15.5%, p = 0.002). Type B exhibited the lowest rate of euploid embryos at only 6.7%, followed by type A at 11.6% and type C at 14.0%, although the differences were not significant (p = 0.182). After completing the multivariate generalized estimating equation (GEE) analysis, type B (p = 0.014) and female carrier (p = 0.002) were identified as independent risk factors for fewer euploid embryos. Conclusion: The occurrence of balanced CCR in patients with reproductive abnormalities may be more frequent than we expected. Despite the proportion of normal/balanced embryos being significantly low, which can be influenced by CCR type and carrier's sex, PGT-SR may improve the reproductive outcomes among CCR cases. These findings can optimize the clinical management and genetic counseling of CCR carriers seeking assisted reproductive technology (ART).

A multi-AS-PCR-coupled CRISPR/Cas12a assay for the detection of ten single-base mutations.

Single-nucleotide polymorphism (SNP) detection is critical for diagnosing diseases, and the development of rapid and accurate diagnostic tools is essential for treatment and prevention. Allele-specific polymerase chain reaction (AS-PCR) is widely used for detecting SNPs with multiplexing capabilities, while CRISPR-based technologies provide high sensitivity and specificity in targeting mutation sites through specific guide RNAs (gRNAs). In this study, we have integrated the high sensitivity and specificity of CRISPR technology with the multiplexing capabilities of AS-PCR, achieving the simultaneous detection of ten single-base mutations. As for Multi-AS-PCR, our research identified that competitive inhibition of primers targeting the same loci, coupled with divergent amplification efficiencies of these primers, could result in diminished amplification efficiency. Consequently, we adjusted and optimized primer combinations and ratios to enhance the amplification efficacy of Multi-AS-PCR. Finally, we successfully developed a novel nested Multi-AS-PCR-Cas12a method for multiplex SNPs detection. To evaluate the clinical utility of this method in a real-world setting, we applied it to diagnose rifampicin-resistant tuberculosis (TB). The limit of detection (LoD) for the nested Multi-AS-PCR-Cas12a was 102 aM, achieving sensitivity, specificity, positive predictive value, and negative predictive value of 100 %, 93.33 %, 90.00 %, and 100 %, respectively, compared to sequencing. In summary, by employing an innovative design that incorporates a universal reverse primer alongside ten distinct forward allele-specific primers, the nested Multi-AS-PCR-Cas12a technique facilitates the parallel detection of ten rpoB gene SNPs. This method also holds broad potential for the detection of drug-resistant gene mutations in infectious diseases and tumors, as well as for the screening of specific genetic disorders.

Guided Cooperation in Hierarchical Reinforcement Learning via Model-Based Rollout.

Goal-conditioned hierarchical reinforcement learning (HRL) presents a promising approach for enabling effective exploration in complex, long-horizon reinforcement learning (RL) tasks through temporal abstraction. Empirically, heightened interlevel communication and coordination can induce more stable and robust policy improvement in hierarchical systems. Yet, most existing goal-conditioned HRL algorithms have primarily focused on the subgoal discovery, neglecting interlevel cooperation. Here, we propose a novel goal-conditioned HRL framework named Guided Cooperation via Model-Based Rollout (GCMR; code is available at https://github.com/HaoranWang-TJ/GCMR_ACLG_official), aiming to bridge interlayer information synchronization and cooperation by exploiting forward dynamics. First, the GCMR mitigates the state-transition error within off-policy correction via model-based rollout, thereby enhancing sample efficiency. Second, to prevent disruption by the unseen subgoals and states, lower level Q -function gradients are constrained using a gradient penalty with a model-inferred upper bound, leading to a more stable behavioral policy conducive to effective exploration. Third, we propose a one-step rollout-based planning, using higher level critics to guide the lower level policy. Specifically, we estimate the value of future states of the lower level policy using the higher level critic function, thereby transmitting global task information downward to avoid local pitfalls. These three critical components in GCMR are expected to facilitate interlevel cooperation significantly. Experimental results demonstrate that incorporating the proposed GCMR framework with a disentangled variant of hierarchical reinforcement learning guided by landmarks (HIGL), namely, adjacency constraint and landmark-guided planning (ACLG), yields more stable and robust policy improvement compared with various baselines and significantly outperforms previous state-of-the-art (SOTA) algorithms.

Causal relationship between gut microbiota, plasma metabolites, inflammatory cytokines and abdominal aortic aneurysm: a Mendelian randomization study.

BACKGROUND: Complex interconnections are evident among gut microbiota, circulating metabolites, inflammatory cytokines, and the pathogenesis of abdominal aortic aneurysms (AAA), with the causal dynamics yet to be comprehensively elucidated. The primary objective of this study was to elucidate the potential causal relationships involving gut microbiota-mediated plasma metabolites, inflammatory cytokines, and AAA. METHODS: We utilized data from genome-wide association studies predominantly comprising individuals of European ancestry, encompassing four major gut microbiota signatures, 233 plasma metabolite signatures (N = 136,016), 91 inflammatory cytokine signatures (N = 14,824), and AAA signatures (N = 1,458,875). Mendelian randomization (MR), employed in a two-sample format, was utilized as a tool to investigate the potential causal pathways from gut microbiota to the development of AAA. Additionally, a two-step MR approach was employed to dissect the impact of plasma metabolites and inflammatory cytokines on the relationship between gut microbiota and AAA and to ascertain the mediated fractions. RESULTS: Our findings indicate that five phylum or family-identical bacteria, 175 plasma metabolites, and seven inflammatory factors are causally associated with AAA. Among them, five bacterial species from the same phylum or family, identified from different GWAS data, were strongly associated with AAA. Of these, two exhibited negative causality and three exhibited positive causality. We found that the phylum Firmicutes and the families Oscillospiraceae might reduce the risk of AAA, whereas the families Prevotellaceae, Sutterellaceae, and Aminobacteriaceae might increase the risk of AAA. Further screening indicated that phylum Firmicutes id.1672 (GCST90017114) may confer a protective effect against AAA by reducing triglyceride levels in medium/small high-density lipoprotein (HDL). CONCLUSION: MR analysis has delineated a causal pathway from gut microbiota, through plasma circulating metabolites and inflammatory cytokines, to the pathogenesis of AAA. The role of intestinal flora and certain biomarkers may provide a reference for the diagnosis of AAA, and contribute to the prevention, diagnosis, and treatment of AAA disease.

Type II photoinitiators with collagen-based cyanine for cell encapsulation under green-red LED.

3D bioprinting with cell-laden materials is an emerging technique for fabricating functional tissue constructs. However, current cell-laden bioinks often lack sufficient cytocompatibility with commonly used UV-light sources. In this study, green to red photoinduced hydrogel crosslinking was obtained by introducing synthesized biosafety photoinitiators and used in light-based direct ink writing (DIW) 3D printing for enabling cell encapsulation successfully. The novel type II photointiators contain iodonium (ONI) and synthesized cyanine dyes CZBIN, TDPABIN, Col-SH-CZ, and Col-SH-TD with strong absorption in the range of 400-600 nm. Collagen-based macromolecule dyes Col-SH-CZ and Col-SH-TD showed excellent cytocompatibility. The photochemistry of these photoinitiators revealed an efficient photoinduced electron transfer (PET) process from the singlet excited states of the dyes to iodonium (ONI), facilitating the crosslinking of the biogels. L929 cells were encapsulated in Gel-MA hydrogels containing various photoinitiating systems and exposed to near-ultraviolet, green, or red LED irradiation. DIW-type 3D printing of Gel-MA bioink with L929 cells was also evaluated. The cell viability achieved with green light encapsulation reached 90 %. This novel approach offers promising prospects for bioprinting functional tissues with enhanced cytocompatibility under visible light conditions.

A metabolome-wide Mendelian randomization study prioritizes causal circulating metabolites for reproductive disorders including primary ovarian insufficiency, polycystic ovary syndrome, and abnormal spermatozoa.

BACKGROUND: Accumulating studies have highlighted the significant role of circulating metabolomics in the etiology of reproductive system disorders. However, the causal effects between genetically determined metabolites (GDMs) and reproductive diseases, including primary ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and abnormal spermatozoa (AS), still await thorough clarification. METHODS: With the currently most comprehensive genome-wide association studies (GWAS) data of metabolomics, systematic two-sample Mendelian randomization (MR) analyses were conducted to disclose causal associations between 1,091 blood metabolites and 309 metabolite ratios with reproductive disorders. The inverse-variance weighted (IVW) method served as the primary analysis approach, and multiple effective MR methods were employed as complementary analyses including MR-Egger, weighted median, constrained maximum likelihood (cML-MA), contamination mixture method, robust adjusted profile score (MR-RAPS), and debiased inverse-variance weighted method. Heterogeneity and pleiotropy were assessed via MR-Egger intercept and Cochran's Q statistical analysis. Outliers were detected by Radial MR and MR-PRESSO methods. External replication and metabolic pathway analysis were also conducted. RESULTS: Potential causal associations of 63 GDMs with POI were unearthed, and five metabolites with strong causal links to POI were emphasized. Two metabolic pathways related to the pathogenesis of POI were pinpointed. Suggestive causal effects of 70 GDMs on PCOS were detected, among which 7 metabolites stood out for strong causality with elevated PCOS risk. Four metabolic pathways associated with PCOS mechanisms were recognized. For AS, 64 GDMs as potential predictive biomarkers were identified, particularly highlighting two metabolites for their strong causal connections with AS. Three pathways underneath the AS mechanism were identified. Multiple assessments were conducted to further confirm the reliability and robustness of our causal inferences. CONCLUSION: By extensively assessing the causal implications of circulating GDMs on reproductive system disorders, our study underscores the intricate and pivotal role of metabolomics in reproductive ill-health, laying a theoretical foundation for clinical strategies from metabolic insights.

Efficacy of adductor canal and popliteal plexus block combined with local anesthetic injection in the interspace between the popliteal artery and posterior capsule of the knee and local infiltrative analgesia for postoperative pain and functional outcome after total knee arthroplasty: A randomized controlled study.

BACKGROUND: Adductor canal block and periarticular infiltration analgesia (PIA) have been shown to relieve pain in total knee arthroplasty (TKA) effectively. However, their analgesic effectiveness has some limitations. Thus, we considered a novel blocking site that could achieve analgesia without affecting the muscle strength of the lower limbs. METHODS: Seventy-two patients undergoing primary unilateral total knee arthroplasty were randomized into two groups. One group was treated with adductor canal and popliteal plexus (APB) combined with interspace between the popliteal artery and posterior capsule of the knee (iPACK) and local infiltration anesthesia (LIA) and the other was treated with PIA. The primary outcomes included postoperative pain, as assessed by the visual analog scale (VAS), and the consumption of oral tramadol. Secondary outcomes included functional recovery and daily ambulation distance. Tertiary outcomes included postoperative adverse effects. RESULTS: The APB group had lower VAS scores after surgery at rest and during motion. Compared with the PIA group, the walking distance of the APB group on the second day was greater. The muscle strength of the APB group was lower than that of the PIA group at the early stage. Patients in the APB group also consumed less tramadol than those in the PIA group. There was no difference in the incidence of adverse events between the two groups. CONCLUSIONS: APB combined with iPACK and LIA is a novel block for TKA, and it can reduce postoperative pain sooner after TKA without affecting postoperative functional recovery or increasing complications.

Electrochemical detection of FTO with N3-kethoxal labeling and MazF cleavage.

N6-Methyladenosine (m6A) is a prevalent modification in eukaryotic mRNAs and is linked to various human cancers. The fat mass and obesity-associated protein (FTO), a key m6A demethylase, is crucial in m6A regulation, affecting many biological processes and diseases. Detecting FTO is vital for clinical and research applications. Our study leverages the specific cleavage properties of the MazF endoribonuclease to design an electrochemical method with signal amplification guided by streptavidin-horseradish peroxidase (SA-HRP), intended for FTO detection. Initially, the compound N3-kethoxal is employed for its reversible tagging ability, selectively attaching to guanine (G) bases. Subsequently, dibenzocyclooctyne polyethylene glycol biotin (DBCO-PEG4-Biotin), is introduced through a reaction with N3-kethoxal. HRP is then employed to catalyze the redox system to enhance the current response further. A promising linear correlation between the peak current and the FTO concentration was observed within the range of 7.90 × 10-8 to 3.50 × 10-7 M, with a detection limit of 5.80 × 10-8 M. Moreover, this method assessed the FTO inhibitor FB23's inhibitory effect, revealing a final IC50 value of 54.73 nM. This result aligns with the IC50 value of 60 nM obtained through alternative methods and is very close to the values reported in the literature. The study provides reference value for research into obesity, diabetes, cancer, and other FTO-related diseases, as well as for the screening of potential therapeutic drugs.