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Aminoglycosides (AGs) are a class of antibiotics with a broad spectrum of activity. However, their use is limited by safety concerns associated with nephrotoxicity and ototoxicity, as well as drug resistance. To address these issues, semi-synthetic approaches for modifying natural AGs have generated new generations of AGs, however, with limited types of modification due to significant challenges in synthesis. This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs. This was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase (GT) in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs, therefore referred to as genkamicins (GKs). The manipulation of the hybrid biosynthetic pathway enabled the targeted accumulation of different GK species and the isolation and characterization of six GK components. These compounds display retained antimicrobial activity against a panel of World Health Organization (WHO) critical priority pathogens, and GK-C2a, in particular, demonstrates low ototoxicity compared to clinical drugs in zebrafish embryos. This study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.

Abstract Discinaceae holds significant importance within the Pezizales, representing a prominent group of macroascomycetes distributed globally. However, there is a dearth of genomic studies focusing on this family, resulting in gaps in our understanding of its evolution, development, and ecology. Here we utilized state-of-the-art genome assembly methodologies, incorporating third-generation single-molecule fluorescence and Hi-C-assisted methods, to elucidate the genomic landscapes of Gyromitra esculenta and Paragyromitra xinjiangensis. The genome sizes of two species were determined to be 47.10 Mb and 48.20 Mb, with 23 and 22 scaffolds, respectively. 10,438 and 11,469 coding proteins were identified, with functional annotations encompassing over 96.47% and 94.40%, respectively. Assessment of completeness using BUSCO revealed that 98.71% and 98.89% of the conserved proteins were identified. The application of comparative genomic technology has helped in identifying traits associated with of heterothallic life cycle traits and elucidating unique patterns of chromosomal evolution. Additionally, we identified potential saprotrophic nutritional modes and systematic phylogenetic relationships between the two species. Therefore, this study provides crucial genomic insights into the evolution, nutritional type, and ecological roles of species within the Pezizales.

Nicotinamide adenine dinucleotide (NAD+) is a central and pleiotropic metabolite involved in cellular energy metabolism, cell signaling, DNA repair, and protein modifications. Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Metabolic stress and aging directly affect the cardiovascular system. Compelling data suggest that NAD + levels decrease with age, obesity, and hypertension, which are all notable risk factors for CVD. In addition, the therapeutic elevation of NAD + levels reduces chronic low-grade inflammation, reactivates autophagy and mitochondrial biogenesis, and enhances oxidative metabolism in vascular cells of humans and rodents with vascular disorders. In preclinical models, NAD + boosting can also expand the health span, prevent metabolic syndrome, and decrease blood pressure. Moreover, NAD + storage by genetic, pharmacological, or natural dietary NAD + -increasing strategies has recently been shown to be effective in improving the pathophysiology of cardiac and vascular health in different animal models, and human health. Here, we review and discuss NAD + -related mechanisms pivotal for vascular health and summarize recent experimental evidence in NAD + research directly related to vascular disease, including atherosclerosis, and coronary artery disease. Finally, we comparatively assess distinct NAD + precursors for their clinical efficacy and the efficiency of NAD + elevation in the treatment of major CVD. These findings may provide ideas for new therapeutic strategies to prevent and treat CVD in the clinic.

Objective To conduct Rh blood group serological testing and third-generation sequencing(TGS) on 22 RhD variant voluntary blood donors in Chongqing and explore the phenotypic distribution and genotyping of RhD variants in Chongqing. Methods From January to August 2023, individuals who participated in blood donation in our blood center were selected as the study objects. RhD variant phenotype identification was performed using routine serological methods. Once the RhD variants were identified, tests on different antigenic epitopes of RhD were conducted using a D-screen assay kit. Furthermore, after the genomic DNA from 22 RhD variant blood samples was extracted, imbraided primers design and multi-segment amplification and splicing were used to sequence the full-length RHD gene for TGS. The RHD gene sequence was analyzed using SnapGene software. Results Among the 22 RhD variants, 8 were DVI type 3 (36.36%), with the main mutation of RHD-CE (3-6)-D hybrid allele. Six cases (27.27%) showed partial weak D15 type, with the main mutation of c.845G>A. There were 6 cases of Asia type Del (27.27%), with the main mutation of c.1227G>A. One case was weak D17 type with a mutation of c.340C>T and 1 case speculated to be partial D (c.491A>T, p. Asp164Val, missense mutation). Conclusion The most common RhD variant phenotype among blood donors in Chongqing is DVI type 3, and the full-length haplotype sequence of RHD variant alleles can be obtained by Pacific Bioscience single-molecule real-time sequencing(SMRT).

Abstract Purpose This study aimed to elucidate the causal relationship between Obstructive Sleep Apnea (OSA) and Chronic Respiratory Diseases (CRDs), employing Mendelian Randomization (MR) to overcome limitations inherent in observational studies. Methods Utilizing a two-sample MR approach, this study analyzed genetic variants as instrumental variables to investigate the causal link between OSA and various CRDs, including chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, and idiopathic pulmonary fibrosis (IPF). Data were sourced from the FinnGen Consortium (OSA, n = 375,657) and UK Biobank, focusing on genome-wide associations between single-nucleotide polymorphisms (SNPs) and the diseases. Instrumental variables were selected based on strict criteria, and analyses included a random-effects inverse-variance weighted method supplemented by several sensitivity analyses. Results The study suggests a protective effect of OSA against COPD (OR = 0.819, 95% CI 0.722–0.929, P-value = 0.002), which becomes non-significant after adjusting for BMI, indicating a potential mediating role of BMI in the OSA-COPD nexus. No significant causal links were found between OSA and other CRDs (asthma, IPF, bronchiectasis) or between COPD, asthma, and OSA. Conclusions Our findings reveal a BMI-mediated protective effect of OSA on COPD, with no causal connections identified between OSA and other CRDs. These results emphasize the complex relationship between OSA, BMI, and COPD, guiding future clinical strategies and research directions, particularly in light of the study’s genetic analysis limitations.

Abstract Variations at the event horizon structure of a black hole will emit the signals of the gravitational wave echoes associated with the ringdown of the binary black hole merger. In this work, combining mass model of M87 and Einasto profile for dark matter halo, we construct one formal solution of black holes in dark matter halo, and this solution includes the regular black hole for geometric parameter $$a < 2M$$ a < 2 M and the wormhole for $$a \ge 2M$$ a ≥ 2 M . Then, we test this solution under axial gravitational perturbation and calculate their quasinormal modes (QNM). Our results show that when geometric parameter $$a>2M$$ a > 2 M , a series of gravitational wave echoes appear after the QNM, and one distinctive feature of gravitational wave echoes is the double barrier. Besides, we also study the impacts of shape parameters $$\alpha $$ α of Einasto profile both on the QNM and gravitational wave echoes, and extract their frequencies using WKB method and Prony method. In principle, with the increasing of shape parameter $$\alpha $$ α , the frequencies of the QNM and gravitational wave echoes between the different shape parameters must be different. But now there is zero difference of the frequencies between shape parameter $$\alpha =0.18$$ α = 0.18 and $$\alpha =0.20$$ α = 0.20 . Zero difference is not allowed, so we give an upper limit for shape parameter $$\alpha $$ α , which is approximately $$\alpha

Abstract Background Hepatitis B virus (HBV) infection is a major concern regarding blood safety in countries with a high HBV prevalence, such as China. We aimed to understand the prevalence of HBV infection among blood donors in Chongqing and provide an important basis for developing appropriate blood screening strategies. Methods Dual enzyme-linked immunosorbent assays (ELISAs) for hepatitis B surface antigen (HBsAg) were conducted in parallel with nucleic acid testing (NAT) of donors. All HBsAg-reactive and/or HBV DNA-positive blood samples were tested for HBsAg and hepatitis B DNA levels. Results A total of 117,927 blood donor samples were collected from the Chongqing Blood Center between April 2020 and November 2020. In total, 473 HBV-ineligible samples were retained for HBsAg and DNA confirmation. A total of 272 samples were confirmed to be HBsAg+, including 2 HBV DNA − and 270 HBV DNA + samples. A total of 201 donations were HBsAg−, including 72 HBV DNA − samples. The rate of HBV infection was 65.33% (309/473) in men, which was significantly higher than that in women (p

Abstract Background This study aimed to investigate the accuracy of identifying enthesitis along with other inflammatory lesions and structural lesions on the MRI of the sacroiliac joints (SIJ) by readers of varying experience and how training sessions and workshops could help improve the accuracy. Methods A total of 224 patients with clinical diagnosis of axial spondyloarthritis who underwent SIJ MRI examinations were retrospectively included in this study. Three readers with 5 years, 3 years and 1 year of experience in musculoskeletal imaging were invited to review the SIJ MRI images independently, while the imaging reports of a senior radiologist (> 10 years’ experience) were used as reference. After the first round of image review, a training session and a workshop on the imaging of SIJ in spondyloarthritis were held and the three readers were asked to review the images in the second round. We calculated the accuracy of identifying inflammatory and structural lesions of the three readers as well as the intra-reader agreement. Results Enthesitis could be observed in 52.23% of the axial spondyloarthritis patients, while 81.58% of the patients with enthesitis were accompanied with bone marrow edema. All the three readers showed better accuracy at identifying structural lesions than inflammatory lesions. In the first round of image review, the three readers only correctly identified 15.07%, 2.94% and 0.74% of the enthesitis sites. After the training session and workshop, the accuracy rose to 61.03%, 39.34% and 20.22%. The intra-reader agreement of enthesitis calculated as Cohen’s kappa was 0.23, 0.034 and 0.014, respectively. Conclusion Readers with less experience in musculoskeletal imaging showed lower accuracy of identifying inflammatory lesions, notably enthesitis. Training sessions and workshops could help improve the diagnostic accuracy of the junior readers.

Background Intravenous immunoglobulin (IVIG)-resistant Kawasaki disease is associated with coronary artery lesion development. Purpose This study aimed to explore the factors associated with IVIG-resistance and construct and validate an interpretable machine learning (ML) prediction model in clinical practice. Methods Between December 2014 and November 2022, 602 patients were screened and risk factors for IVIG-resistance investigated. Five ML models are used to establish an optimal prediction model. The SHapley Additive exPlanations (SHAP) method was used to interpret the ML model. Results Na+, hemoglobin (Hb), C-reactive protein (CRP), and globulin were independent risk factors for IVIG-resistance. A nonlinear relationship was identified between globulin level and IVIG-resistance. The XGBoost model exhibited excellent performance, with an area under the receiver operating characteristic curve of 0.821, accuracy of 0.748, sensitivity of 0.889, and specificity of 0.683 in the testing set. The XGBoost model was interpreted globally and locally using the SHAP method. Conclusion Na+, Hb, CRP, and globulin levels were independently associated with IVIG-resistance. Our findings demonstrate that ML models can reliably predict IVIG-resistance. Moreover, use of the SHAP method to interpret the established XGBoost model's findings would provide evidence of IVIG-resistance and guide the individualized treatment of Kawasaki disease.

Abstract Cell fate decisions remain poorly understood at the molecular level. Embryogenesis provides a unique opportunity to analyze molecular details associated with cell fate decisions. Works based on model organisms have provided a conceptual framework of genes that specify cell fate control, for example, transcription factors (TFs) controlling processes from pluripotency to immunity1. How TFs specify cell fate remains poorly understood. Here we report that SALL4 relies on NuRD (nucleosome-remodeling and deacetylase complex) to interpret BMP4 signal and decide cell fate in a well-controlled in vitro system. While NuRD complex cooperates with SALL4 to convert mouse embryonic fibroblasts or MEFs to pluripotency, BMP4 diverts the same process to an alternative fate, PrE (primitive endoderm). Mechanistically, BMP4 signals the dissociation of SALL4 from NuRD physically to establish a gene regulatory network for PrE. Our results provide a conceptual framework to explore the rich landscapes of cell fate choices intrinsic to development in higher organisms involving morphogen-TF-chromatin modifier pathways.

Abstract Oracle bones (Obs) are a significant carrier of the shang dynasty civilization, primarily consisting of tortoise shells and animal bones, through the study of which we can gain a deeper understanding of the political, economic, religious, and cultural aspects of the shang dynasty. The oracle bone drill chisel (Obdc) is considered an essential non-textual material. The segmentation of Obdc assists archaeologists determine the approximate age of the Obs, which possesses considerable research value. However, the breakage of thousands of years of underground buried Obs, the blurring of the edges of the area burned by the Obdc, the different shapes, and the inconsistent number have brought challenges to the accurate segmentation of the Obdc. In this article, we propose a group convolutional attention and pvt dual-branch network (GCA-PVT-Net) for Obdc segmentation. To our knowledge, this paper is the first to research the automatic segmentation of Obdc. It is a hybrid Convolutional neural network (CNN) and Transformer framework. The work offers the following contributions: (1) The Obdc images are labeled based on the delineation criteria of different drill chisel (DC) shapes to create the Obdc dataset. (2) A convolutional attention module (CAM) is proposed as both an encoder and decoder. The feature extraction process, which effectively integrates global and local information, ensures better modeling of long-term correlations in images while preserving details. (3) A channel feature aggregation module (CFAM) is designed to enhance the effective integration of channel features, enabling feature fusion across various branches and at different levels. (4) The edge deep supervision strategy is applied to smooth the jagged edge of the predicted images at the decoder’s end. Extensive experiments on the Obdc dataset show that GCA-PVT-Net outperforms other state-of-the-art (SOTA) methods. The comparative experimental results show that the edge accuracy and segmentation accuracy of the model reach the top 1.

Abstract Cell fate is likely regulated by a common machinery, while components of this machine remain to be identified. Here we report the design and testing of engineered cell fate controller NanogBiD, fusing BiD or BRG1 interacting domain of SS18 with Nanog. NanogBiD promotes mouse somatic cell reprogramming efficiently in contrast to the ineffective native protein under multiple testing conditions. Mechanistic studies further reveal that it facilitates cell fate transition by recruiting the intended Brg/Brahma-associated factor (BAF) complex to modulate chromatin accessibility and reorganize cell state specific enhancers known to be occupied by canonical Nanog, resulting in precocious activation of multiple genes including Sall4, miR-302, Dppa5a and Sox15 towards pluripotency. Although we have yet to test our approach in other species, our findings suggest that engineered chromatin regulators may provide much needed tools to engineer cell fate in the cells as drugs era.

Abstract Dark matter density can be significantly enhanced by the supermassive black hole at the galactic center, leading to a structure called dark matter spike. Dark matter spike may change the spacetime properties of black holes that constitute deviations from GR black holes. Based on these interesting background, we construct a set of solutions of black holes in a dark matter spike under the Newtonian approximation and full relativity. Combining the mass model of M87, we study the quasinormal modes of black holes in the scalar field and axial gravitational perturbation, then compared them with Schwarzschild black hole. Besides, the impacts of dark matter on the quasinormal mode of black holes have been studied in depth. In particular, in the axial gravitational perturbation, our results show that the impacts of dark matter spike on the quasinormal mode of black holes can reach up to $$10^{-4}$$ 10 - 4 . These new features from quasinormal mode of black holes under the Newtonian approximation and full relativity may provide some help for the establishment of the final dark matter model, and provide a new thought for the indirect detection of dark matter.

Bevacizumab is a common strategy for the treatment of recurrent glioblastoma. Survival status is a crucial issue for patients with recurrent glioblastoma, and the apparent diffusion coefficient (ADC) values of the lower Gaussian curve have been reported to have the potential to predict prognosis in recurrent glioblastoma. In the present study, we aimed to clarify the survival prediction of ADC values in patients with recurrent glioblastoma receiving bevacizumab treatment through a systematic review and meta-analysis of randomized clinical trials, comparing ADC values higher than the cut-off values with those lower than the cut-off values to determine which type of ADC values can be associated with significant survival benefits. Different survival indicators were analyzed, including overall survival (OS) and progression-free survival (PFS). Ten studies with a total of 782 patients with recurrent glioblastoma were included. The focused outcomes were OS and PFS. Our results showed that ADC values lower than the cut-off values were associated with significant benefits for OS status compared with ADC values higher than the cut-off values. Similar significant benefits were observed for PFS. The meta-analysis results suggest that ADC values lower than the cut-off values might be associated with significant benefits for OS and PFS when compared with ADC values higher than the cut-off values. However, bias in relation to the different stages of recurrent glioblastoma and different types, doses, and regimens of bevacizumab should not be ignored.

Abstract Background Atherogenic index of plasma (AIP) is a non-traditional lipid parameter that can reflect the burden of atherosclerosis. A lipid profile resembling atherosclerosis emerged during pregnancy. Although lipid metabolism is pivotal in diabetes pathogenesis, there is no evidence linking AIP to gestational diabetes mellitus (GDM). Therefore, our objective was to explore the relationship between AIP and GDM and assess AIP's predictive capability for GDM. Methods This was a secondary analysis based on data from a prospective cohort study in Korea involving 585 single pregnant women. AIP was calculated as log10 (TG/HDL). We examined the relationship between AIP and GDM using logistic regression models, curve fitting, sensitivity analyses, and subgroup analyses. Receiver operating characteristic (ROC) analysis was also used to determine the ability of AIP to predict GDM. Results The average age of the participants was 32.06 ± 3.76 years. The AIP was 0.24 ± 0.20 on average. The GDM incidence was 6.15%. After adjustment for potentially confounding variables, AIP showed a positive linear relationship with GDM (P for non-linearity: 0.801, OR 1.58, 95% CI 1.27–1.97). The robustness of the connection between AIP and GDM was demonstrated by sensitivity analyses and subgroup analyses. An area under the ROC curve of 0.7879 (95% CI 0.7087–0.8671) indicates that AIP is an excellent predictor of GDM. With a specificity of 75.41% and sensitivity of 72.22%, the ideal AIP cut-off value for identifying GDM was 0.3557. Conclusions This study revealed that the AIP at 10–14 weeks of gestation was independently and positively correlated with GDM risk. AIP could serve as an early screening and monitoring tool for pregnant women at high risk of GDM, thereby optimizing GDM prevention strategies. Trial registration ClinicalTrials.gov registration no. NCT02276144. Graphical abstract

Abstract Pluripotent stem cells have the potential to generate embryo models that can recapitulate developmental processes in vitro. Large animals such as pigs may also benefit from stem-cell-based embryo models for improving breeding. Here, we report the generation of blastoids from porcine embryonic stem cells (pESCs). We first develop a culture medium 4FIXY to derive pESCs. We develop a 3D two-step differentiation strategy to generate porcine blastoids from the pESCs. The resulting blastoids exhibit similar morphology, size, cell lineage composition, and single-cell transcriptome characteristics to blastocysts. These porcine blastoids survive and expand for more than two weeks in vitro under two different culture conditions. Large animal blastoids such as those derived from pESCs may enable in vitro modeling of early embryogenesis and improve livestock species’ breeding practices.

Abstract Intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD) was associated with coronary artery lesions. Neutrophil percentage-to-albumin ratio (NPAR) is an index of mortality in several inflammatory diseases. This study focused on the association of NPAR with IVIG- resistance in KD. Clinical and laboratory data of 438 children with KD before IVIG treatment were retrospectively analyzed. Notably, high NPAR was associated with older age, high WBC, NP, ALT, total bilirubin and CRP, as well as with high the incidence of IVIG-resistance, and with low hemoglobin (Hb), PLT, ALB and sodium levels. NPAR (OR: 2.366, 95% CI: 1.46–3.897, p = 0.001) and Hb (OR: 0.967, 95% CI: 0.944–0.989, p = 0.004) were independent risk factors for IVIG-resistance. NPAR showed linear relation with IVIG-resistance (p for nonlinear = 0.711) and the nonlinear correlation was found between IVIG-resistance and Hb (p for nonlinear = 0.002). The predictive performance of NPAR was superior to Beijing model (z = 2.193, p = 0.028), and not inferior to Chongqing model (z = 0.983, p = 0.326) and the combination of NPAR and Hb (z = 1.912, p = 0.056). These findings revealed that NPAR is a reliable predictor of IVIG-resistance.

Estimation of model accuracy plays a crucial role in protein structure prediction, aiming to evaluate the quality of predicted protein structure models accurately and objectively. This process is not only key to screening candidate models that are close to the real structure, but also provides guidance for further optimization of protein structures. With the significant advancements made by AlphaFold2 in monomer structure, the problem of single-domain protein structure prediction has been widely solved. Correspondingly, the importance of assessing the quality of single-domain protein models decreased, and the research focus has shifted to estimation of model accuracy of protein complexes. In this review, our goal is to provide a comprehensive overview of the reference and statistical metrics, as well as representative methods, and the current challenges within four distinct facets (Topology Global Score, Interface Total Score, Interface Residue-Wise Score, and Tertiary Residue-Wise Score) in the field of complex EMA.

The energy storage features on natural convection in Casson fluids are investigated in this work using the finite element method. By measuring cylinders and wavy surfaces, we may examine flow patterns and the effectiveness of heat transmission systems. We study the variation of the mass and heat transfer rates as a function of the cylinder geometry. To approximately determine velocities and temperatures, the Ladyzhenskaya-Babuška—Brezzi (LBB)-stable element is employed. Following this discretization, the resulting discrete nonlinear system is linearized using Newton's method and subsequently solved using PARDISO. Fractional applications in Casson fluid analysis reveal insights into energy storage effects, employing finite element methods to explore flow patterns, heat transmission efficiency, and geometric variations while observing the impact of parameters such as Rayleigh, Hartmann, and Lewis numbers on fluid behavior and thermal properties. The preceding research has verified the accuracy of the numerical results. According to the results, concentration gradients and other modifications to liquids become more noticeable as the Rayleigh number grows. Convective heat transmission is reduced as the Ha is raised. When the Le grows, the deformation Nuavg and Shavgalso increase. Reducing the beta makes the isotherms more stable and less affected by the motion of the fluid.

With the urgent need of energy saving and consumption reduction in today's world, the topic of increasing the energy conversion efficiency of ventilation fans has been attracted a lot of attentions, it has become a key issue in the field of ventilation. The understanding on the evolution mechanism of irreversible energy loss in impeller is the premise and basis for realizing the efficient energy conversion of ventilation fans. At present, the irreversible energy loss mechanism in impeller is still lack of research. Therefore, the internal flow field of the contra-rotating axial fan at different flowrates is obtained by numerical simulation and experimental methods. A theoretical model of irreversible energy loss in impeller of ventilation fans is established based on entropy production theory, and the relationship between the irreversible energy loss in impeller and the flow field parameters is clarified. A quantitative analysis is conducted on different types of energy loss in impeller, and the spatial evolution law and causes of energy loss are clarified by combining with the flow characteristics in impeller. The results show that the entropy production method is reliable in calculating the irreversible energy loss in impeller. Direct viscous dissipation loss and wall friction loss are important components of energy loss, while turbulent dissipation is the main cause of energy loss, accounting for 60% to 80% of the total energy loss. For the front impeller, the energy loss caused by turbulent dissipation reaches the minimum at 1.0 QBEP, while the energy loss of the rear impeller increases with the decrease of flowrate. The energy loss is mainly concentrated in the region of Span=0.6−1.0, reaching 70% of the total energy loss at optimal flow condition. The spiral vortex caused by blade tip leakage flow and overflow of blade leading edge, backflow in impeller, flow separation at blade pressure and suction surface, and blade trailing edge wake will cause energy loss. The high energy loss region caused by flow separation and wake is relatively small, and the energy loss is relatively limited. However, the vortex and backflow significantly affect the flow in impeller, ultimately leading to a significant energy loss in the region near the blade tip. The research results can provide a reference for the evaluation of irreversible energy loss of ventilation fans.

Cholemic nephropathy （CN） is a disease with renal dysfunction as a major manifestation in patients with advanced chronic liver disease complicated with severe jaundice. Currently no effective non-invasive diagnostic modality is available for CN. Renal biopsy has been a gold standard for its clinical diagnosis. Furthermore, it is frequently misdiagnosed or confused with hepatorenal syndrome so that patient prognosis remains poor. The overall objective of clinical management is lowering a high level of bilirubin and blunting renal injury. If drug therapy fails, artificial liver systems may be employed for improving renal function. The underlying pathological mechanisms of CN have not been fully elucidated. However, recent studies implied that the development of disease was correlated closely with abnormal renal transporters, oxidative stress and inflammatory responses. Based upon previous studies, the authors summarized the latest researches on CN through focusing upon clinical diagnosis, potential pathogenesis and therapeutic strategies for providing theoretical rationales for advanced researches and clinical interventions of CN.

Abstract Azole antifungal drugs are commonly used to treat vulvovaginal candidiasis (VVC). The nephrotoxicity and developmental toxicity of azole drugs have not been systematically analyzed in the real world. We used the FDA Adverse Event Reporting System (FAERS) to investigate the adverse events (AEs) associated with imidazole therapy for VVC. FAERS data (from quarter 1 2004 to quarter 3 2022) were retrieved using OpenVigil 2.1, and AEs were retrieved and standardized according to the Medical Dictionary for Regulatory Activities (MedDRA). In the top 10 System Organ Class (SOC), all four drugs have been found to have kidney and urinary system diseases and pregnancy. We found significant signals, including clotrimazole [bladder transitional cell carcinoma, (report odds ratio, ROR = 291.66)], [fetal death, (ROR = 10.28)], ketoconazole[nephrogenic anemia (ROR = 22.1)], [premature rupture of membranes (ROR = 22.91 46.45, 11, 3)], Miconazole[hematuria (ROR = 19.03)], [neonatal sepsis (ROR = 123.71)], [spontaneous abortion (ROR = 5.98)], Econazole [acute kidney injury (ROR = 4.41)], [spontaneous abortion (ROR = 19.62)]. We also discovered new adverse reactions that were not reported. Therefore, when using imidazole drugs for treatment, it is necessary to closely monitor the patient's renal function, pay attention to the developmental toxicity of the fetus during pregnancy, and be aware of potential adverse reactions that may occur.

Abstract Background Pudendal neuralgia is a chronic and debilitating condition. Its prevalence ranges from 5 to 26%. Currently, therapeutic approaches to treat pudendal neuralgia include patient education, medication management, psychological and physical therapy, and procedural interventions, such as nerve block, trigger point injections, and surgery. Drug therapy has a limited effect on pain relief. A pudendal nerve block may cause a significant decrease in pain scores for a short time; however, its efficacy significantly decreases over time. In contrast, pudendal nerve pulsed radiofrequency can provide pain relief for 3 months, and ganglion impar block has been widely used for treating chronic perineal pain and chronic coccygodynia. This study aimed to determine the efficacy and safety of monotherapy (pudendal nerve pulsed radiofrequency) and combination therapy (pudendal nerve pulsed radiofrequency plus ganglion impar block) in patients with pudendal neuralgia. Methods This randomized, controlled clinical trial will include 84 patients with pudendal neuralgia who failed to respond to drug or physical therapy. Patients will be randomly assigned into one of the two groups: mono or combined treatment groups. The primary outcome will be a change in pain intensity measured using the visual analog scale. The secondary outcomes will include a Self-Rating Anxiety Scale score, Self-Rating Depression Scale score, the use of oral analgesics, the Medical Outcomes Study Health Survey Short Form-36 Item score, and the occurrence of adverse effects. The study results will be analyzed using intention-to-treat and per-protocol analyses. Primary and secondary outcomes will be evaluated between the mono and combined treatment groups. Subgroup analyses will be conducted based on the initial ailment, age, and baseline pain intensity. The safety of the treatment will be assessed by monitoring adverse events, which will be compared between the two groups. Discussion This study protocol describes a randomized, controlled clinical trial to determine the efficacy and safety of mono and combination therapies in patients with pudendal neuralgia. The study results will provide valuable information on the potential benefits of this combination therapy and contribute to the development of more effective and safer treatments for patients with pudendal neuralgia. Trial registration Chinese Clinical Trial Registry (ChiCTR2200061800).

Abstract Optimizing short‐term load forecasting performance is a challenge due to the randomness of nonlinear power load and variability of system operation mode. The existing methods generally ignore how to reasonably and effectively combine the complementary advantages among them and fail to capture enough internal information from load data, resulting in accuracy reduction. To achieve accurate and efficient short‐term load forecasting, an integral implementation framework is proposed based on convolutional neural network (CNN), gated recurrent unit (GRU) and channel attention mechanism. CNN and GRU are first combined to fully extract the highly complicated dynamic characteristics and learn time compliance relationships of load sequence. Based on CNN‐GRU network, the channel attention mechanism is introduced to further reduce the loss of historical information and enhance the impact of important characteristics. Then, the overall framework of short‐term load forecasting based on CNN‐GRU‐Attention network is proposed, and the coupling relationship between each stage is revealed. Finally, the developed framework is implemented on realistic load dataset of distribution networks, and the experimental results verify the effectiveness of the proposed method. Compared with the state‐of‐the‐art models, the CNN‐GRU‐Attention model outperforms in different evaluation metrics.

Abstract Nuclear condensates have been shown to regulate cell fate control, but its role in oncogenic transformation remains largely unknown. Here we show acquisition of oncogenic potential by nuclear condensate remodeling. The proto-oncogene SS18 and its oncogenic fusion SS18-SSX1 can both form condensates, but with drastically different properties and impact on 3D genome architecture. The oncogenic condensates, not wild type ones, readily exclude HDAC1 and 2 complexes, thus, allowing aberrant accumulation of H3K27ac on chromatin loci, leading to oncogenic expression of key target genes. These results provide the first case for condensate remodeling as a transforming event to generate oncogene and such condensates can be targeted for therapy. One sentence summary: Expulsion of HDACs complexes leads to oncogenic transformation.

Abstract In-depth comprehension and modulation of the electronic structure of the active metal sites is crucial to enhance their intrinsic activity of electrocatalytic oxygen evolution reaction (OER) toward anion exchange membrane water electrolyzers (AEMWEs). Here, we elaborate a series of amorphous metal oxide catalysts (FeCrOx, CoCrOx and NiCrOx) with high performance AEMWEs by high-valent chromium dopant. We discover that the positive effect of the transition from low to high valence of the Co site on the adsorption energy of the intermediate and the lower oxidation barrier is the key factor for its increased activity by synchrotron radiation in-situ techniques. Particularly, the CoCrOx anode catalyst achieves the high current density of 1.5 A cm−2 at 2.1 V and maintains for over 120 h with attenuation less than 4.9 mV h−1 in AEMWE testing. Such exceptional performance demonstrates a promising prospect for industrial application and providing general guidelines for the design of high-efficiency AEMWEs systems.

Abstract Engineering atom-scale sites are crucial to the mitigation of polysulfide shuttle, promotion of sulfur redox, and regulation of lithium deposition in lithium–sulfur batteries. Herein, a homonuclear copper dual-atom catalyst with a proximal distance of 3.5 Å is developed for lithium–sulfur batteries, wherein two adjacent copper atoms are linked by a pair of symmetrical chlorine bridge bonds. Benefiting from the proximal copper atoms and their unique coordination, the copper dual-atom catalyst with the increased active interface concentration synchronously guide the evolutions of sulfur and lithium species. Such a delicate design breaks through the activity limitation of mononuclear metal center and represents a catalyst concept for lithium–sulfur battery realm. Therefore, a remarkable areal capacity of 7.8 mA h cm−2 is achieved under the scenario of sulfur content of 60 wt.%, mass loading of 7.7 mg cm−2 and electrolyte dosage of 4.8 μL mg−1.

Abstract Background Transforming growth factor-β (TGF-β) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-β pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-β signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors. Methods This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis. Results Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25–8.60 h from 5 – 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-β1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. Conclusions GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. Trial registration ClinicalTrial. gov ( https://www.clinicaltrials.gov/ ), NCT05051241. Registered on 2021-09-02.

Abstract Background The objective was to investigate the efficacy of different doses of levothyroxine therapy among pregnant women exhibiting high-normal thyroid stimulating hormone levels and positive thyroid peroxidase antibodies throughout the first half of pregnancy. Methods Pregnant women exhibiting high-normal thyroid stimulating hormone levels and thyroid peroxidase antibodies positivity throughout the initial half of pregnancy were selected from January 2021 to September 2023. Based on the different doses of levothyroxine, the pregnant women were categorized into the nonintervention group (G0, 122 women), 25 µg levothyroxine intervention group (G25, 69 women), and 50 µg levothyroxine intervention group (G50, 58 women). Serum parameters, gastrointestinal symptoms, small intestinal bacterial overgrowth (SIBO), maternal and neonatal outcomes were compared after the intervention among the three groups. Results After the intervention, in the G25 and G50 groups, the thyroid stimulating hormone, triglyceride and low-density lipoprotein levels were notably less in contrast to those in the G0 group (P

The impact of cadmium (Cd) toxicity on fish liver injury has received much attention in recent years. Currently, autophagy, apoptosis and endoplasmic reticulum stress were reported in Cd exposed fish liver, and if there are other mechanisms (such as ferroptosis) and relevant signaling pathways involved in fish remains unknown. An experiment was conducted to investigate Cd toxicity in Channa argus (Cantor, 1842) exposed to 0, 1.0, and 2.0 mg Cd/L of water for 96 h. Cd disrupted the structure of mitochondria in the liver. Besides, Cd induced ferroptosis by significantly increasing the level of Fe2+, ROS, MDA and significantly decreasing the level of Ferritin, GSH, GSH-Px, GPX4, GST and SOD (p < 0.05 in all cases). In addition, the mRNA expression of ferroptosis related genes, gpx4 and slc7a11, were significantly downregulated by Cd. Moreover, Cd exposure significantly inhibited the Nrf2/Keap1 signaling pathway, one of the pathways involved in ferroptosis, by upregulating the mRNA levels of keap1a and keap1b, and downregulating the mRNA levels of nrf2 and its target genes (ho-1, nqo1 and cat). Cd exposure also caused extensive accumulation of vacuoles and lipid droplets in liver, as well as an increase in triglyceride content. Cd significantly affected lipid metabolism related enzyme activity and gene expression, which were also regulated by Nrf2/Keap1 signaling pathway. In summary, these results indicate that ferroptosis is a mechanism in waterborne Cd exposed fish liver injury via the Nrf2/Keap1 signaling pathway and the Cd induced hepatic steatosis is also modulated by Nrf2/Keap1 pathway at the whole-body level in fish. These findings provide new insights into the fish liver injury and molecular basis of Cd toxicity.

Energy demand has greatly increased today and phase change storage technology is rapidly growing due to its renewable nature. This study explores a new Triple Tube Heat Exchanger (TTHX) model, which divides phase change materials (PCMs) into two regions to improve the connection between TTHX and PCM, to improve the thermal conductivity of PCMs with different fins' number, arrangement, and angle, consequently enhancing thermal storage efficiency. A more efficient exchanger is developed by using Molten Salt as PCM and adding TiO2 and Al2O3 nanoparticles with different concentrations. Liquid fraction, temperature, and velocity obtained from numerical simulation are employed to characterize thermal storage efficiency. ANSYS 2022R1 is used for pre-modeling and numerical computations. The simulation results are turned into graphs and charts for PowerPoint and Origin analysis. We find that PCM's heat transfer efficiency is increased by 34.3 % when effective fins are added, and the addition of 5%TiO2 further increases it by 8.73 %. With the addition of Al2O3 and its concentration variation, combined with the effective fins, the heat transfer efficiency of the PCM can be enhanced by 40.73 %.

Hepatotoxicity caused by the anticancer medication oxaliplatin (OXA) significantly restricts its clinical use and raises the risk of liver damage. Huaier, a fungus found in China, has been demonstrated to have various beneficial effects in adjuvant therapy for cancer. However, the preventive impact of Huaier against OXA-induced hepatotoxicity is still unknown. The potential molecular pathways behind the hepatoprotective activity of Huaier against OXA-induced hepatotoxicity were investigated in the current study Mice were intraperitoneally injected with 10 mg/kg of OXA once a week for six consecutive weeks to establish a liver injury model. Huaier (2 g/kg, 4 g/kg, and 8 g/kg) was administered weekly to mice by gavage for six weeks. Commercial kits were used to determine the contents of glutathione, catalase, superoxide dismutase, and malondialdehyde. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to assess the impact of Huaier therapy on the expression of the PI3K pathway. Huaier exhibited a good protective effect on OXA-induced hepatotoxicity in a dose-dependent manner, which was connected to the suppression of oxidative stress, according to the results of biochemical index detection and histological staining analysis. In addition, Huaier could counteract the OXA-induced suppression of the PI3K/AKT signaling pathway. Moreover, the hepatoprotective effect and PI3K activation of Huaier were eradicated by LY294002. These findings imply that by decreasing oxidative stress, Huaier can minimize OXA-induced liver injury, establishing the groundwork for Huaier to lessen chemotherapy-induced hepatotoxicity in clinical practice.

Summary: Previous studies have indicated that various blood cell traits are associated with a higher risk of venous thromboembolism (VTE). However, the causal relationship remains uncertain. We collected data from the China pulmonary thromboembolism registry study and the China pulmonary health study, using propensity score matching and two-sample Mendelian randomization analyses with summary statistics from genome-wide association studies of blood cell traits and VTE in the East Asian population. Our findings revealed that platelet (PLT) count and hemoglobin (Hb) levels were significantly higher in VTE patients compared to the general population (p value

This paper uses three analytical methods to find the novel results in the two-dimensional time-dependent MHD oscillatory flow and heat transfer in an asymmetric wavy porous channel. The corresponding constitutive equations become complex by considering the pressure gradient as a complex function. This results in the existence of both real and imaginary solutions for fluid velocity and temperature. The changes in parameters like the Hartmann number, wavelength, Grashof number, and porous medium shape factor will affect the real fluid velocity. Still, only radiation parameter changes will affect the real fluid velocity and temperature. Increasing the Hartmann number, porous medium shape factor, and radiation parameter will drastically reduce real fluid velocity. The Reynolds number should theoretically affect the imaginary velocity, but according to the boundary condition definition, the imaginary velocity value becomes zero. Altering the frequency of the wavy walls and the Peclet number will only affect the imaginary temperature component, and increasing these parameters will increase the average imaginary temperature profile. The uniqueness of this study lies in the resolution of complex differential equations in a way that has not been attempted before. The results indicated that each set of three solutions was nearly identical, highlighting the outcomes' precision.

The current study deeply investigates nanofluid's heat and mass transport in a staggered-shaped enclosure with wavy walls. A nonhomogeneous mathematical model with thermophoresis and Brownian diffusion is considered in our study. The finite element method is implemented to solve the set of governing equations. Impacts of magnetic field (B0) and its orientation (γ), undulation number (N), amplitude (A) and nanoparticle types are examined for heat and mass flow. Investigations show that the most demoting trend is obtained when the inclination of B0 is either vertical or horizontal. It is concluded that mean Nusselt (Nuavg) and Sherwood number (Shavg) are increasing functions of Ra. When Ra is changed from 103 to 107, the Shavg value is increased up to six times. The impacts of wall shape show that as we increase A, the Nuavg decreases while the maximum can be obtained for the flat boundary. For small N, Shavg is an increasing function. Shape optimization revealed that there exists a critical point between Shavg and N after which it declines. Investigations further show that this point can be changed. Some critical points have been calculated that can be counted as novel results.

The world is facing two major problems today, as imbalance of supply and demand of the energy and the continues deterioration of the environment. Latent thermal energy storage with phase change material plays a vital rule in resolving this problem. The current study investigates the numerical simulation of phase change material with novel fins configuration in the triplex-tube storage unit. But their low thermal conductivity is the main problem by affecting the energy storage. To enhance the heat transfer rate within the system, novel longitudinal triangular and traditional rectangular fins with a combination of hybrid nanoparticles (Cu-TiO2) are employed. In summary, utilizing novel fins to improve heat transfer rate in conjunction with nanoparticles is highly effective for improving the phase change material melting process in thermal energy storage systems. The usage of nanoparticles speeds up the melting rate 33.5%- Case A, 20%-Case B, 19.4%-Case C, and 18% for Case D. Moreover, when compared to rectangular-shaped fins, the use of longitudinal triangular -shaped fins accelerates the PCM melting rate. For instance, the melting rate in Case C (fins with longitudinal triangular form) is higher than in Case F (fins with a rectangle shape).

The transporter protein ABC subfamily G member 2 (ABCG2) is implicated in epilepsy; however, its specific role remains unclear. In this study, we assessed changes in ABCG2 expression and its role in epilepsy both in vitro and in vivo. We observed an instantaneous increase in ABCG2 expression in epileptic animals and cells. Further, ABCG2 overexpression significantly suppressed the oxidative stress and apoptosis induced by glutamate, kainic acid (KA), and lipopolysaccharide (LPS) in neuronal and microglia cells. Furthermore, inhibiting ABCG2 activity offset this protective effect. ABCG2-deficient mice (ABCG2−/−) showed shorter survival times and decreased survival rates when administered with pentylenetetrazole (PTZ). We also noticed the accumulation of signal transducer and activator of transcription 1 (STAT1) and decreased phosphorylation of mammalian target of rapamycin kinase (mTOR) along with increased ISGylation in ABCG2−/− mice. ABCG2 overexpression directly interacted with STAT1 and mTOR, leading to a decrease in their ISGylation. Our findings indicate the rapid increase in ABCG2 expression acts as a shield in epileptogenesis, indicating ABCG2 may serve as a potential therapeutic target for epilepsy treatment.

Abstract Cholestasis, a chronic liver condition, disrupts bile acid homeostasis and complicates drug disposition, posing significant challenges in medicating cholestatic patients. Drug metabolism enzymes and transporters (DMETs) are pivotal in drug clearance. Research indicates that cholestasis leads to alterations in both hepatic and extrahepatic DMETs, with changes in expression and function documented in rodents and humans. This review synthesizes the modifications in key drug disposition components within cholestasis, focusing on cytochrome P450 (CYP450), drug transporters, and their substrates. Additionally, we briefly discuss certain drugs that have demonstrated efficacy in restoring DMET expression in cholestatic conditions. Ultimately, these insights necessitate a reevaluation of drug selection and dosing guidelines for patients with cholestasis.

Tetrodotoxin (TTX) is a highly potent and widely distributed ion-channel marine neurotoxin; it has no specific antidote and poses a great risk to human health. Therefore, detecting and quantifying TTX to effectively implement prevention strategies is important for food safety. The development of novel and highly sensitive, highly specific, rapid, and simple techniques for trace TTX detection has attracted widespread attention. This review summarizes the latest advances in the detection and quantitative analysis of TTX, covering detection methods based on biological and cellular sensors, immunoassays and immunosensors, aptamers, and liquid chromatography-mass spectrometry. It further discusses the advantages and applications of various detection technologies developed for TTX and focuses on the frontier areas and development directions of TTX detection, providing relevant information for further investigations.

To uncover the security aspects of the Water-Energy-Food-Nexus (WEFN) and develop innovative methods for evaluating its security, we initially utilize the coefficient of variation-cumulative information contribution rate (COV-CICR) model to select assessment metrics. This approach ensures a well-suited set of indicators for assessing the security of the WEFN. Subsequently, the WEFN security assessment model is developed by utilizing a random forest model that has been fine-tuned with the aquila optimizer. To illustrate this model's application, we use the example of the Hongxinglong branch of China's Beidahuang Farming Group Co., Ltd. The study conducted a detailed analysis of the spatiotemporal variations in the security of the WEFN (Water-Energy-Food Nexus) system across 12 subsidiary farms. Furthermore, it identified key driving factors and elucidated their mechanisms by accounting for data fluctuations. The research included calculating the contribution index of these key driving factors to accurately determine the dominant factors under varying conditions. The results indicate that over time, the WEFN security level in the study trended upward. From 2002–2008, the WEFN security level slowly increased. From 2009–2018, WEFN security remained stable. From 2018–2021, the security level rapidly accelerated. Spatially, the WEFN security in the southern region is lower than that in the northern region, while the central region’s security remained stable. The primary controlling factors for WEFN security also vary at different scales. In comparison to the BP, RF, and PSO-RF models, the AO-RF model demonstrates outstanding advantages in terms of fitting performance, reliability, reasonableness, and stability. This fully supports the applicability of the AO-RF model in WEFN security assessment. The research findings enrich the integrated application of intelligent optimization and machine learning in WEFN studies, introduce a novel analytical model for WEFN security drivers, and expand our understanding of the new mechanisms underlying WEFN security operations.

Background: Multiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and impaired neurochemical transmission. Considering the critical role of iron in neurotransmitter synthesis and transport, our study aims to identify distinct patterns of whole-brain iron accumulation in MSA and PD, and to elucidate the corresponding neurochemical substrates. Methods: A total of 122 PD patients, 58 MSA patients and 78 age-, sex-matched health controls underwent multi-echo gradient echo sequences and neurological evaluations. We conducted voxel-wise and regional analyses using quantitative susceptibility mapping to explore MSA or PD-specific alterations in cortical and subcortical iron concentrations. Spatial correlation approaches were employed to examine the topographical alignment of cortical iron accumulation patterns with normative atlases of neurotransmitter receptor and transporter densities. Furthermore, we assessed the associations between the colocalization strength of neurochemical systems and disease severity. Results: MSA patients exhibited increased susceptibility in the striatal, midbrain, cerebellar nuclei, as well as the frontal, temporal, occipital lobes, and anterior cingulate gyrus. In contrast, PD patients displayed elevated iron levels in the left inferior occipital gyrus, precentral gyrus, and substantia nigra. The excessive iron accumulation in MSA or PD correlated with the spatial distribution of cholinergic, noradrenaline, glutamate, serotonin, cannabinoids, and opioid neurotransmitters, and the degree of this alignment was related to motor deficits. Conclusions: Our findings provide evidence of the interaction between iron accumulation and non-dopamine neurotransmitters in the pathogenesis of MSA and PD, which inspires research on potential targets for pharmacotherapy.

ObjectiveThis study aimed to explore the correlation between microbiota dysbiosis and hypothyroidism in early pregnancy by 16S rRNA amplicon sequencing combined with metagenomic sequencing.MethodsSixty pregnant women (30 with hypothyroidism and 30 normal controls) were recruited for 16S rRNA amplicon sequencing, and 6 patients from each group were randomly selected for metagenomic sequencing to assess the gut microbiome profile.ResultsThe 16S rRNA results showed that beta-diversity in the hypothyroidism group was decreased. The relative abundances of the Prevotella and Paraprevotella genera increased in the hypothyroidism group, and Blautia predominated in the controls. The metagenomics results revealed that Prevotella_stercorea_CAG_629, Prevotella_hominis, Prevotella_sp_AM34_19LB, etc. were enriched in the hypothyroidism group at the species level. Functional analysis revealed that the pyridoxal 5’-phosphate synthase pdxT subunit module was decreased, and the short-chain fatty acid (SCFA) transporter and phospholipase/carboxylesterase modules were strongly enriched in the hypothyroidism group. Hypothyroidism patients had increased C-reactive protein (CRP), interleukin-2 (IL-2), IL-4, IL-10, and tumor necrosis factor (TNF)-α levels. The pyridoxal 5’-phosphate synthase pdxT subunit, the SCFA transporter, and the phospholipase/carboxylesterase module were associated with different Prevotella species.ConclusionIn early pregnancy, women with hypothyroidism exhibit microbiota dysbiosis, and Prevotella may affect the metabolism of glutamate, SCFA, and phospholipases, which could be involved in the development of hypothyroidism during pregnancy.

Abstract Solar‐driven CO2 reduction into value‐added C2+ chemical fuels, such as C2H4, is promising in meeting the carbon‐neutral future, yet the performance is usually hindered by the high energy barrier of the C─C coupling process. Here, an efficient and stabilized Cu(I) single atoms‐modified W18O49 nanowires (Cu1/W18O49) photocatalyst with asymmetric Cu─W dual sites is reported for selective photocatalytic CO2 reduction to C2H4. The interconversion between W(V) and W(VI) in W18O49 ensures the stability of Cu(I) during the photocatalytic process. Under light irradiation, the optimal Cu1/W18O49 (3.6‐Cu1/W18O49) catalyst exhibits concurrent high activity and selectivity toward C2H4 production, reaching a corresponding yield rate of 4.9 µmol g−1 h−1 and selectivity as high as 72.8%, respectively. Combined in situ spectroscopies and computational calculations reveal that Cu(I) single atoms stabilize the *CO intermediate, and the asymmetric Cu─W dual sites effectively reduce the energy barrier for the C─C coupling of two neighboring CO intermediates, enabling the highly selective C2H4 generation from CO2 photoreduction. This work demonstrates leveraging stabilized atomically‐dispersed Cu(I) in asymmetric dual‐sites for selective CO2‐to‐C2H4 conversion and can provide new insight into photocatalytic CO2 reduction to other targeted C2+ products through rational construction of active sites for C─C coupling.

IntroductionThe marine economy has played an important role in stabilizing national economic growth and ensuring economic security. Achieving high-quality and sustainable development of the marine economy is a strategic task for China to build a maritime power. Confronting various risk factors such as financial crises, natural disasters, geopolitical conflicts, industrial transformation, and public health security, etc., marine economic resilience (MER) has received widespread attention in recent years and is considered to be crucial for high-quality and sustainable development of the marine economy. MethodsThis study takes 11 coastal provinces in China as cases, integrates 6 condition variables by building a Resistance capability-Recovery capability-Renewal capability (3R) configuration model, and uses the fuzzy-set qualitative comparative analysis (fsQCA) approach to empirically explore the configuration effect between multiple land factors and MER. Results and discussion(1) None of the 6 conditions in the three dimensions of resistance capability, recovery capability, and renewal capability alone constitute the necessary conditions for strong or weak MER, indicating that a single condition has weak explanatory power for MER; (2) There are two configurations for strong MER: Strong Resistance-Recovery Type and Comprehensive Strong Type. Industrial structure, governmental capability, and digital economy are the core conditions for strong MER configurations; (3) There are four weak MER configurations: Comprehensive Weak Type, Weak Recovery-Renewal Type, Weak Resistance-Recovery Type I, and Weak Resistance-Recovery Type II. This study may expand the research scope of MER influencing factors and enriching the research perspective of land-sea integration, as well as providing decision-makers with practical policy implications.

BackgroundTislelizumab is the first PD-1 inhibitor in China to demonstrate superior efficacy in second-line or third-line treatment of patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This study aimed to evaluate the cost-effectiveness of tislelizumab compared to docetaxel from a Chinese healthcare system perspective.MethodsA dynamic Markov model was developed to evaluate the cost-effectiveness of tislelizumab in comparison to docetaxel in second or third-line treatment. The efficacy data utilized in the model were derived from the RATIONALE-303 clinical trial, while cost and utility values were obtained from the drug data service platform and published studies. The primary outcomes of the model encompassed quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to validate the robustness of the base case analysis results.ResultsThe tislelizumab group demonstrated a cost increase of CNY 117,473 and a gain of 0.58 QALYs compared to the docetaxel group, resulting in an ICER value of CNY 202,927 per QALY gained.ConclusionThe administration of tislelizumab in patients with advanced or metastatic NSCLC not only extends the progression-free survival (PFS) and overall survival (OS). Moreover, this treatment demonstrates a favorable cost-effectiveness profile across the Chinese population.

Introductionmyo7aa, the homolog of the human Usher 1B syndrome pathogenic gene, myo7A, plays an important role in stereociliary development and maintenance, therefore, is critical for hearing and balance. However, the molecular mechanisms that myo7aa regulate hearing and balance still need to be studied.MethodsIn this study, we generated two independent zebrafish myo7aa knockout lines using CRISPR/Cas9 technology. To investigate the effects of myo7aa on hearing, YO-PRO-1 staining and startle response assay were used. To gain insight into the specific molecular mechanisms by which myo7aa affects hearing, transcriptome sequencing and bioinformatics analysis were employed.ResultsOur study showed that hair cells of myo7aa-/- zebrafish can not take up YO-PRO-1 fluorescent dye and are insensitive to acoustic stimulation in myo7aa-/- zebrafish compared to wild type. Genes related to the Rho GTPase signaling pathway, such as arhgap33, dab2ip, and arghef40, are significantly down-regulated in myo7aa-/- zebrafish embryos at 3 dpf. GTP and ATP compensation can partially rescue the hair cell defects in myo7aa knockout zebrafish.DiscussionOur findings suggest that zebrafish myo7aa affects congenital hearing by regulating Rho GTPase signaling, and loss of myo7aa leads to abnormal Rho GTPase signaling and impairs hair cell function. myo7aa, myo7A, arhgap33, dab2ip, arghef40 and myo7aa-/- fonts in the abstract are italicized. -/- is a superscript format.

Background miRNAs are small, conserved, single-stranded non-coding RNA that are typically transported by exosomes for their functional roles. The therapeutic potential of exosomal miRNAs has been explored in various diseases including breast cancer, pancreatic cancer, cholangiocarcinoma, skin diseases, Alzheimer’s disease, stroke, and glioma. Pathophysiological processes such as cellular inflammation, apoptosis, necrosis, immune dysfunction, and oxidative stress are closely associated with miRNAs. Internal and external factors such as tissue ischemia, hypoxia, pathogen infection, and endotoxin exposure can trigger these reactions and are linked to miRNAs. Paraquat-induced fibrosis is a protracted process that may not manifest immediately after injury but develops during bodily recovery, providing insights into potential miRNA intervention treatments. Rationale These findings could potentially be applied for further pharmaceutical research and clinical therapy of paraquat-induced pulmonary fibrosis, and are likely to be of great interest to clinicians involved in lung fibrosis research. Methodology Through a literature review, we identified an association between miR-15a-5p and miR-152-3p and their involvement in the Wnt signaling pathway. This allowed us to deduce the molecular mechanisms underlying regulatory interactions involved in paraquat-induced lung fibrosis. Results miR-15a-5p and miR-152-3p play roles in body repair processes, and pulmonary fibrosis can be considered a form of reparative response by the body. Although the initial purpose of fibrotic repair is to restore normal body function, excessive tissue fibrosis, unlike scar formation following external skin trauma, can significantly and adversely affect the body. Modulating the Wnt/β-catenin signaling pathway is beneficial in alleviating tissue fibrosis in various diseases. Conclusions In this study, we delineate the association between miR-15a-5p and miR-152-3p and the Wnt/β-catenin signaling pathway, presenting a novel concept for addressing paraquat-induced pulmonary fibrosis.

The evolutionary analysis showed that the GF14 family was conserved, however, there was limited evidence linking GF14s to plant height. In our investigations, we discovered a co-expression relationship between ZmGF14s and functionally characterized genes linked to plant height. In the co-expression network, we identified ZmGF14-3, a gene expression exhibiting a positive correlation with plant height in three maize varieties, we postulated that this gene could be intimately linked to plant height development. Subsequently, we cloned ZmGF14-3 from the maize B73 inbred line and overexpressed it in Arabidopsis, resulting in markedly dwarfed transgenic phenotypes. Measurements of endogenous phytohormones disclosed a significant reduction in concentrations of Gibberellic Acid 7 (GA7) and Indole-3-Acetic Acid (IAA) in the overexpressed Arabidopsis, furthermore, qPCR results highlighted a pronounced decrease in the expression levels of plant height-related genes when compared to the wild type, therefore, it is plausible to posit that ZmGF14-3 plays a pivotal role in regulating the growth and development of maize through interactions with various phytohormone-related genes. Thus, delving into the potential interactions between ZmGF14-3 and these genes holds the promise of yielding valuable insights into the molecular mechanisms underpinning plant height development in maize.

The melting impacts on the three-dimensional hybrid nanofluid flow by a stationary stretching disk is examined. The flow configuration is due to the stretching of the disk. The magnetic field is applied normal to the disk in order to generate the resistance in the liquid. The performance of heat transfer in the liquid, the thermal radiation and heat generation/absorption impacts are taken into consideration. The melting heat transfer impact on the surface is analyzed here. The impact of stretching and rotating mechanisms along with applied physical impacts on the hybrid nanofluid flow and heat features are of the present concern for this physical problem. A conventional transformation is presented to lead to a set of coupled similarity equations which are highly non-linear in nature. A numerical method subject to bvp4c technique is adopted for the solution process. Results reveal that increasing trend of stretching of the disk lowers the boundary layer thickness and consequently highers the rate of heat transfer. It is found the reduction in thickness of thermal boundary layer by the strength of stretching. Additionally, the temperature distribution rises by the influence of melting temperature. Further, the skin fraction coefficient seen to be enhanced with the enlargement of nanoparticles volume fraction.